Gavin Giovannoni

Does your neurologist walk the talk?

Thanks to Daniel Kahneman and Amos Tversky behavioural psychology and behavioural economics have become very sexy. Kahneman & Tversky have spawned an industry of nudge theorists; people who devise ways of getting populations of people to do things that are good for them.

People with MS are no different from the general population when it comes to doing what they are told to do. We have major issues getting MSers to adhere to lifestyle interventions.

In this long-term follow-up study below MSers who report higher levels of health promotion activities and greater functional ability tend to experience lower levels of fatigue, pain and sleep disturbance and higher levels of cognitive abilities in subsequent years.

Is this the chicken or the egg; i.e. did MSers who were simply doing better more likely to engage in healthy activities compared to those doing less well? The only way to sort this out is to do a randomised controlled trial, which is virtually impossible for lifestyle interventions. What we need are ways of getting MSers to adopt a Brain Healthy lifestyle as part of their routine management plan. The following is the list of things to do:

Smoking – if you are a smoker stop smoking.
Exercise – try and do 5x 30 min aerobic sessions per week. If this is too hard and you are not too disabled you can try HIIT (high-intensity interval training) instead.
Diet – eat a healthy diet. My philosophy is to eat ‘real-food’ that is culturally compatible with your family and friends. Avoid ‘fad diets’ and processed foods, particularly processed carbohydrates.
Alcohol – don’t consume too much alcohol, it is neurotoxic even in relatively small amounts.
Sleep – please make sure you don’t have a sleep disorder and make sure you get good quality sleep.
Comorbidities – make sure you are screened for co-morbidities (hypertension, diabetes, impaired glucose tolerance, high cholesterol levels and dyslipidaemia) and get them treated.
Infections – try and make sure you don’t get recurrent avoidable infections. The big one in MSers is UTIs.
Concomitant medications – review your medications and try and reduce your anti-cholinergic burden as much as possible.
Stress, depression and anxiety – if you suffer from these get them treated and managed actively. If you haven’t tried mindfulness therapy it is worth giving it a go.
Social capital – work on your social networks. Make sure you have time for friends and family.
Menopause – if you are menopausal you may want to consider hormone replacement therapy. The evidence on whether HRT makes a difference to MS outcomes is weak but interesting enough to consider it if you are a woman.
Wellness – this not only refers to your lifestyle but how it relates to the environment and your spirituality. Many argue you need to live in harmony with the environment to be truly well. I tend to agree. For example, my problem is my carbon footprint, which is impacting on my wellness.

If you have any suggestions to help other MSers with adhering to these principles, or you have any other to add to the list, please feel free to comment. Don’t be shy.

I also think you need to find yourself a neurologist and/or HCP who walks the talk. It is difficult to take a neurologist who is obese, smokes and clearly does not look after himself or herself, seriously when they tell you to improve your lifestyle. Or maybe I am wrong?

Becker et al. Functional and health promotion predictors of PROMIS® scores in people with multiple sclerosis. Health Psychol. 2019 May;38(5):431-434.

OBJECTIVE: The purpose of this study was to examine the impact of perceived functional abilities and health promotion activities on subsequent symptom experience among those who have lived with multiple sclerosis (MS) for many years.

METHODS: This longitudinal mailed survey study examined Health Promoting Lifestyle Profile II (HPLP) scores and MOS SF 36 scores as predictors of PROMIS® Pain Interference, Pain Intensity, Fatigue, Sleep Disturbance, and Applied Cognition Abilities Scoresamong 260 adults with MS. The community-dwelling sample was initially recruited from the mailing list of the MS Society in a large southwestern state. Respondents were predominantly female, with an average age of 67 years. They had been diagnosed an average of 30 years. Forty per cent reported relapsing-remitting MS, and 41% have the more severe progressive form of the disease.

RESULTS: HPLP and SF 36 Role Physical, Role Emotional, and Social Function scores assessed in 2013 were moderately correlated (r > .30) with PROMIS® Fatigue and PROMIS® Cognitive Abilities scores measured in 2014 and were somewhat predictive of PROMIS® Pain and Sleep Disturbance scores (r > .20). These results were replicated in an analysis using data from Years 2016 and 2017.

CONCLUSIONS: Findings suggest that those who report higher levels of health promotion activities and greater functional ability may experience lower levels of fatigue, pain, and sleep disturbance and higher levels of cognitive abilities in the subsequent year.

