I am at the NMSS’ Pathways to Cures think tank where exercise is a major theme in terms of restoring lost function. A lot of discussions have been about how we motivate and get pwMS to exercise. Some suggested using motivational interviewing techniques and behavioural psychology to motivate and nudge pwMS to exercise. The elephant in the room is that some people simply don’t like exercise. Are you one of them?
Not many people know that your participation in exercise is largely driven by genetics. It is clear from the twin study below that genetic variation is important in relation to individual behaviour when it comes to exercise. Heritability of exercise participation in males and females was similar and ranged from 48% to 71%; this may explain why you love or hate exercise. At the moment we don’t know what this heritability in relation to exercise is due to. As the investigators’ point out in their conclusion that it may ‘involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality’.
One of the other aspects of exercise that was discussed was its biology, in other words how does exercise work. If we can work this out we could potentially explore drugs to mimic exercise. The problem with this reductionist approach is that exercise is very complex and hence likely to be very dirty. For example, exercise can be aerobic (oxygen) or anaerobic (lack of oxygen) and can involve resistance. Then there is intensity and duration. Is HIIT (high-intensity interval training) better than aerobic exercise? What about movement? Does exercise require you to move; is a treadmill run equivalent to an outdoor run? How important is exercise frequency; is daily better than 3-4 times a week versus the weekend warrior’s activity on Saturday and Sunday?
The bottom line is that we know exercise works for some pwMS. However, as always we have many unanswered questions. One that Robert Motl, the doyen of exercise research in MS, raised with me in one of the coffee breaks is that we don’t know if exercise may have negative effects in certain groups of pwMS. For example, during a relapse or in more advanced MS. Is flogging a dying horse, i.e. making people with walking impairment exercise their lower limbs, potentially bad for them in that overuse of the pathway through exercise is speeding up its degeneration? We need to be careful in not making pwMS feel guilty about not exercising when we don’t have a mature evidence-base to recommend it or not.
Background: A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used.
Methodology: Self-reported data on leisure time exercise behavior from Australia, Denmark, Finland, Norway, The Netherlands, Sweden and United Kingdom were used to create a comparable index of exercise participation in each country (60 minutes weekly at a minimum intensity of four metabolic equivalents).
Principal findings: Modest geographical variation in exercise participation was revealed in 85,198 subjects, aged 19-40 years. Modeling of monozygotic and dizygotic twin resemblance showed that genetic effects play an important role in explaining individual differences in exercise participation in each country. Shared environmental effects played no role except for Norwegian males. Heritability of exercise participation in males and females was similar and ranged from 48% to 71% (excluding Norwegian males).
Conclusions: Genetic variation is important in individual exercise behavior and may involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality. This collaborative study suggests that attempts to find genes influencing exercise participation can pool exercise data across multiple countries and different instruments.
I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me.
As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people.
Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences.
So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me!
If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease?
Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.
There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease.
My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS.
Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with.
In the area of MS prevention, it will take more than a patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.
My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?
Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there.
On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.
For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold.
I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.
I belong to an international group that addresses important issues in multiple sclerosis that arise between HCPs and pwMS. For 2020 I have suggested we tackle the issue of ageing in MS. I have been asked why I think ageing an important topic in MS. I have put forward the following list of issues that have come to mind. Can you help me with suggestions or specific age-related issues I may have left off the list? Thanks.
As the MS population gets larger we are seeing more people with MS becoming old. This raises several important issues around their management.
Most clinical trials exclude older people with MS. Can we be sure that DMTs have the same risk-benefit ratio in the older MS population as the younger population?
Comorbidities are commoner in the older population. How do these affect the safety profile of DMTs? For example, the recent vascular complications seen with alemtuzumab were much commoner in patients with vascular comorbidity, who tended to older. Another example is PML; there is little doubt that age is a risk factor for developing PML.
Non-specific white matter lesions or vascular lesions are common as you get older. How are we the MS community going to deal with these when we are so dependent on MRI as a monitoring tool for the effectiveness of DMTs. How do we differentiate between new MS lesions and new vascular lesions? Will the central vein sign be sufficient for this?
