Category: Lab Lessons

Glass-half-full

Barts-MS rose-tinted-odometer  ★★★★★

I was attacked yesterday for painting a too bleak picture of MS outcomes and for not focusing on the fact that some pwMS actually age well and do well in the long-term. I apologise for being so negative, hence this post to address the data gap. 

The best data we have on the longterm follow-up of pwMS in a ‘community-setting’ is the Gothenburg study. In Gothenburg, they were fortunate to have 50+ year systematic follow-up of an original cohort of pwMS, who were born between 1950 and 1964. Of the 202 patients with an initial relapsing-remitting course, the probability of non-progressive disease after 40 years was 22% and after 50 years it was 14%. So 1 in 7 patients with relapse-onset disease had not become secondary progressive after 50 years of follow-up. Importantly, these patients were functioning well socially. Nine of them had an EDSS of 0-2.5, and four patients had a score of 3 or 3.5, with most of their disability dating back to attacks from decades ago. These 1 in 7 patients have what I call ‘burnt-out’ MS.

Eight of these patients, who underwent a complete and detailed neuropsychological examination, showed some cognitive impairment concerning memory and executive function compared to an age and socially matched control group. This indicates that even in these ‘burnt-out ageing-well’ cohort that MS has clipped some of their cognition. i.e. they have some hidden disabilities. 

At the last follow-up of this group of patients in 2009-10, when the group had reached the average age of the Swedish population life expectancy, only 13 patients remained alive and non-progressive. That is 6.5% were alive and well compared to an expected rate of 50% for the general population. 

It is important to point out that as these patients are from a pre-DMT era these figures should be viewed as the worst-case-scenario. I would expect them to be much better than this now and, importantly, they will get better over time as we learn to diagnose and treat MS earlier and more effectively. 

I like to think of MS outcomes as a bell-curve with a small proportion of people who can expect to age normally. But as we improve outcomes we shift the curve to the right with more and more pwMS having a good outcome.  

I don’t like to think of myself as a glass-half-empty, hopefully, this bell curve will make you realise that I am a glass-half-full. 

Bengt Skoog et al.  A Representative Cohort of Patients With Non-Progressive Multiple Sclerosis at the Age of Normal Life Expectancy. Brain, 135 (Pt 3), 900-11 Mar 2012.

Multiple sclerosis may have a non-progressive symptomatology for decades; however, it is not clear whether the disease activity may abate completely. We identified a cohort of patients, resident in Gothenburg at the time of disease onset, between the years 1950-64 (n = 307). These geographical and temporal restrictions, along with favourable conditions for a ‘spider’ epidemiological study, were optimal for an unbiased selection; this 15-year incidence cohort was essentially followed prospectively for 37-59 years after onset. The shortest follow-up time for patients without primary or secondary progression was 45 years. For patients with an initial relapsing-remitting course and multiple sclerosis diagnosis according to the Poser criteria (n = 202), the probability of non-progressive disease after 40 years was 22% (standard error 3.0%), and after 50 years it was 14% (standard error 3.2%). For attack onset including patients with possible multiple sclerosis, the corresponding probabilities after 40 and 50 years were 35% (standard error 3.3%) and 28% (standard error 3.5%), respectively. At the last follow-up in 2009-10, when patients reached the average age of the Swedish population life expectancy, only 13 patients from the multiple sclerosis diagnosis cohort, according to the Poser criteria, remained alive and non-progressive. Their annualized attack frequency diminished with time from 0.29 to 0.015. These patients had been functioning well socially. Nine patients had an Expanded Disability Status Scale score of 0-2.5, and four patients had a score of 3 or 3.5, with deficits dating back to attacks decades ago. Eight patients participated in a complete neuropsychological examination, which showed a slight difference (P < 0.01) concerning verbal memory and executive function compared to an age and socially matched reference group, whereas results for five other cognitive domains were within the normal range. Magnetic resonance images fulfilled the Barkhof-Tintoré criteria for multiple sclerosis in 10 of 11 patients, with conspicuously few subcortical lesions relative to extensive periventricular lesions and lesions extending from the inferior midline aspect of the corpus callosum. Prediction of the non-progressive stage was possible with moderate hazard ratios and low sensitivity. Early features that predicted a non-progressive course were complete remission of the onset attack, low or moderate initial relapse frequency and-when the patients with possible multiple sclerosis were included-dominating afferent symptoms. The clinical disease activity had abated in these 13 patients, with the caveat that transition to secondary progression continued to occur after four decades, albeit with decreasing risk.

CoI: multiple

What is advanced MS?