Reinventing the wheel or the 4×4

We were rightly criticised last year for holding a meeting that highlighted the problem of variance in the provision of MS services, in the NHS. without a plan and vision about how to change things. I hope we have listened to you. The follow on meeting that we are hosting next month (8th-9th July) has a more ambitious agenda; it will even come with a 3-year action plan.

I have always made the argument that variance, when it comes to the provision of healthcare services, is a euphemism for inequality and that simply represents the haves and have-nots in society and the world. Why should someone with MS who lives in place B, or country Y, get a different service to someone with lives in place A or country X? On the other side of the coin, variability creates the engine for change; it is the catalyst for people to do something about the poor services they are providing or receiving; that is assuming they know about the quality of their service and are willing to do something about it.

My colleagues have told me that I shouldn’t beat myself up too much over the problems and criticisms of our first meeting; after all, it was very instructive in that it:

Brought us together as a wider MS community and allowed us to recognise and reflect on the challenges we face in addressing the variance in the NHS.
The meeting was inclusive in that there was no hierarchy in terms of the importance of the people who deliver MS services. We identified ourselves as equals, or partners, and included people with MS.
The meeting made us realise that we have cognitive biases that need to be addressed to make the community inclusive and more diverse. Diversity of ideas is going to be the catalyst for the next phase of our project.
We also realised that variance is not necessarily bad. We need some variance and ways to measure it so that the outliers at the upper end stimulate change. The next meeting is called ‘Raising the Bar’ and refers to improving services across the board.
The meeting also allowed us to get away from the NHS rat race and provided quality thinking time, i.e. time to reflect on the task at hand. This has allowed us to set priorities or specific work streams that will allow us to set key objectives for the programmes of work going forward.

As the chair of the committee, I have been asked to set out my vision for the initiative and define what success will look like for this initiative. To make it tangible I have defined targets at year 1, 2 and 3 and beyond.

YEAR 1

At the end of next year, I would expect all participating centres to actively engage in a national quality audit. This will include providing metrics on the NICE quality standards and several other new metrics that will allow us to assess how good or bad we are at achieving what we have set out to achieve.

My vision is 4×4, i.e. for 75% of patients with uncomplicated MS to be diagnosed within 4 weeks of the specialist MS team receiving a referral letter with a diagnosis of suggestive of MS and for 75% of pwMS, eligible for DMTs under the NHSE guidelines, to be have been offered, counselled and given a date for starting a DMT. Is this too much to expect? These time frames are compatible with our International Brain Health standards so why wouldn’t we aspire to meet them?

YEAR 2

At the end of year 2, all participating centres will have a patient partner programme in place to upskill pwMS on how to navigate their local MS services and how to self-monitor and self-manage their MS. This programme will be developed in partnership with patient organisations and will depend on local champions to make it happen. We are in an era in which knowledge has been democratised. Why shouldn’t people with MS participate in providing their own healthcare and contributing to their own healthcare?

YEAR 3

Participating centres will be working differently and managing MS holistically. This will include programmes to screen and manage comorbidities and to promote lifestyle interventions. Participating centres will collect data on these new activities as part of the annual national audit. As part of this holistic management of MS, there will be a ‘no patient left behind’ philosophy embedded in all MS services. This will require systems to make sure that all people with MS, who are covered by a particular service, will have access to that service. We don’t want vulnerable, less educated or less well off patients to be disadvantaged by the service.

LEADERSHIP

It was clear to us at last year’s meeting that for our vision to be realised we need a new generation of leaders to make things happen. We are therefore proposing putting in place a leadership training programme to equip people with the skills to make things happen. The leadership programme will be small and selective and will focus on doing, i.e. as part of the programme delegates will be expected to participate in and complete a national project. This will be run by Gabriele De Luca who is a shining example of what good leaders can do. Gabriele has experience from the AAN young leadership programme and is passionate about the field himself. It may be worthwhile coming to, and participating in, our meeting just to access the leadership training programme.

SHARING BEST PRACTICE

As always the wheel has usually been invented. Most ideas are not new, but how they have been tested and implemented may be new. We are proposing to use the Variance platform to share best practice. Why reinvent something if it already exists? We expect all centres to share their successes and failures so that others can learn from them. This will hopefully allow MS centres to share their materials and experiences with other centres so as to raise the bar for everyone and to create a collegiate atmosphere. The advantage the MS Academy has is that we already have the infrastructure to make sharing relatively easy.

So if you are reading this post and are attending this year’s meeting don’t be shy; please submit a poster to the meeting on something in your service that you are proud of, or even something you are not so proud of. We will select 3 or 4 posters for a platform presentation to allow wider discussion.