Brain volume loss (BVL) accelerates with ageing. Does this also happen in MS? As we start to use annual brain volume loss as a treatment target in MS should we not be age-adjusting for what is considered normal BVL?
Neurological function and cognition fall off with age. How do we know that it is ageing or MS that is causing the loss of neurological function?
Because MS reduces brain and cognitive reserve are pwMS more likely to get other neurodegenerative diseases and at an early age?
As you get older your immune systems don’t function well. This is called immunosenescence. How does this impact on the safety of immunosuppressive DMTs?
Ageism is a problem in medicine; how do we prevent it from affecting how we manage older people with MS?
DMTs become less effective as you get older. How can we be sure they are working in the older MS population?
How do you stop DMTs in the older MS patient who is stable?
Are their DMTs that are safer in the older population? Are their DMTs with greater risk in the older population? For example, I am sure anti-CD20 therapies and other continuous immunosuppressive therapies will have a worse risk profile in the older MS population, compared to, for example, cladribine that only causes short-term immunosuppression.
Does MS cause premature ageing, i.e. premature biological ageing?
Lifestyle and wellness programmes for helping to manage MS tend to be for younger people. How can we adapt these for the older MS population?
We are seeing an increasing number of people presenting with syndrome compatible with demyelination in their fifties and sixties. How do the McDonald diagnostic criteria perform in this age-group? Do we need to modify our diagnostic criteria for the older population?
Most of the information resources for pwMS is designed for younger people. Are the information resources appropriate for the older MS population? Do we need age-adjusted information resources? Do you think the current educational resources for the ageing MS population are adequate?
How does ageing affect MS? Is premature ageing a driver of delayed worsening in MS?
What can I do to prevent age-related neurodegeneration making MS worse?
Do the anti-ageing interventions that work in the general population work in pwMS?
What about advanced directives or living wills? Are these more important for the older MS population?
Social isolation becomes more pronounced with ageing and increasing disability. Should there be age-specific social prescribing programmes?
Sexual function is a problem in MS but is often ignored in the elderly. Should sexual function and other symptomatic problems be looked at in the older MS population to define the problem in this population group?
By definition an immune reconstitution therapy (IRT) for MS is given as a short course, i.e. as a one-off treatment in the case of HSCT or intermittently as in the case of alemtuzumab or cladribine. IRTs are not given continuously and additional courses of the therapy are only given if there is a recurrence of inflammatory activity. IRTs have the ability to induce long-term remission and in some cases potentially a cure.
Immune reconstitution simply refers to the restoring of a competent immune system after a cycle, or cycles, of depletion. Immune competence in the context of an IRT refers to the ability of the immune system to respond to infection, in particular, opportunistic infections, mount an antibody response to vaccines and to perform normal systemic tumour surveillance.
Immune reconstitution has been best shown in the context of hematopoietic stem cell transplantation (HSCT). In the case of an IRT, for example, alemtuzumab or cladribine, which are given as short courses breakthrough disease activity can be used as an indicator to retreat rather than to necessarily switch therapy. Therefore, there a rebaselining MRI should be delayed until after the final initial course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered
A major concern in relation to the wide adoption of IRTs is the uncertainty about the duration of their effectiveness and the concern that disease activity may reoccur at a level below the clinical and MRI monitoring thresholds used in routine clinical practice. If disease activity does reoccur will it cause irreversible end-organ damage? In addition, some IRTs, in particular, alemtuzumab and HSCT, are associated with a high rate of secondary autoimmunity and rarely with early and severe rebound disease activity.
One strategy we are exploring is to use an IRT as true induction therapy and then maintain the treatment effect with safer maintenance therapies. In the case of alemtuzumab and HSCT, certain maintenance therapies could potentially prevent secondary autoimmunity and early rebound disease activity.
We are in the process of preparing a grant application to explore the safety of an induction-maintenance treatment. Would you be interested in helping by completing the following survey?
I have been a big proponent of self-monitoring and using data and its interpretation to change my own and hopefully my patients’ behaviour. However, since reading Shoshana Zuboff’s book on surveillance capitalism over the Christmas break I am having second thoughts.