Barts-MS rose-tinted-odometer – zero stars

Someone recently asked what is advanced MS? I suspect they have been getting frustrated with our use of this adjective without a clearer understanding of what it really means. To find out if you have advanced MS you need to put yourself through a battery of stress tests to find-out much reserve you have left to deal with MS and life in the future.

What is advanced MS is a very important topic and we at Barts-MS have tried not to define it using the EDSS as it entrenches the physically-disabling, particularly lower-limb function, worldview of MS.  

Advanced MS is really when someone has lost reserve in a particular neuronal system and they are noticing worsening in that system that is impacting on their ability to function at a personal, social or occupational level and by inference is affecting their quality of life. 

Using this definition someone can have advanced MS with very little physical disability. As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.

A software engineer with MS who depends on her cognitive skills for writing code, concentrating for prolonged periods of time and multitasking may find it very difficult-staying at the top of her game. She will notice much earlier her progressive cognitive loss based on her performance or lack of performance in her work. In comparison, a professional athlete may not necessarily notice early cognitive impairment but will be more susceptible to the effects of MS on their coordination and endurance, for example, the marathon runner with a dropped foot.

These examples are the two extremes, but they illustrate why we need stress tests of the nervous system to be able to ascertain how much reserve there is which will give us some idea how advanced MS is in a particular domain. One thing that is not done very well in MS clinics is cognition. Most MS centres don’t have the resources to monitor cognition properly. This needs to change (#ThinkCognition). 

In almost every MS clinic I do I see patients who complain of cognitive symptoms; increasing forgetfulness, difficulty multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; this was in the pre-natalizumab era.

Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had advanced (secondary progressive) MS manifesting as progressive dementia.

You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.

Until recently we the MS community used the Paced Auditory Serial Addition Test (PASAT) for monitoring cognition in clinical trials. The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. The PASAT is presented using audiotape or disk to ensure standardization in the rate of stimulus presentation. Single digits are presented every 3 seconds and you have to add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. The PASAT is very difficult and requires multitasking; it is a very good cognitive stress test. 

One of the reasons we dropped the PASAT test is because of its learning effect, when you do the PASAT test your scores improve because of so-called ‘learning’ or ‘practice’ effects. In reality this is a general phenomenon of most neurological stress tests; our nervous systems are wired for learning. 

In the FREEDOMS 1 and 2 pivotal phase 3 fingolimod trials, we showed that not being able to improve on the PASAT at baseline predicted a worse outcome. We hypothesised that pwMS who couldn’t learn, i.e. were unable to improve their PASAT scores at baseline, would do worse and this is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo. 

Not surprisingly, the poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve or resilience. In other words, they had more advanced MS. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. In reality, their MS disease activity in the past had primed their brains to continue to deteriorate despite being on a DMT; previous damage or smouldering MS was now driving their disease worsening. This is why the treatment response on DMTs drop off with ageing and disease duration. Please note this applies to all DMTs, including HSCT. 

It is important to prevent the ravages of MS by treating as early and effectively as possible. Some pwMS are luckier than others; i.e. you may present very early in the course of your MS before too much end-organ damage has accrued. In others, the asymptomatic period of the disease may be longer, during which time you acquire a lot of end-organ damage. Regardless of what group you are in, you still need to seriously consider getting on top of your MS disease activity as soon as possible to prevent any further damage.  

It is clear from several data sources that on average pwMS do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions and relapses) and those that reduce brain volume loss. In reality, these are the high and very high efficacy DMTs. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly the DMTs that ‘normalise’ brain volume loss.

This post illustrates why we should be monitoring cognition in routine MS clinical practice. Although this topic gets discussed and debated all the time most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, will change as data emerges that DMTs have positive effects on cognitive function, even in advanced MS. For example, siponimod has been shown to delay cognitive worsening compared to placebo in people with SPMS. 

At Barts-MS we will continue to run our #ThinkCogniton campaign. By shifting the MS worldview from a physical one to a cognitive one we will hopefully get the MS community to manage MS more actively. 

Maria Pia Sormani et al. Learning Ability Correlates With Brain Atrophy and Disability Progression in RRMS. J Neurol Neurosurg Psychiatry, 90 (1), 38-43 Jan 2019.

Objective: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.

Methods: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.

Results: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.

Conclusions: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

CoI: multiple

Flu, it’s not too late to be vaccinated

Barts-MS rose-tinted-odometer  ★★★

Not walking my talk. Having not taken up the NHS offer of the seasonal flu vaccine and having just spent the last 3 days bed-bound with severe flu I found the following research paper very timely. 