If you have not registered already please do so now there are a few remaining places.

What has getting old got to do with MS?

The brain and spinal cord were not necessarily designed by evolution to last longer than approximately 35 years. It is only relatively recently that as a species we have extended our lifespans. Once you go beyond approximately 35 years of age there is a gradual loss of nerve cells, axons and synapses. This explains why as we get older we notice the effects of ageing; reduced vision, loss of hearing, poor balance and, sadly, age-related cognitive impairment. In short, life after 20 or 30 years is an age-dependent neurodegenerative disease, which is sexually transmitted.

If we live long enough we will all develop cognitive impairment. What protects us from age-related changes is so-called brain reserve, i.e. the size of the brain and spinal cord, and cognitive reserve, which relates to education level and environmental enrichment. We know that MS reduces both brain and cognitive reserve and as a result MSers have reduced reserve and hence the buffer that protects them from the impact of ageing. In other words MSers age earlier.

Another downside of ageing is that repair mechanisms also start to fail. In the paper below neural progenitor cells (NPCs) from MSers with progressive MS have been found to express cellular ageing markers when compared with age-matched controls, implying that cellular ageing or senescence is an active process in progressive MS and contributes to limited remyelination and recovery.

I suspect one of the reasons why the effectiveness of DMTs fall-off with age is that some of the treatment effects are due to the recovery of function when you switch off inflammation. The less recovery of function the less the will be the relative effectiveness of the particular DMT being studied.

Can you do anything about premature or early ageing? Yes, you can. We know from studies in the general population there are many things that MSers can do to maximise brain and cognitive reserve. This is called Brain Health and involves lifestyle factors such as exercise, diet, sleep and avoiding smoking and excessive alcohol consumption. It is also important to screen pwMS for comorbidities or other diseases and have them treated; these include smoking, hypertension, diabetes, obesity and abnormal lipids. As for diet, there have not been any that have been studied extensively enough in MS. However, data from animal models and other fields indicate that calorie restricted, intermittent fasting and ketogenic diets have the most promise with regard to brain health. However, I need more evidence of their beneficial effects before promoting these diets as an adjunctive treatment for MS.

For those of you are interested dimethyl fumarate (DMF) triggers some of the anti-ageing pathways linked to these diets. Therefore, DMF may be working in MS as an anti-ageing drug already. The question I have is does enough DMF get into the CNS to have an effect on the end organ or is its potential anti-ageing mechanisms limited to the systemic compartment?

Please note that ageing is a biological process and as we decode the molecular programmes that cause ageing we may be able to develop treatments that reverse or slow down ageing. An example of this is metformin, a drug for treating diabetes that has recently been shown by Robin Franklin in Cambridge to reprogramme oligodendrocyte precursors in older animals to behave as if they were young cells and become more efficient at remyelinating axons. I, therefore, envisage a future in which we use anti-ageing drugs as add-on therapy to treat MS.

Nicaise et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9030-9039.

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

Paediatric-onset MS

As you are aware approximately 3% of people with multiple sclerosis develop their first symptoms in childhood and adolescence. As the incidence and prevalence of MS are increasing we are seeing more children and adolescents with the disease. Why?

Relative to MS in adults, most neurologists and other healthcare professionals are unfamiliar with the diagnostic evaluation, clinical course, outcome, and management of MS in children.

To remedy some of these deficiencies we are running a dedicated triMS.online meeting on Paediatric MS on Tuesday 11th, June 2019. We have an exciting programme of international speakers. As with all triMS.online meetings you don’t necessarily have to watch them live, but can log-in after the event and watch the content in your own time. You can also ask questions, which the speakers will respond to for up to 4 weeks after the event.

www.trimsonlineconference.com

Don’t forget to register and please forward the invitation to your colleagues.

CoI: multiple

Information asymmetry

Outside the field of medicine, for example in law and economics, information asymmetry deals with the study of decisions where one party has more or better information than the other. This asymmetry creates an imbalance of power in decision making and transactions, which can sometimes cause these decisions or transactions to go awry and cause a breakdown in trust or market failure as worst-case scenarios. Examples of this problem are (01) adverse selection, (2) moral hazard, and (3) monopolies of knowledge.

Information asymmetry extends to the field of medicine. For example, if a Pharma company has better information than regulators about serious adverse events of their newly licensed drug they may take covert actions to bypass new regulation. There are many examples of this and this undermines the effectiveness of regulation and the trust we have in the Pharmaceutical industry.