Surveillance capitalism is how tech companies are using the surplus data they collect on us to create detailed individualised digital profiles and to then use the profiles to target us with adverts or to repackage the data and to sell it on for third parties to use. This is a big business and is getting bigger.
In parallel to this happening in the commercial sector, it is beginning to happen in medicine, i.e. we are developing health and wellness, and disease-specific self-monitor, apps for our patients. A lot of these apps are being developed and controlled by the pharmaceutical companies and there is no transparency about how the data will be potentially used in the future. Combine data from these health apps with general data collected from other sources and we have a big brother scenario, where third parties can start to target you subliminally. For example, the data could be used to suggest you change your treatment.
To avoid the misuse of self-monitoring data we are going to have to develop an ethical code of practice that is transparent to all concerned. I personally think we should own our own data and if it is harvested, either overtly or covertly, we should know how it is being used. We should also have the right to delete our harvested data and hence prevent third parties exploiting it.
The following is my presentation from ECTRIMS two years ago when I make the argument for self-monitoring. I am now going to have to include a disclaimer saying yes self-monitoring has the potential to transform the way we manage MS, but it is important that the data collected as part of self-monitoring is owned by the person being monitored and that the data cannot be used for other reasons without informed consent. Do you agree?
BACKGROUND: Digital self-monitoring, such as through smartphone applications (apps) or activity trackers, could be applied to monitor the health of people with multiple sclerosis (MS). This self-monitoring could facilitate personalized therapies and self-management of MS. The acceptance of digital self-monitoring tools by patients depends on them being able and willing to use these tools in their daily lives.
METHODS: In-depth interviews were conducted with seven adults with MS before and after participation in a study in which they used an activity tracker and an MS-specific smartphone app for 4 weeks. We inquired about experiences with the tools in daily life and needs and wishes regarding further development and implementation of digital self-monitoring for people with MS.
RESULTS: The smartphone app and the activity tracker increased respondents’ awareness of their physical status and stimulated them to act on the data. Challenges, such as confrontation with their MS and difficulties with data interpretation, were discussed. The respondents desired 1) adaptation of digital self-monitoring tools to a patient’s personal situation, 2) guidance to increase the value of the data, and 3) integration of digital self-monitoring into treatment plans.
CONCLUSIONS: These findings show that patients can provide detailed descriptions of their daily life experiences with new technologies. Mapping these experiences could help in better aligning the development and implementation of digital self-monitoring tools, in this case smartphones and activity trackers, with the needs and wishes of people with MS.
I have tried to include all the necessary information on MS DMT treatment decision-making into one easy to use and understand infographic. This infographic explains that when you see a patient with MS you have to decide if they have inactive MS or active MS. If they are active you have to decide how active their MS is (active vs. highly-active vs. rapidly-evolving severe MS).
You then have to decide on the best treatment approach, i.e. the conventional step-care approach, rapid escalation or flipping the pyramid. To achieve this you need to profile patients into whether or not they have a good, intermediate or poor prognostic profile. Finally, you choose a treatment target, i.e. NEDA-2, NEDA-3, NED-4 or -5, or beyond.
When I prepared this slide I had a debate with myself about whether or not I should leave off the ‘watchful waiting’ approach, but decided that there may be a place for it for people with inactive MS with a very good prognostic profile. And to be honest with you I have several patients in my own practice who for whatever reason we have adopted a watchful waiting approach.
The good news is that there is a group of patients who do well with watchful waiting. In this Austrian study below, they looked at the outcome of a group of patients who in partnership with their HCPs had decided against DMTs. This group displayed features, which significantly differed from other patients; they tended to have a higher age at MS onset, were more likely to present with sensory symptoms, have a complete remission of symptoms and have a lower burden of disease on MRI.
Importantly, watchful waiting in this group of patients seemed to work in that the decision not to start treatment was associated with a lower risk for conversion to secondary progressive MS.
Interestingly, the group of patients who did not start a DMT against the advice of their HCP did much worse and had a 20% higher risk of converting to SPMS.