Using the Norwegian registries these investigators show that pwMS are much more susceptible to the complications of influenza, i.e. pwMS are much more likely to require emergency hospital admission as a result of influenza infection. Reasons for this are three-fold. Firstly, people with advanced MS may not have as strong gag and cough reflexes with a higher chance of aspiration of their secretions with secondary pneumonia. They may also have weakened respiratory muscles that increase their chances of getting a segmental collapse of their lungs and secondary pneumonia. Secondly, many pwMS are on immunosuppressive medications which blunt their immune response to the influenza virus making the virus more virulent and likely to affect multiple organ systems. Finally, on average pwMS have reduced resilience to infections independent of being on immunosuppressive medication, this probably relates to deconditioning, temperature-related conduction-block in response to fever and the fact that many pwMS are disabled. In summary, pwMS handled infections less well than the general population and are more likely to get complications. 

Disappointing is the observation that pandemic vaccination did not influence the risk of hospitalization in this study. I suspect this was because the pandemic vaccine used in this study epoch was not effective. 

Even if you don’t need hospitalisation having influenzae is very unpleasant and make your MS symptoms much worse. There have been some studies that have shown that not all patients recover back to their baseline when they get worsening of their MS symptoms in response to an infection. The latter observation would imply that the infection triggered an MS relapse. Avoiding infections is, therefore, one of our aims as part of the holistic management of MS.

As I sit here and type this blog post I am still incredibly tired with brain fog and many persistent symptoms that will take a week or more to clear. The physical symptoms are one thing, what about the social impact? I just spent the three days of the festive season in bed ignoring my family and social commitments. The bottom line is if you can avoid having flu, why wouldn’t you? It is not too late to be vaccinated. 

Ghaderi et al. Hospitalization following influenza infection and pandemic vaccination in multiple sclerosis patients: a nationwide population-based registry study from Norway. Eur J Epidemiol. 2019 Dec 23. doi: 10.1007/s10654-019-00595-2.

Patients with multiple sclerosis (MS) are at increased risk of infections and related worsening of neurological function. Influenza infection has been associated with increased risk of various neurological complications. We conducted a population-based registry study to investigate the risk of acute hospitalization of MS patients in relation to influenza infection or pandemic vaccination in Norway. The entire Norwegian population in the years 2008-2014 was defined as our study population (N = 5,219,296). Information on MS diagnosis, influenza infection and vaccination were provided by Norwegian national registries. The self-controlled case series method was used to estimate incidence rate ratios (IRRs) with 95% confidence intervals (95% CI) in defined risk periods. 6755 MS patients were identified during the study period. Average age at first registration of an MS diagnosis was 51.8 years among men and 49.9 years among females (66.9%). The IRR for emergency hospitalization among MS patients the first week after an influenza diagnosis was 3.4 (95% CI 2.4-4.8). The IRR was 5.6 (95% CI 2.7-11.3) after pandemic influenza, and 4.8 (95% CI 3.1-7.4) after seasonal influenza. Pandemic vaccination did not influence risk of hospitalization [IRR within the first week: 0.7 (95% CI 0.5-1.0)]. Among MS patients, influenza infection was associated with increased risk for acute hospitalization while no increased risk was observed after pandemic vaccination. Influenza vaccination could prevent worsening of MS-related symptoms as well as risk of hospitalization.

CoI: multiple

HSCT Units can you please show me the data?

Barts-MS rose-tinted-odometer  0/★

I am often asked why given the extraordinary efficacy of HSCT in early RRMS, but not advanced MS, why I don’t refer more of my patients for HSCT early on in the course of their disease. There are several reasons these are the main ones. 

Firstly, to be eligible for HSCT under our London guidelines patients have to fail at least two DMTs one of which has to be a high-efficacy DMT (fingolimod, cladribine, natalizumab, ocrelizumab and alemtuzumab). 

Secondly, the infertility risk is too high. It is quoted to be in the order of 40-45% and most women and men want to keep their ovaries and testes in a functional state. Although the process of sperm banking and oocyte or egg harvesting, and storage, are routine it takes time to set it up and get it done. In my experience, the harvesting and storage delays treatment by several months. This delay is not ideal for someone with highly active MS. In addition, the costs of sperm and egg banking are not always covered by the NHS. Funding for this is a post-code lottery and depends on where you live. 

Thirdly, the mortality that is quoted for HSCT often puts people off. The London team talk about a mortality risk of up to 2%. In reality, the real risk is closer to 0.5%, i.e. a 1 in 200 risk of dying from the procedure. For some people, this risk is unacceptably high. 