Another example of information asymmetry is what happens in the typical doctor-patient relationship. Doctors may have more information than their patients, which results in an imbalance of power in decision making. Unless the doctor takes steps to correct this information asymmetry as part of the consultation process this can have serious consequences if decisions go wrong or are even perceived to go wrong; the result is usually a breakdown in trust between the doctor and patient and can have other more unpleasant ramifications.

As a practising neurologist, I always try and correct any information asymmetry between myself and my patients, but this is not always possible given the time constraints placed on us within the NHS. Many other factors, in particular, cultural and language barriers, prevent you from correcting information asymmetry. It also plays both ways; in the modern era, patients often know more about their disease and are more up to date with the latest developments in their disease area, than their doctors. In this situation are the doctors prepared to take time to listen and learn?

One of the reasons for starting this blog was to correct information asymmetry and to create a platform for the dissemination of knowledge and how this knowledge impacts on clinical practice. I, therefore, read with interest a letter in this weeks BMJ from a retired GP and patient, which succinctly addresses the problem of information asymmetry. Do you agree with him? I am particularly impressed with his concluding sentence: “The big danger of a monopoly on knowledge is just that: the absence of mechanisms to challenge it.”

If you have any personal examples of how information asymmetry has affected the management of your MS please feel free to share them with us.

Can we create a platform/mechanism to allow people like Roger Weeks and yourselves to challenge this ‘monopoly of knowledge’?

Roger Weeks. A monopoly on knowledge is bad for patients. BMJ 2019;365:l2254

Patients and their doctors should be grateful to deBronkart for highlighting the lack of access to new information about illnesses. Clearly, the advice of Abigail Adams to her president and husband, John Adams, has been ignored not just in the US but worldwide. The unlimited power of academics with a monopoly on knowledge is unchanged. The delivery of such knowledge to patients (and their doctors) at their moment of need may well not be solved by the highly unlikely achievement of open access publishing (as raised in some of the rapid responses to the commentary). Information needs about diseases and their treatment are not well served by the current patient information leaflets universally found in medication packs because they relate only to the product and to conditions treatable by the product.

As a doctor, I see that comprehensive electronic information on conditions is needed. It should include all treatments and pathways, with drug and non-drug treatments (such as physical treatments including manipulation, operations, and mind and even alternative treatments), and be accessible to all on demand. These information resources need to be as global as possible to inform patients about new developments in treating their disorder and about selected drugs. The information should be based on reliable sources, including the National Institute for Health and Care Excellence, the NHS, summaries of product characteristics, patient leaflets, Food and Drug Administration labels, and selected research papers. I contribute to work on this.

As a patient with all the latest available information on my late onset eosinophilic asthma treatment, I find great difficulty in persuading specialists to provide me with a new biological agent (with a stated 60% benefit rate), even though I can demonstrate that all their reservations are based on pre-conceived ideas, not fact. The big danger of a monopoly on knowledge is just that: the absence of mechanisms to challenge it.

The three Amigos

This week some of us with decanting to Edinburgh for the annual Association of Neurologists meeting.

From an MS perspective, we will have lots to discuss including whether or not the UK MS community has the appetite to take on one, or all of these, studies. Which one do you think is the most important?

The SALVAGE study, which is challenging NHS England’s DMT stopping criteria and saying that even if you end up in a wheelchair it is worth protecting your upper limb function.

The ADIOS study. This is questioning whether or not we need to dose ocrelizumab continuously, or can we use it as an immune reconstitution therapy (IRT), or using adaptive dosing based on peripheral memory B-cell kinetics.

The #AttackMS study to treat MS as early as possible to see if we can maximise disease outcomes for people with CIS or early MS.

Don’t be shy we need you, and the wider MS community, to get behind these studies if we are to have a chance of getting them funded.

CoI: multiple

The Natalizumab #AttackMS Trial

We propose the very early use of natalizumab to maximise outcomes in people with very early relapsing MS.

In the European Union, natalizumab is licensed to treat adults with highly active relapsing-remitting multiple sclerosis for the following patient groups:

Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (DMT)

Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

The reason for this restrictive labelling is historical and relates to the undefined risk of developing PML prior to the implementation of JC virus serological testing to derisk PML. As a consequence of natalizumab’s restricted label, an increasingly small number of patients with MS are being treated with natalizumab.

Natalizumab’s attributes of being a very high efficacy agent, having a rapid onset of action, being relatively safe in the short-term (12 months) and having the ability to reverse its mode of action (washout or using plasma exchange) make it the ideal DMT to treat active MS acutely to prevent further damage.