The moral of this story is that shared-decision making works and that patients should listen to what their HCPs think. Or HCPs should develop their communication skills explaining why DMTs are beneficial to some, but not all, pwMS.
BACKGROUND: The frequency and long-term prognosis of relapsing multiple sclerosis (RMS) never receiving disease-modifying treatment (DMT) is unclear.
METHODS: We included 1186 RMS patients with a mean of 17.4 years follow-up and divided them into patients treated with any DMT (DMT) and patients untreated by shared (USD) or patient-autonomous decision (UAD).
RESULTS: The USD group displayed features, which significantly differed from the two other groups: higher age at onset, mainly sensory onset symptoms, complete remission of onset symptoms, less T2 and contrast-enhancing T1 lesions on initial brain MRI. In a multivariate cox regression, USD was associated with lower risk for secondary progression (SPMS) conversion (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.55-0.97, p = 0.011) compared to DMT, while UAD was associated with an increased SPMS conversion risk only in the “McDonald era” (HR 1.19, CI 1.02-1.58, p = 0.028).
CONCLUSION: Apart from the doubtless substantial improvement of the overall prognosis of RMS by DMT, it seems likely that not every patient necessarily needs immediate or even “hard and early” treatment. A “watchful waiting” approach with continuous clinical evaluation might be instead a viable option in RMS patients with favorable prognostic features at onset.
Happy New Year. We hope you all had a good festive break. The following are some of what we at Barts-MS want to achieve and work towards in the next decade.
#PreventMS We have little doubt that MS is a preventable disease and by tackling many of the environmental risk factors we may be able to turn around the MS epidemic and see a fall, or at least a levelling off, in the incidence of MS. This does not mean the prevalence of the disease, i.e. the number of people with MS, will fall. As we get better at managing MS more pwMS will be living longer and healthier lives. We need the whole MS community to get behind #PreventMS
#ThinkCognition The MS community will accept that MS is foremost a preventable dementia. MS-related cognitive impairment will become a major treatment target, both symptomatically and for disease modification. Physical impairment won’t go away, but it will become less of an issue with the wide adoption of early effective treatment to prevent disability. We will shift our treatment targets away from focal inflammation and relapses to target the #RealMS, i.e. smouldering disease. Smouldering MS will become the new frontier and we want to be one of the pioneering groups working in this area.
#CombinationTreatment We now realise that monotherapy will only get us so far in terms of reducing the burden of MS. We will need to explore combination therapy strategies and learn from our colleagues in other disease areas. Hopefully, the regulators will understand the need to move to a combination treatment paradigm and create the necessary regulatory framework for this to happen in.
#ThinkHolistically It is clear that the philosophy of marginal gains will need to be adopted to maximise the brain health for the lifetime of people living with MS. DMTs are clearly not enough. This will mean reconfiguring MS services to tackle comorbidities and to help pwMS adopt the necessary lifestyle changes to make small, but important, differences to their outcomes.
#ThinkMetabolic This is a new theme for the decade. We are our metabolism and MS is first and foremost a metabolic disease. Can we hack our metabolism in a way that will improve MS outcomes? I am sure we can and this will be done using diet, supplements, exercise and medications to alter our microbiomes and stimulate our metabolism to work with us with the aim of maximising brain health. There is good evidence that caloric restriction, intermittent fasting and ketogenic diets do this already. Can we make this more scientific? Can we add medication to the mix to make sure we are getting it right?
#RaisingTheBar The next decade will see massive transformation in the way we provide NHS services to pwMS. Gone will be the old Victorian model of healthcare and it will be replaced by a network model that is run by people with the disease and not the HCPs. The current healthcare model is broken and unsustainable.
#ThinkSocial The MS community will realise that the social determinants of health (SDoH) are as important to pwMS as they are for other disease areas. We will see service developments in the NHS to tackle SDoH and social isolation. We are not sure of what format these will take, but anyone who ignores the SDoH will not be able to maximise their outcomes.