What I haven’t really discussed with my patients is the secondary cancer risk post-HSCT. As HSCT involves receiving the chemotherapy compound cyclophosphamide the secondary cancer risk can’t be ignored. Cyclophosphamide is an alkylating agent that cross-links DNA. It is a mutagen and is known to cause cancer. Its metabolites are excreted in the urine and increase the risk of bladder cancer rate massively. Although we use mesna to protect the bladder against acute cyclophosphamide toxicity it does not prevent the cancer risk. The bladder risk is particularly high in MS if you have bladder dysfunction with incomplete emptying and/or need to use a catheter. 

There is, however, one small French study of 354 people with progressive MS who were treated with cyclophosphamide that looked at cancer risk post-cyclophosphamide. The cumulative incidence of cancer after cyclophosphamide was 3.1% at 5 years and 5.9% at 8 years, which is described as being similar to the expected background rate. 

At present we don’t have figures for how high the cancer risk is post-HSCT in pwMS. I suspect the cancer risk is likely to be in the order of 3-5x higher than the background rate. This figure is based on studies in other disease areas. Is this important? Yes, I have many female patients saying no to ocrelizumab on the basis of a possible increased risk of breast cancer with ocrelizumab. Surely, the HSCT units should be auditing their data and providing us with a cancer risk based on the longterm follow-up of their patients? If they want to convince the wider MS community to adopt HSCT and potentially use it as a first-line DMT then we need to know the longterm risks associated with its use. 

van den Brand et al. Cancer Risk After Cyclophosphamide Treatment in Idiopathic Membranous Nephropathy. Clin J Am Soc Nephrol, 9 (6), 1066-73 2014 Jun 6. 

Background and objectives: Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.

Design, setting, participants, & measurements: Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer.

Results: Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.

Conclusion: Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.

Le Bouc et al. No increase in cancer incidence detected after cyclophosphamide in a French cohort of patients with progressive multiple sclerosis. Mult Scler. 2012 Jan;18(1):55-63. 

BACKGROUND: Cyclophosphamide is still used in progressive forms of multiple sclerosis (MS) in view of its suggested efficacy and safety in the short term. No data exist on its long-term safety in MS, particularly on the risk of malignancy.

OBJECTIVE: The objective of this study was to evaluate cancer incidence in MS after cyclophosphamide treatment.

METHODS: We performed a historical prospective study in a cohort of MS patients treated with cyclophosphamide. We collected demographic data and medical history from medical databases and patient interviews. Reported cancers were histologically confirmed. Cancer incidence was compared with the incidence in the general population by estimating standardized incidence ratios (SIRs).

RESULTS: We included 354 patients, with a median follow-up of 5 years (range 2-15) after cyclophosphamide treatment. Fifteen patients developed a solid cancer, which occurred at a median of 3 years (range 0.5-14) after cyclophosphamide introduction. The cumulative incidence of cancer after cyclophosphamide was 3.1% at 5 years and 5.9% at 8 years. We found no increase in cancer incidence after cyclophosphamide treatment in men (SIR = 0.83, 95% confidence interval [CI] 0.30-1.82), women (SIR = 0.99, 95% CI 0.43-1.95), or men and women combined (SIR = 0.92, 95% CI 0.50-1.54).

CONCLUSION: We found no evidence of an increased risk of cancer associated with cyclophosphamide treatment in MS patients.

CoI: multiple

To smoke or not to smoke that is the question

Barts-MS rose-tinted-odometer  ★ ★ ★ ★ ★

Yawn! I am getting tired of the saying the same-old things on this blog. Is it time to retire and do something new? 

We have done some modelling work and predict that ~20% of new or incident cases of MS could be prevented if we stop the population from smoking. The question is how do we achieve this? Taxation has worked to some extent in that we are seeing a fall in the number of current smokers, but the numbers of teenagers smoking looks as if it is quite resistant to change. The solution must be education, education, education and a war against the tobacco industry. 

Public Health England

If social media is such a powerful tool to hack the brains of voters, why don’t public health departments use this technology to promote their agenda? What we need are companies like Cambridge Analytica to do some good in the world and to promote a ‘Don’t Start Smoking’ campaign. 

We did try and get some insights into why teenage girls start smoking when Amy Sankey, a work experience student, did a survey in her school for us. Despite the almost universal awareness of the harms of smoking in terms of lung cancer, most girls, however, did not know that there is a link between smoking and autoimmunity. I suspect even if they knew about the link it would be unlikely to prevent them from starting to smoke. 