There is emerging evidence that the earlier you treat MS the better the outcome. We have anecdotal evidence, from individual patients, that even short delays in starting DMTs may have consequences for individual patients with multiple sclerosis. In many parts of the world healthcare systems are not configured for the rapid diagnosis and treatment of multiple sclerosis, which results in many pwMS waiting months, and in some cases years, to be diagnosed and treated. We feel this laissez-faire approach to the management of MS is wrong and is counterintuitive to how we approach other neurological diseases in particular stroke where time matters.

We hypothesise that by treating people who are likely to have MS acutely with natalizumab we will improve outcomes, i.e. these patients will acquire less disability and may even have improved rates of disability improvement, compared to patients managed in a standard way.

We have therefore designed the #AttackMS Natalizumab trial to test these hypotheses and have approached Biogen to fund and/or sponsor this study.

The trial plans to recruit patients with clinically isolated syndromes, with an abnormal MRI (two or more lesions suggestive of demyelination), within 7 days of onset and to randomise them to being treated with natalizumab (300mg ivi 4 weekly) or placebo. Subjects will then be managed according to a protocol that will ensure they are diagnosed and considered for licensed treatments within an 8-week period. The latter has been chosen as it is within the timeframe set out by an international panel of MS experts as being an appropriate period of time for being diagnosed with MS and started on treatment (please note in most healthcare systems it takes longer than this). At 8 weeks, i.e. after their third infusion of natalizumab or placebo, subjects will be unblinded; those on natalizumab will then continue on natalizumab for another 10 infusions and those on placebo will be started on the DMT that their treating neurologist and themselves have chosen. Subjects will then be followed for a further 10 months.

The primary outcome will be an area-under-the-curve (AUC) analysis of serum neurofilament levels, a biomarker of neuroaxonal damage, performed on serial blood samples taken over the period of the study. Secondary outcome measures will include MRI, clinical and patient-related outcome measures (PROMS).

MRI metrics will include (1) new T2 lesions as a marker of focal inflammation, (2) single lesion MTR as a marker of remyelination, (3) T1 hypodensity as a marker of tissue damage. Clinical outcomes will focus on disease improvement using a composite of the EDSS, T25W, 9HPT, SDMT, and low-contrast visual acuity (LCVA). PROMS will include a fatigue scale and important symptom for pwMS that has been shown to be improved by natalizumab.

At the end of the 12 months of the study treating neurologists and participating subjects in the natalizumab arm will be informed about their JCV serostatus and a decision will be made to continue on natalizumab or switch to another DMT. Subjects will then be rolled over into an extension study to be followed for a further 12 to 24 months to collect long-term clinical and MRI outcomes. The latter is important to assess brain atrophy or brain volume loss.

What we are interested in hearing from you the MS community is this trial ethical and do you think the scientific principles underpinning it are sound?

If you work for Biogen and are reading this blog post and are wearing your commercial hat you will see this trial may be the vehicle you need to resuscitate natalizumab as a mainstream DMT and to convince the EMA to reconsider natalizumab role in the management of MS and grant it a first-line license it deserves; particularly for people who are JCV seronegative.

At Barts-MS we are so convinced that the #AttackMS treatment paradigm will improve MS outcomes for individuals with MS that we have started using it already in a few isolated patients with highly active MS. We want to take this paradigm to all our of our patients. Yes, all of our patients, because we want to maximise their outcomes.

From a political perspective, this trial may nudge the MS community to be more proactive about treating MS and cement the message that we have been promoting for several years that ‘Time is Brain’. Why should we value the MS brain any less than the stroke brain?

CoI: multiple

Jetlag

Just arrived back from the AAN 2019 in Philadelphia. Jetlagged, which is why I am writing this at 2 am in the morning.

As always the AAN is more a meeting of meetings or networking in academic lingo. These meetings have allowed us to progress several of our ideas including (1) DrK’s #MSAttack study with natalizumab, (2) to think more deeply about our proposed ADIOS Trial (adaptive dosing ocrelizumab study), (3) support for our plasma cell and (4) social capital hypotheses and to (5) to gain a deeper understanding of the emerging new ’safety’ issues surrounding alemtuzumab.

Alemtuzumab is getting an unnecessarily rough ride. I had an opportunity to review all of the vascular events and AEs that led to the EMA triggering article 20. These are all rare events. The intracranial haemorrhages appear to be related to transient hypertension and may relate to the amount of hydration the US infusion centres use when administering alemtuzumab. It is clear that MSers develop a transient rise in blood pressure when receiving alemtuzumab, which means this rare complication can be derisked with anti-hypertensives.