#ThinkHand We will see the completion of the #ORATORIO-HAND and #CHARIOT-MS trials and the recognition that MS is modifiable throughout its disease course. We anticipate a whole raft of other trials starting that will target upper-limb and hand function as their primary outcome. We anticipate DMTs being started and continued in advanced MS (EDSS>=7.0).
#MSDiagnosis We anticipated that the McDonald diagnostic criteria being challenged by technology, in particular, biomarkers, and having to rapidly adapt to a changing landscape. Asymptomatic MS will be a new diagnostic category. We will be providing screening to high-risk individuals and diagnosing and treating MS in the asymptomatic stages.
#MS_is_1_not_2_or_3_diseases The MS community, including the regulators, will realise that MS is a biological disease and that salami-slicing up MS into pseudo-disease categories is doing pwMS a disservice.
#DemystifyHSCT The wider MS community will adopt HSCT as a very high efficacy DMT for treating MS. HSCT will become just another DMT on the list of potential treatment options. Many of the head-2-head studies comparing HSCT to licensed high-efficacy licensed DMTs will show that HSCT is at least as effective, and probably more effective, than our licensed DMTs but will come with higher risks. The wide adoption of HSCT as an MS treatment option will mean that pwMS won’t have to travel abroad for treatment.
#GRAD_Initiative The international community will get behind the Grass-Roots Affordable DMT (GRAD) Initiative to make sure people living with MS in resource-poor environments get access to MS services and affordable treatments. This has to happen as soon as possible; we can’t expect pwMS living without treatments to have to wait a decade.
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.
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.
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.
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.
We have been running a campaign that #MS_is_1_not_2_or_3_diseases for sometime. This is based on the biology of MS and not what we see clinically. The pathology that underpins so-called progressive MS is the loss of axons, loss of neurons and loss of synapses, which are the chemical connections between neurons. All three of these processes begin very early in the so-called asymptomatic stage of MS. What dictates whether or not we see the effects of these subtle changes depends on how much we stress the neurological system concerned and how much resilience, or reserve, this system has to handle the stress.
A good example is a marathon runner with MS who develops a dropped foot after running for about an hour at race pace. A year earlier he would only notice that symptoms towards the end of the marathon. Does this marathon runner have SPMS? If this runner had not stressed his motor pathway with vigorous competitive exercise the issue of whether or not he has SPMS would not arise. In other words, the question of SPMS would only arise when his dropped foot would impact on normal activities of daily living, for example walking, which may have only occurred in 10 years time if he had not been a runner.
What this anecdote tells us that the diagnosis of SPMS is a moving target and depends on what system, or systems, MS has shredded, how you use that system and how much reserve is left in that system to compensate for the damage. We know progressive cognitive dysfunction is the driver of early unemployment in so-called knowledge jobs. Why aren’t these patients being labelled as having SPMS? That is because neurologists, first and foremost, view MS as a physically disabling disease rather than a cognitively disabling disease. This needs to change; #ThinkCognition.
The diagnosis of SPMS is therefore in the eye of the beholder. In my eyes, progressive MS is present from the beginning of the disease. Trying to identify a point in time when you can be diagnosed with SPMS is futile and to discuss transitioning MS is a misnomer. Neurologists think we are smart when we classify our patients as having relapsing-remitting MS, or relapsing SPMS, or non-relapsing SPMS. Let me tell you this is a fallacy.
For example, I am doing a relapse assessment on a patient later today who was thought to have non-relapsing SPMS. Four weeks ago she went off her legs with new-onset weakness in her good leg. Her MS nurse said this is likely to be progressive MS and asked her to sit it out. Over the last few weeks, she has been recovering function in that leg and has started to mobilise again. Based on her history it is likely she has had a relapse. I am seeing her, to document the likely relapse, to assess whether or not she needs a course of steroids and to counsel her about her future treatment options. At present, she is not on any DMT having completed two courses of off-label cladribine several years ago.
The problem the MS community faces is that we view MS through clinical and MRI spectacles and we don’t think about the biology of the disease. If we took a biological approach to MS all MS would be labelled as being inflammatory, all MS would be active and all MS would progressive. Based on this thinking all people with MS would need to be offered treatment with a combination therapy approach and treated holistically.