We are interested in smoking as a risk factor for MS as it is telling us something about the cause of the disease. It appears that smoking must be acting via the lungs and is due to tobacco itself. Use of oral, non-smoked, tobacco is in fact associated with a reduced risk of getting MS, hence it is not tobacco exposure. Solvent exposure is also associated with an increased risk of getting MS, which supports the lung hypothesis of developing MS. 

Lung hypothesis #1 argues that damage to the lung from smoking or solvents creates a pro-inflammatory environment that is sufficient to activate pre-existing autoreactive T-cells. In comparison, lung hypothesis #2 argues that smoking damages proteins by a process called post-translational modification and that these proteins stimulate an immune response that then cross-reacts with normal antigens to set-up autoimmunity. The argument for the latter in triggering rheumatoid arthritis, an autoimmune disease of joints, is quite compelling but is less compelling when it comes to MS. We hope to study whether post-translational modification of CNS antigens is relevant in MS via an ECTRIMS fellowship we have supported.  

What is interesting is that smoking interacts with genetic risk factors for developing MS and with EBV infection suggesting that there is a critical gene-environment interaction that causes MS. Wouldn’t it be interesting to study and find out what these interactions are? We have an exceptionally bright and able young researcher, Ben Jacobs, who wants to do a PhD on this exact topic; gene-environment interactions. At the moment we are ruminating about the best approach he should take to address this question. It is not an easy experiment so if you have suggestions please feel free to contact us.

I would also like to remind you that smokers who have MS have a much poorer prognosis, which is why we recommend that you stop smoking if you can.

If you are interested in smoking and MS there is a new review that has just come out. 

Rosso &  Chitnis. Association Between Cigarette Smoking and Multiple Sclerosis: A Review. JAMA Neurol. 2019 Dec 16. doi: 10.1001/jamaneurol.2019.4271

IMPORTANCE: Cigarette smoking is a common environmental exposure and addiction, which has severe health consequences. Smoking is a risk factor for multiple sclerosis (MS); also, smoking has been associated with disease activity and overall prognosis for patients with MS.

OBSERVATIONS: Cigarette smoking is an irritative agent on the lungs, in which a proinflammatory cascade starts that culminates in autoimmunity. Inflammation may increase the risk of MS in some individuals, in a process driven by antigen cross-reactivity between lung antigens and myelin antigens. Genetics plays a central role in the individual predisposition to mounting an autoimmune reaction. Also, free radicals, cyanates, and carbon monoxide in cigarette smoke may be directly toxic to neurons. Patients with MS who smoke have higher rates of disease activity, faster rates of brain atrophy, and a greater disability burden. Some of the outcomes of smoking were found to be reversible, which makes counselling key.

CONCLUSIONS AND RELEVANCE: The pathways involved in cigarette smoking should be further analyzed to understand the mechanisms whereby smoking worsens MS prognosis. The proinflammatory and neurotoxic outcomes of cigarette smoking may be shared by other environmental exposures, such as pollution and organic solvents. From a global perspective, efforts should be made to diminish the prevalence of cigarette smoking in patients with MS.

CoI: multiple

Chicken or Egg?

Rose-tinted-odometer = ★

Brain Health is a major theme of this blog. Why? 


We think that to ‘maximise brain health for the life of a person with MS (pwMS)’ we need to manage MS actively and holistically and promote brain-healthy behaviours. The ‘we’ here is not only HCPs but you and society, which includes regulators, politicians, educationalists, pharma, etc.   

Another thing that people don’t get is that ‘life is a sexually-transmitted age-dependent neurodegenerative disease’ and that if we live long enough our nervous system fails. As MS reduces our reserve, by shredding axons, synapses and causing neuronal loss it brings age-dependent neurodegeneration forward. 

Early ageing and MS worsening overlap and we face a big challenge separating progressive MS from premature ageing. This is why when people state that treatment X, for example, HSCT, halts progression they are exposing their naivety and lack of understanding of MS. HSCT is not anti-ageing and hence that component of MS worsening can’t be altered. In the case of HSCT, it may hasten the ageing process as some of the chemotherapy agents used as part of HSCT are neurotoxic. 

HSCT supporters will typically point to the amazing EDSS data showing disease stabilisation and in some cases improvement. But MS is more than lower limb function and walking. What needs to be presented are multi-domain outcomes across multiple functional systems, in particular, cognition. MS is first and foremost a ‘preventable dementia’ and hence we need to monitor cognition over time and see what our treatments are doing to cognition.