When it comes to the cases of arterial dissections and arterial thromboses on alemtuzumab I was not convinced alemtuzumab is to blame. The majority of the cases had comorbidities or had had procedures that are a more likely explanation for the ischaemic events. In many of the cases, the events were poorly characterised and it was not clear if they had occurred at all; this is particularly in relation to the so-called myocardial infarctions.

It is clear that most if not all of the ‘vascular cases’ have arisen in the USA. Why? I suspect it is because alemtuzumab is being used in a much riskier and older population compared to the other parts of the world. Herein lies the problem. The fact that the EMA has now copied the FDA and made alemtuzumab a 3rd-line DMT will shift the use of alemtuzumab into a riskier older population and thereby increase the likelihood of us seeing these vascular AEs in Europe.

To be honest I am not convinced that the risk-benefit profile of alemtuzumab has changed at all. I would, therefore, appeal to the EMA to include the new AEs in the SmPC, but not to change alemtuzumab’s label. We need to be able to offer alemtuzumab to MSer with early MS when they have the most to gain from the treatment. I am sure MSers are in the best position to weigh up the risks and benefits of alemtuzumab. My big fear is that restricting access to alemtuzumab will simply increase HSCT tourism abroad.

If I needed proof that our blog is read it was in abundance at the AAN. Several people were interested in our ADIOS trial and were thinking of doing versions of their own. The one caveat was new data that Stephen Hauser presented showing that the efficacy of ocrelizumab may be linked to the level of B-cell depletion, i.e. the greater the peripheral B-cell depletion the greater the treatment effect of ocrelizumab on disability progression. There was no dose-related signal on MRI or relapses because these have a floor effect, i.e. virtually all patients are NEDA 1&2 and hence it is impossible to use these outcomes to assess a dose-effect. The one caveat is the dose effect on disability was confounded by body weight; i.e. the larger the patients the less B-cell depletion. As you know MSers with an increased BMI (body mass index) are at increased risk of comorbidities, which may explain why they do less well on ocrelizumab and the observation has nothing to do with the level of peripheral blood B-cell depletion.

The peripheral B-cell depletion data, however, needs to be taken further and tissue and CNS B-cell depletion kinetics need to be studied further. I am convinced the ADIOS trial will be a good place to start with some of these studies. Clearly, it is time to get our grant writing hats on. We need to do this study in the UK.

DrK and I had several meetings with key stakeholders in Biogen about our #MSAttack study. There is little doubt about the efficacy of natalizumab in MS, its safety even in JCV-positive MSers when used for short periods, its rapid onset of action (weeks) and it reversibility (washout) that make it the only suitable DMT for this study. We have changed our trial design slightly, but hopefully, we will be able to get this study funded in the near future. If the #MSAttack study is successful it will change the way we treat and think about active MS and may help natalizumab obtain a first-line indication, which many MSers and CISers deserve; particularly if you want to save brain and spinal cord.

NeuroDoc Gnanapavan got very excited when she saw some posters supporting the use of proteasome inhibitors as a treatment for autoimmune disease. This supports our new SIZOMUS trial (Safety of IxaZOmib targeting plasma cells in Multiple Sclerosis) to try and scrub the brain clean of plasma cells. We will be letting you know much more about this trial in the next few weeks now that we have ethics and MHRA approvals. We will be needing volunteers for this study.

Saul, or Dr Reyes to some, is now one of the pioneers in studying social capital and MS outcomes. His poster on the topic was well received. It is clear that the social determinants of health outcome are very important and have not been systematically studied in MS. Dr Reyes will be changing all that and has many activities planned as part of his ECTRIMS fellowship The poster he presented at the AAN is self-explanatory, but if you have any queries please don’t hesitate to ask.

I have a new hero or heroine; Dr Riley Bove, from UCSF. Riley has developed a telemedicine service to help people with neurological problems in resource-poor areas. The service is provided for free by the USCF residents and staff and is linked to an educational course to train the staff in these countries. The whole service is run using Zoom an online teleconferencing service. Well done Riley; if you lived in the UK I would be putting your name forward for an honours award from our Queen. And if I had more bandwidth I would join and contribute to your service; maybe something for my retirement? Could this platform be expanded to help diagnose and manage MS in resource-poor settings?

It is now 4:10 am and I am beginning to feel a bit groggy. So I will signoff now but will come back with some more AAN highlights in the week.

CoI: multiple

AAN 2019 Living Well

I arrived in Philadelphia on Thursday to attend the 2019 AAN annual meeting. The programme of this year continues much of what was started in 2017 and 2018 around burnout and its opposite wellness.

