marginal gains – Prof G's MS Blog Archive

What has my age got to do with having MS?

Barts-MS rose-tinted-odometer: ★★★ (some readers have asked for this feature to stay)

How old are you? It depends. You may be aware that there can be a disconnect between your chronological or actual age and your biological age. As ageing or senescence is a biological process driven by metabolic, genomic and environmental factors you can see how there can be a disconnect between the two. As a result, many of us in medicine are beginning to think about unhealthy or accelerated ageing as a disease process. Making ageing a disease will create incentives for pharmaceutical and nutraceutical companies to invest in ageing R&D with the hope of producing medications or dietary supplements to slow-down or reverse the effects of ageing.

Ageing is important in MS as there is emerging evidence that MS causes premature ageing of the CNS (central nervous system), which means that pwMS are more likely to experience age-related neurodegeneration sooner than they have to and this almost certainly contributes to delayed disability worsening in pwMS.

It is clear that ageing impacts one’s ability to recover from CNS damage. It has been known for some time from clinical and animal studies that remyelination and neuronal plasticity are less efficient as you get older, which is why older pwMS recover from relapses less well than younger people. The animal studies below show that there is real biology behind these observations. Oligodendrocyte (myelin-producing) progenitor cells (OPCs) isolated from the brains of neonate, young and aged female rats show an approximately 50% difference in the levels of proteins they make. Differences were noted in both myelin-associated proteins and proteins that control several metabolic pathways. This study has clinical implications and can act as a read-out for finding drugs that could be used as anti-ageing agents.

There are several interesting biological targets and drugs that already exist for targeting ageing. Metformin, a drug for treating diabetes, is one of the lead compounds going in an MS clinical trial at the moment. It is believed that its antiageing effects of performing are mediated via the so-called NRF2 or programmed cell survival pathway. Interestingly, fumarates (e.g. dimethyl fumarate) and ketogenesis also activate this pathway. Could DMF, and the other fumarates, be the panacea antiageing drug we need for tackling progressive or more advanced MS? Yes, I think so but to convince Biogen to follow the money is proving more difficult than we anticipated. We approached them recently to do a combination DMF-plus trial with another class of drug to augment DMF’s response and they said no. Pity because I think they are missing a trick and an opportunity to create new intellectual property.

Physiological ketosis from caloric restriction, intermittent fasting or low-carbohydrate diets is another way of activating the NRF2 pathway. The biology behind this is probably via β-hydroxybutyrate, a ketone body, which works via the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, this is the same receptor DMF activates.

Other anti-ageing treatments and strategies include exercise and avoiding getting comorbidities, which accelerate ageing, in particular, the metabolic syndrome (obesity, hypertension, glucose intolerance or diabetes) and smoking. The driver of the metabolic syndrome seems to be hyperinsulinaemia and the diets referred to above are all very effective in suppressing or reducing circulating insulin levels.

So in 2021 if you have MS you need to think seriously about what you can do to tackle early and accelerated ageing. Most of the things you can do now involve lifestyle changes, which are often hard to implement. My advice would be to implement the changes slowly and you may find over time that the behavioural changes you make will stick. There is a lot of evidence for this from the field of behavioural psychology.

The above advice is part of the holistic approach to the management of MS I have been pushing for several years and my adoption of the ‘marginal gains philosophy’ for managing MS.

“If we break down everything we can think of that goes into improving MS outcomes, and then improving each by 1%, we will get a large improvement in MS outcome when we put them all together.”

“Ask not what your neurologist and HCP can do for you, but what you can do yourself to optimise your own MS management and long-term MS outcome.”

de la Fuente et al. Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing. Mol Cell Proteomics. 2020 Aug;19(8):1281-1302.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Alcohol Awareness Week

This week is alcohol awareness week in the UK and the NHS is encouraging its patients/clients to look in the mirror and ask whether or not they are drinking too much. As part of the holistic management of MS and our marginal gains strategy for managing MS, we are encouraging all pwMS to do the same.