The study below relates to ‘normal ageing’ but may be relevant to pwMS. It shows that playing analogue or board games reduces age-related cognitive decline. I suspect, based on the cognitive reserve hypothesis, these findings will apply to pwMS as well. Do you play board games? If you do you it may delay or slow down MS-related cognitive decline. Who would have thought of playing Monopoly as a potential DMT in MS?

Altschul & Deary. Playing Analog Games Is Associated With Reduced Declines in Cognitive Function: A 68-Year Longitudinal Cohort Study. The Journals of Gerontology: Series B, gbz149. Published 18-Nov-2019.

Objectives: Playing analog games may be associated with better cognitive function but, to date, these studies have not had extensive longitudinal follow-up. Our goal was to examine the association between playing games and change in cognitive function from age 11 to age 70, and from age 70 to 79.

Method: Participants were 1,091 non-clinical, independent, community-dwelling individuals all born in 1936 and residing in Scotland. General cognitive function was assessed at ages 11 and 70, and hierarchical domains were assessed at ages 70, 73, 76, and 79 using a comprehensive cognitive battery of 14 tests. Games playing behaviors were assessed at ages 70 and 76. All models controlled for early life cognitive function, education, social class, sex, activity levels, and health issues. All analyses were preregistered.

Results: Higher frequency of playing games was associated with higher cognitive function at age 70, controlling for age 11 cognitive function, and the majority of this association could not be explained by control variables. Playing more games was also associated with less general cognitive decline from age 70 to age 79, and in particularly, less decline in memory ability. Increased games playing between 70 and 76 was associated with less decline in cognitive speed.

Discussion: Playing games were associated with less relative cognitive decline from age 11 to age 70, and less cognitive decline from age 70 to 79. Controlling for age 11 cognitive function and other confounders, these findings suggest that playing more games is linked to reduced lifetime decline in cognitive function.

CoI: none

Apathy, does it affect you?

We all know that MS is a bad disease with a massive socio-economic impact. However, the personal toll is even larger. Reduced life expectancy, higher suicide rates, unemployment, high divorce rates, depression, anxiety, fatigue, substance abuse, cognitive impairment, loneliness, social isolation and poverty are just a few of things that can and do happen to pwMS.

One I have not discussed before is apathy, which is common in MS and is part of a symptom complex in people with more advanced MS. PwMS who are apathetic simply lose interest and have no enthusiasm for life and interventions to help them. Apathy is not necessarily depression. In this cross-sectional Italian study, a third of respondents were apathetic. This is much higher than I would have predicted but may explain why pwMS as a group are not as activated as other disease-specific communities, i.e. MS has shredded that part of the brain that motivates them to do things. 

I would add that if you are reading this blog post you are unlikely to be suffering from apathy. It is the pwMS who don’t read this blog that worry me. As apathy predicts poor outcome in MS we should add it to the prognostic profile calculator we use to profile MS patients in terms of treatment decisions. PwMS who are apathetic should also be considered as being at high risk of complications and hence should be seen more often. 

Apathy is another reason to treat MS early and effectively. 

Raimo et al. Assessing apathy in multiple sclerosis: Validation of the dimensional apathy scale and comparison with apathy evaluation scale. Mult Scler Relat Disord. 2019 Nov 25;38:101870. 

BACKGROUND: Apathy is a predictor of cognitive decline in the course of multiple sclerosis (MS). Early identification of apathetic patients is relevant in clinical settings.

OBJECTIVE: To assess the applicability and psychometric properties of the self-rated version of the Dimensional Apathy Scale (DAS) in a large cohort of patients with MS and to compare its diagnosing accuracy with that of the Apathy Evaluation Scale (AES).

METHODS: One hundred and twenty-four patients underwent a clinical interview based on diagnostic criteria for apathy, DAS, AES, and assessment of depression, global cognitive functioning, and non-verbal intelligence.

RESULTS: According to diagnostic criteria, apathy occurred in 33.4% of the patients. The DAS showed high consistency, and good convergent, discriminant and criterion validity. Factor analysis indicated a three-factor structure: executive, behavioural and emotional apathy. Unlike AES, no significant association between DAS score and severity of neurological disability (expressed by EDSS total score) was found, suggesting that the DAS might be less related to levels of disability. Receiver operating characteristics analyses, with clinical diagnostic criteria for apathy as the gold standard, revealed that a DAS score of 28/29 and an AES score of 35/36 were optimal cut-off values for identifying clinically relevant apathy. The two scales had similar diagnostic accuracy in the present sample.

CONCLUSIONS: The DAS is a valid and reliable multidimensional tool to assess apathy in MS, with diagnostic accuracy similar to that of the AES. However, the DAS score appears to be less strongly related to neurological disability.