The AAN states: “Neurology is the only medical speciality that has both one of the highest rates of burnout and the lowest rates of work-life balance. AAN leadership is well aware of your daily challenges and how emotional exhaustion can lead to the loss of interest and enthusiasm for practising medicine. It’s important to remember that it is possible to prevent burnout as well as restore well-being. Your health matters to the AAN and we’re here to help. Each day AAN staff and member volunteers are working on your behalf to decrease regulatory hassles to make it easier to be a successful neurologist. Additionally, we’ve compiled the following resources to provide you with tips, tools, and strategies for cultivating well-being and resiliency in your life.”

After last years meeting, I penned the following which I posted on Medium. Little has changed but is clear that neurologists and clinicians, in general, are facing an existential crisis.

Is the art of medicine, and by inference neurology, in terminal decline? Reflections on attending the 2018 American Academy of Neurology meeting in Los Angeles.

The most important part of attending large International conferences is the time for thought, reflection and importantly introspection. The AAN 2018 was no exception. The programme was informative, in a disturbing sort of way, in that a lot of the teaching sessions were dedicated to survival in the workplace; i.e. dealing with burnout, mentorship, work-life balance, mindfulness and meditation, giving and receiving feedback and many issues related to private practice.

When I was a trainee I was expected to be resilient; I simply had to get on with the job at hand. I was too busy to think about or identify these sorts of issues. I am not even sure if ‘burnout’ was an identified problem back in the late ’80s when I started my clinical training. For me, and most of my colleagues, internal medicine and neurology was a calling; ‘our vocation’. Being a doctor was more than simply doing a job. What has changed? My wife tells me the millennials have changed things; they are not as accepting as we were of the status quo and want something different out of life. Play and leisure define the millennials and not their work. Is this true? If yes, maybe I need to play more and work less hard?

The millennials demanding something different from life doesn’t explain it all. Something more seismic is happening to society and medicine. In the current era, often referred to as the post-industrial era, technology has democratised knowledge and the medical profession’s power base of asymmetric knowledge has been eroded. This is leading to an existential crisis for the profession. Unless you have a technical skill that you have honed over years with practice, for example, a surgical skill, our knowledge-based skills are being challenged by the crowd and algorithms. This is leaving the average neurologist frightened and bewildered; like a rabbit caught in the headlights. In the past, my colleagues used to get excited about major advances in medicine. Now what seems to excite them most are reminiscences from the past, from the era when our seniors seemed to be the masters of the universe.

Gone are the days of the clinical anecdote. Big data is now king. I heard a talk at the AAN2018 on pathogen discovery using deep nucleic acid sequencing of clinical samples (blood, spinal fluid, biopsies, etc.) and clever bioinformatics; unsurprisingly, it outperformed the clinicians. Gone are the days when an astute well-trained clinician would have the edge over their colleagues. In the current era technology and big data trump clinical skills and human knowledge.

Another example of a threat to neurology is the revolution that is happening in relation to gene therapy and RNA interference. Both are creating an unprecedented need for presymptomatic genetic diagnosis. Why waste time screening for single genes? Why not simply do whole genome sequencing on everyone at birth so that we can identify treatable genetic diseases, risk profile everyone for common diseases and then let algorithms analyse and reanalyse the genomes of the world’s populations as new information becomes available? It won’t be doctors that will be making diagnoses or treatment decisions it will be algorithms.

Neurologists still cling to the neurological examination claiming it is too complex for a machine to do and interpret. This is clearly not true. Data is emerging that the way we use our smartphones and how we interact with the web tells tech giants, such as Google and Facebook if we are depressed or have signs of early Parkinsonism. Image analysis using artificial intelligence of pictures taken of suspicious skin lesions and the retinae of diabetics are outperforming dermatologists and ophthalmologists at diagnosing skin malignancies and diabetic retinopathy. The same goes for image analysis in radiology and pathology. Why wouldn’t machines get better than us at interpreting physical function?

As we enter a world of smart wearables and other smart technologies it is only a matter of time before a robot will be able to perform and interpret a neurological examination better than we can. I have little doubt that the neurological examination will be deconstructed, improved on and ultimately performed by machines.

So how are we physicians and neurologists going to ensure our survival? Dare I suggest we redefine our role? Clearly, the part we play as diagnosticians will become less important as the algorithms take over this role. Treatment of disease will increasingly be delivered by assistants using care pathways and standardised protocols. IT systems linked to the electronic record will analyse variance. Any variance from the protocol will trigger an investigation into our practices. I am already aware of this happening in multiple sclerosis in relation to possible over- and under-prescribing of highly-effective disease-modifying therapies or DMTs.