The following study below describes the development of a new HCP-completed questionnaire to support HCP-patient interactions in evaluating disease transition or progression to SPMS. Using a prompt like this in clinical practice will almost certainly lead to an earlier label change in the notes, i.e. SPMS being diagnosed earlier. Will this help the patient? In the UK once you are labelled as having SPMS you are meant to stop DMTs. Would things change if NICE approved siponimod for the treatment of active SPMS under the NHS? If siponimod was green-lighted by NICE the SPMS label had better be ‘active-SPMS’ and not ‘inactive-SPMS’. The latter label would make the patient ineligible for treatment.
Another problem around the corner is that what happens if you now are now labelled as active-SPMS and start on siponimod and you then have to stop taking it because of lack of efficacy, poor tolerance or an adverse event? Will we be able to relabel the patient as having relapsing MS and put them back on a DMT that is licensed for relapsing MS? I call this flip-flopping and it happens all the time in clinical practice. However, it is likely that NHS England will put in place systems to prevent this from happening. My solution is to get rid of labels and let the neurologist and the patient decide on what treatment they want.
I think all the licensed treatment for MS, including HSCT, work in patients with active MS but have very little impact on smouldering disease. Smouldering MS is really the next frontier in the management of MS.
I hope the above demonstrates the folly of our ways. We need to call-out MS for what it is; an inflammatory neurodegenerative disease from the outset. Our guiding treatment principle should be to diagnose and treat MS early and effectively to prevent end-organ damage. Our therapeutic aim should be to maximise brain health for the duration of our patients’ lives. Anything less would be doing them a disservice.
OBJECTIVES: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) evolves over time and it can be challenging for physicians to identify progression early. Typically, SPMS is diagnosed retrospectively with a significant delay, based on a history of gradual worsening, independent of relapses, following an initial relapsing-remitting disease course. As such, SPMS is often associated with a considerable period of diagnostic uncertainty. This study aimed to explore and characterize key symptoms and impacts associated with transitioning from RRMS to SPMS and inform the content for a tool to support evaluation of early subtle signs suggestive of progressive disease.
METHODS: The qualitative study involved 60-min, face-to-face, concept elicitation (CE) interviews with 32 patients with MS (US = 16 and Germany = 16); and 30-min, telephone, CE interviews with 16 neurologists (US = 8 and Germany = 8). Multivariate analysis on data from a real-world observational study of 3294 MS patients assessed the differences between early-RRMS and early-SPMS, and identified factors that were significant drivers of this difference. These studies informed selection of the key variables to be included in a pilot tool. Sixteen physicians used the pilot tool, presented as a paper questionnaire, with a sample of patients whom they suspected were progressing to SPMS (n ≥ 5). Following this, the physicians participated in a 30-min cognitive debriefing (CD) interview to evaluate the relevance and usefulness of the tool. Qualitative analysis of all anonymized, verbatim transcripts was performed using thematic analysis.
RESULTS: Patients and physicians reported signs that indicated progression to SPMS including gradual worsening of symptoms, lack of clear recovery, increased severity and presence of new symptoms. No specific symptoms definitively indicated progression to SPMS, however a number of potential symptoms associated with progression were identified by SPMS patients and physicians, including worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Quality of life domains reported to be more severely impacted in SPMS than MS in general included: physical activity, work, daily activities, emotional and social functioning. Multivariate analysis of the observational study data identified several variables strongly associated with progression to SPMS including, requirement of assistance in daily living, presence of motor symptoms, presence of ataxia/coordination symptoms, and unemployment. Physicians reported that items included in the tool were easy to understand and relevant. Physicians also reported that there is an unmet need for a tool to help identify signs of SPMS progression and so the tool would be useful in clinical practice.
CONCLUSIONS: This was the first stage of development of a novel, validated, physician-completed tool to support physician-patient interactions in evaluating signs indicative of disease progression to SPMS. Qualitative and quantitative methods (involving physician and patients) were used to determine tool content. The usefulness and unmet need for such a tool in clinical practice was confirmed via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm and validate the tool so that it can be reliably implemented in clinical practice.