Killjoys peddle fake news

For all the killjoys out there DMTs do work, i..e. they modify the course of MS and prevent you from reaching all disability milestones including the time to diagnosis of SPMS and EDSS 10.0 or death.

Please don’t listen to the zealots who are trying to spin fake news that the only treatment to prevent the development of progressive MS is HSCT; they are wrong. There are other options; the study below shows you can do it with currently licensed DMTs that are safer than HSCT. One message that is loud and clear with this data is that the earlier you treat the better and you have a much better outcome if you flip the pyramid and start on high-efficacy DMTs first-line.

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Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. 

IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.

EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS.

RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.

CoI: multiple

Will the real MS say hello?

The difference between religion, a belief system, and science, an experimental system, is that you can falsify the latter, but not the former. So when KoL (key opinion leaders) say they believe something they don’t really mean it literally. What they are really stating is a hypothesis that needs to be interrogated. 

So when I say that relapses and focal MRI activity are not MS, but are occurring in response to the cause of MS I am stating a hypothesis that needs to be falsified. Underpinning science are philosophical constructs on which to test hypotheses. One such construct, or system, is the Prentice criteria for defining a so-called surrogate endpoint in clinical medicine. 

According to the Prentice criteria for a surrogate endpoint to be considered as a substitute for the disease (or is the disease), it requires that (1) the baseline measurement of the endpoint is predictive of outcome, (2) changes in the measurement of the endpoint over time is predictive of outcome and (3) changes in the measurement of endpoint in response to a therapy is also predictive of outcome (Prentice, 1989). I would add a fourth criterion that (4) the measurement of the endpoint should predict outcome independent of treatment, i.e. it should behave in the same way whether a subject is on placebo or active treatment. 

When you apply these four criteria to relapses and/or focal MRI activity (new and/or enlarging T2 lesions or Gd-enhancing lesions) they don’t predict disability outcomes. This is why I state that the real MS is smouldering MS and the focal inflammatory activity is the immune system’s response to what is causing the disease. Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smouldering away. 

The analogy I use is one put forward way back in 1994 to Ed Thompson my supervisor when I was a PhD student. I subsequently felt confident enough to present it at a European Charcot Foundation meeting in Lausanne under the title of ‘The yin and yang of inflammation in multiple sclerosis’. I subsequently published the hypothesis as a book chapter in 2004 (see below). 

It is interesting that my ideas, or hypotheses, about MS from 25 years ago haven’t changed very much. This is called cerebral stagnation. Maybe it is time to move on? 

The primary neurodegenerative hypothesis (1994): Although multiple sclerosis is a clinically heterogeneous disease it can be viewed as an inflammatory neurodegenerative disease with the clinical spectrum or phenotype determined by the presence or absence of focal inflammation, similar to that which occurs in infectious diseases, e.g. leprosy. The underlying neurodegenerative component of the disease may or may not be ongoing but it is modified by superimposed focal inflammatory events. The focal inflammation may be an appropriate host response directed at an unidentified aetiological agent or an inappropriate autoimmune response. These focal inflammatory events are responsible for clinical attacks and MRI disease activity. Although damaging in themselves the focal inflammation provides the biological substrate in the form of trophic and growth factors which promote repair and clinical recovery. Inhibiting the focal inflammatory events, e.g. with generalised immunosuppression, would reduce the relapse rate and MRI activity and remove the important trophic and growth factor support provided by the inflammatory infiltrates, but it may not affect the underlying primary neurodegenerative processes. This strategy would simply convert relapsing-remitting disease into non-relapsing progressive disease. There is evidence from infectious diseases that this phenotypic variability is linked to genetic susceptibility. 

Why use leprosy as an analogy? Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems responses to antigens. Depending on the immune response you get a different clinical picture. If you a brisk inflammatory response you get tuberculoid leprosy and it presents with very inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy that is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone that is referred to as borderline subtypes. Interestingly people can convert from having lepromatous to tuberculoid leprosy if the shift their immune response to a so-called type 1 immune response that is driven by a cytokine called interferon-gamma.  

Figure from the American Society of Microbiology.

Primary progressive MS is lepromatous MS and relapsing-remitting MS is tuberculoid MS and the SPMS sits in the middle. Interestingly, gamma interferon may have the same effect in MS as it does in leprosy. We know that an early trial of gamma-interferon had to be aborted as it triggered relapses. I hypothesise that if you treat PPMS with gamma-interferon you would convert it to RRMS. Unfortunately, this is an experiment that is unlikely to occur but happens naturally when you get a viral infection. Interestingly, infections are a common trigger of relapses. These clinical observations are congruent with the ‘Leprosy Hypothesis of MS‘.