Excessive alcohol consumption is bad for MS in several ways. It disrupts your sleep pattern and may, therefore, make fatigue and other mental health issues worse. It can affect your balance and coordination and increase your risk of falls and fractures. Alcohol lowers your seizure threshold and increases your chances of having seizures. Longterm alcohol consumption is associated with accelerated brain volume loss and hence increases your chances of developing cognitive impairment and is likely to exacerbate MS-related cognitive impairment.

Alcohol is not good for bone health and is a known cause of osteopaenia. Alcohol is metabolised by the liver and can result in liver toxicity. Alcohol interacts with many drugs affecting their activity and metabolism and may interact with MS-related medication resulting in unpredictable side effects.

Alcohol is very calorific and may contribute to weight gain. In general, excessive alcohol consumption is bad for you.

Why don’t you log onto Drink Coach, or download the App, and take the alcohol test to see if you have a drinking problem?

CoI: multiple

Ask your GP

Should we expect your GP or family doctor to take on more of the day-2-day management of your MS?

In the UK specialist physicians are called consultants because there was always too few of them to get their hands dirty with the day-to-day management of patients with special medical problems. General practitioners used to refer their patients to a specialist for a ‘consultation’ and then get a long letter back with instruction on how to manage their patient. In other words, GPs used to do all the legwork.

In the last 25 years, this has changed. For most long-term conditions, which have become more complicated in terms of their management, the NHS now expects multidisciplinary teams to manage these patients. This has changed the relationships between specialists and GPs and not necessarily in a positive way for patients. For example, we have to rely on GPs to prescribe and help monitor specialist medicines. Not all GPs feel comfortable doing this. If the medicine is off-label they often refuse to prescribe it. There are two reasons for this, (1) why should they pay for an off-label medicine and (2) why should they take on the risks of off-label prescribing. To overcome this we have to put in place so-called shared-care guidelines, which are designed to protect the GPs. Under a shared-care guideline, we have to start and monitor the new medication for the first few months, before the GP takes over the prescribing. The paperwork involved in prescribing drugs under a shared-care guideline is not trivial and takes many meetings and months to get in place, which is why we rely so heavily on our neuroscience specialist pharmacist. Neurologists don’t have the time or space in their job plans to take this on. Notice my use of management speak to delegate this task to our pharmacist.

Because we now see most of our MSers once or twice a year for MS-related problems some rarely see their GPs and hence fall through the cracks, i.e. they are not being routinely monitored for comorbidities (diabetes, hypertension, hypercholesterolaemia, etc.). This causes problems for MSers because MSologists and MS HCPs are not trained and do not have the time to screen for and manage comorbidities.

To implement the marginal gains philosophy into routine MS practice we are going to have to change the way we work with GPs and other community-based HCPs to make the management of MS and all its problems seem seamless to MSers. At the moment it isn’t. A large number of my patients have problems navigating the complexity of the NHS to get the care they need; this is not only community-based services but the services we provide within a secondary care environment.

The Canadian review below on the potential role of the GP or family physician in managing spasticity is refreshing. I see no reason why GPs can’t be upskilled to take on the day-to-day management of many of the symptomatic problems faced by MSers. Spasticity is just one of the symptoms that can be tackled, why can’t they take on bladder, bowel & sexual dysfunction, anxiety, depression, pain, sleep disorders, social isolation, falls prevention, bone health, immunosuppression, diet, smoking, addiction, etc.

What are your experiences with your GP managing your MS compared to your neurologist or MS nurse specialist? Do you think the communication between your MS service and GP could be improved? Do you agree with applying the marginal gains philosophy to the management of your MS?

Milligan et al. Demystifying spasticity in primary care. Can Fam Physician. 2019 Oct;65(10):697-703.

OBJECTIVE: To raise awareness of spasticity in primary care and clarify how to identify, diagnose, and manage it effectively and efficiently in patients with pre-existing neurologic conditions.