To survive in the brave new world neurologists will need new skills, particularly in relation to sifting, curating and communicating information. We will increasingly be called upon to fight fake news and anti-science movements so as to protect our patients from harm. To be effective in this role will need to actively engage with the new media and acquire new digital skills. Neurologists will need to become better listeners and better communicators. We will need to shift the focus from a disease-centric worldview to a preventative and holistic worldview. Treating disease will become a smaller part of our work. We will need to train and support teams of assistants and nurse practitioners who will do the majority of the hands-on work. We will need to become knowledgeable and skilled in lifestyle and wellness counselling. More importantly, we are going to have to walk the talk; we are going to have to live our lives the way we want our patients to live theirs. Neurologists who lead by example will become the pioneers of a new type of neurological practice. Based on my experience at the AAN2018 I would call this Wellness Neurology.

Are you prepared to retrain as a wellness neurologist?

I am still haunted by the concluding lines from The Great Gatsby that are as relevant to me today as they were when I read them as a 16-year old: “So we beat on, boats against the current, borne back ceaselessly into the past.”

The new black death is ageing

I say to many of patients one of the most powerful predictors of progressive, or more correctly worsening, MS is ageing. Age also predicts recovery of function; the younger you are the better you do. This study shows that ageing restricts the ability of stem cells to make oligodendrocytes to promote remyelination.

As you are aware age also predicts response, or lack or response, to DMTs. The older you are the less effective DMTs are. The list linked to ageing and poor prognosis goes on ….

I have always said ‘life is a sexually transmitted neurodegenerative disease with a 100% mortality’. This usually gets a mutated laugh until people start pondering the joke and its implications and then gradually realise that I am being serious.

Evolution never designed, and selected, the human brain and nervous system to function much past the age of 35. It is only relatively recently that life expectancy has increased dramatically with the requirement of our brains to function into ‘old age’. It is clear that when we measure cognitive function, and brain volume, it is all downhill from about 35 years of age.

Those of us who are older than 35 notice the subtle cognitive impairments that increase with age and the gradual malfunction and deterioration in our nervous systems. When last have you tried tight-rope walking? Your failing balance system is simply a reflection of the global rot that is also shredding your cognition. Fortunately, we have enough reserve to adapt and cope with the slow decline in our mental faculties. However, if we live long enough we are all likely to become demented. Dementia in this setting is simply the reduction of cognition to a point when you can’t manage socially and occupationally. To prevent the inevitable consequence of ageing is there anything we can do to optimise our brain health so our ‘brains outlive’ our ‘bodies’?

There is a lot we can do to improve brain health. However, some of the interventions may require the administration of medications in the future. For the anti-ageing revolution to happen, and be adopted by society, we need to make ageing a disease.

By defining ageing as a disease it changes everything. Firstly, it creates incentives for the pharmaceutical industry to invest in the necessary R&D to get drugs to market. If ageing is a disease healthcare providers will pay for interventions. The corollary is that if ageing is not defined as a disease, any interventions to delay or modify ageing, will be limited to lifestyle interventions. By defining ageing as a disease it will allow us to develop tools for population screening to identify people who are either healthy or in the presymptomatic phase of known neurodegenerative disease. This will then allow us to test preventive strategies to delay the onset of symptomatic disease.

If on the other hand, you have MS we already know you have a neurodegenerative disease that shreds reserve capacity and brings forward ageing mechanisms, which is why we need to manage MS as early and as effectively as possible and holistically. This is why the new treatment target is ‘to maximise brain health for the lifetime of the person with MS’.

Please be aware that ageing is a biological process and hence we can target the biology with both lifestyle interventions and drugs. For example, recent evidence suggests metformin, a diabetes drug, may reverse some of the ageing programmes. Dimethyl fumarate (DMF), a licensed MS DMT, seems to activate antiageing pathways that overlap with pathways linked to specific dietary interventions, i.e. calorie-restricted, intermittent fasting and ketogenic diets. Should all MSers be on metformin and/or DMF and/or one of these diets? We need trials to test these hypotheses. But at least there are investigators exploring the questions.

Please let me know if you find the anti-ageing hypothesis of MS compelling; it overlaps with diet, sleep, exercise and many other things that I can discuss in future blog posts.

Rivera et al. Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination. Glia. 2019 Apr 30. doi: 10.1002/glia.23624.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

CoI: multiple