Do these observations support the ‘Field Hypothesis’ and the ‘Viral Hypothesis’ of MS?

Panitch et al. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987 Jul;37(7):1097-102.

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.

CoI: multiple

Post-partum relapses after alemtuzumab

One of the problems of immune reconstitution therapies (IRTs), such as HSCT, alemtuzumab and cladribine, is nagging worry that at some time in the future your MS will reactivate. Some people with MS (pwMS) try and avoid potential triggers of disease activity, for example, vaccinations and pregnancy, particularly the post-partum state. Unfortunately, there is some evidence the latter may trigger disease activity, but at quite a low rate. 

The following is the data on 122 pregnancies post-alemtuzumab presented earlier this year at ECTRIMS. The annualised relapse rate (ARR) fell to 0.02 during pregnancy, i.e. 2 relapses in 100 years, with 98% of patients being relapse-free. In comparison, in the first year after pregnancy, the ARR was 0.22, i.e. 22 relapses in 100 years of follow-up, with 82% of patients being free of relapse. The ARR was then similar to pre-pregnancy levels in the second and third years after pregnancy (0.12 each year; with 89% and 92% of patients relapse-free in each year, respectively).

One of the reasons for women with MS choosing an IRT is to start or extend their families. Based on this data I would recommend that they do just that and in the unlikely event of post-partum disease activity (1 in 5 chance) it can be dealt with by an additional course of treatment or possibly starting another DMT. What do you think?

We have many patients in our centre who have had children after alemtuzumab in our centre. I refer to them as the alemtuzumab babies because they represent the success of treating MS early and effectively. It was only 20 years ago that the previous generation of neurologists were advising their patients with MS not to have children. How times have changed?

Celius et al.  Postpartum relapse after first on-study pregnancy in RRMS patients treated with alemtuzumab in the phase 2 and 3 clinical development program over 8 years. ECTRIMS Online Library. Celius E. Sep 12, 2019; 279136; P776

Introduction: In childbearing women with MS, relapses may increase in frequency and severity during the postpartum period. In phase 2 and 3 clinical trials of alemtuzumab (CAMMS223 [NCT00050778]; CARE-MS I [NCT00530348]; CARE-MS II [NCT00548405]) and their extensions (CAMMS03409 [NCT00930553]; TOPAZ [NCT02255656]), alemtuzumab significantly reduced relapse rates in RRMS patients versus SC IFNB-1a and maintained efficacy over 8 years. Product labelling recommends use of contraception in women of childbearing potential for 4 months after treatment.

Aims: To examine over 8 years relapse rates before, during, and after the first pregnancy in alemtuzumab-treated patients in the CARE-MS and extension trials.

Methods: Contraceptive use was required during core studies, and for 6 months after alemtuzumab administration in the extension studies. The analysis included patients who received alemtuzumab (baseline: 5 days; 12 months later: 3 days) in phase 2 or phase 3 trials or their extension studies and became pregnant after receiving at least one dose of alemtuzumab. Patients could receive other DMT or additional as-needed alemtuzumab (12 mg/day on 3 days; ≥12 months apart) in the extensions. After pregnancy, other DMT was allowed in CAMMS03409; other DMT or further alemtuzumab was allowed in TOPAZ. The analysis only considered a patient’s first pregnancy, regardless of the outcome. Pregnancy had to occur by Month 85 to allow for at least 1-year follow-up post-pregnancy onset.

Results: Over 8 years, 122 pregnancies met inclusion criteria; 72% of pregnancies began >12 months after the last alemtuzumab dose, 18% began >4 to 12 months after the last dose, and 10% began ≤4 months after the last dose. Annualised relapse rate (ARR) in the year prior to study entry was 1.8. Two years and 1 year before pregnancy, ARR was 0.10 and 0.12 respectively, with 91% and 89% of patients free of relapse. ARR fell to 0.02 during pregnancy (98% of patients relapse-free). In the first year after pregnancy, ARR was 0.22, and 82% of patients were free of relapse. ARR was similar to pre-pregnancy levels in the second and third years after pregnancy (0.12 each year; 89% and 92% of patients relapse-free in each year). Safety will be discussed in the presentation.

Conclusion: In the year after the first pregnancy in alemtuzumab-treated patients, an increase in relapse rates was minimal and less than that expected from the literature. Relapse rates returned to pre-pregnancy levels by the second year postpartum.

CoI: multiple

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