SOURCES OF INFORMATION: PubMed was searched for articles published from 1970 to May 2018 using the terms spasticity, spasticity in physical disability, spasticity in mobility impairment, and spasticity with family medicine or primary care. Other relevant guidelines and resources were reviewed and used.

MAIN MESSAGE: Spasticity is a common secondary complication in conditions such as spinal cord injury, multiple sclerosis, stroke, cerebral palsy, and other neuromuscular physical disabilities and can have a negative effect on health and quality of life. Factors such as inconsistent definition, poorly understood mechanism, and relatively low prevalence make spasticity seem like a daunting condition to manage. Furthermore, its variable presentation and effect on a patient’s quality of life, and its range of treatments with varying levels of evidence, can make treatment challenging in primary care and in other clinical settings. Family physicians play an important role in recognizing and inquiring about spasticity and its changes, triggers, and effects on function. Ruling out reversible causes is important. Many management strategies can be instituted by family physicians.

CONCLUSION: Managing spasticity might be unfamiliar to many practitioners. It is important for physicians to understand spasticity and the potential treatment options available to improve quality of life. The current review provides concise information on the clinical relevance of spasticity in primary care and how to assess and manage it effectively and efficiently in those with chronic neurologic conditions.

CoI: multiple

Self-diagnosis

Dear Neuro,

You see me once a year for 15 minutes, you look at my MRI report and blood results, you ask me a lot of questions, you examine me and then you tell me that everything is fine. At my last visit, you said my MS was stable, you mentioned to me that I was NEDA, because I had had no relapses, no new lesions on my MRI and my EDSS was static at 3.0.

I have now looked up and read about NEDA (no evident disease activity) and I disagree with your assessment. I am clearly getting worse. The Christmas before last I remember going for a 5-mile walk with my family after lunch and managed it fine. When I tried the same walk last Christmas I had to turn back after a mile because my right leg was dragging.

I also have other problems that you didn’t pick up on during the consultation. I now have to get up 2 or 3 times at night to pass urine. My memory is much worse than it was last year. My head feels foggy all the time as if I have a permanent mild hangover. I now avoid any social occasions with colleagues after work. The truth is I am too tired to at the end of the day to do anything else than get home. I feel exhausted most of the time. I have stopped gardening.

I think I have developed secondary progressive MS. Do you agree? Would it be possible to see you sooner to discuss this? Is there anything you can do about my deterioration in functioning?

Yours sincerely

Patient Y

Does this story sound familiar?

At first glance, it is easy to say this person has SPMS. But do they?

Based on the definition of SPMS it seems likely, i.e. objective worsening of function for at least 6-12 months independent of relapse activity. Based on the latter it seems Patient Y is not having relapses. As for the objective worsening of function the interpretation is in the eye of the beholder. As far as the neurologist is concerned the patient is not deteriorating because the EDSS is stable. In comparison, the patient has documented, albeit rather crudely, a drop if in functioning. Who do you believe?

The scenario illustrates what will happen when MSers begin to self-monitor and prepare for clinic appointments in advance, i.e. they will potentially be self-diagnosing secondary progressive or worsening MS.

However, I want you to take a step back and ask could the deterioration be due to something else, something reversible? If it is due to something else it may be treatable and potentially reversible.

Does this patient have any reversible comorbidities that could be responsible for the deterioration? Smoking, hypertension, diabetes, metabolic syndrome, obesity, underactive or overactive thyroid function, renal, liver, heart or lung disease? If a woman, is she menopausal? What about mental health issues; depression and anxiety? Is this patient drinking too much alcohol? Is the patient malnourished? They may be eating a diet of toast and tea.

Is this patient sleeping well? Getting-up 2 or 3 times a night to pass urine means their sleep hygiene is very poor. Just improving this patient’s bladder problems will have a major impact on their daytime fatigue and work performance.

What about a chronic infection? Could this patient have a low-grade urinary tract infection? What about their oral health; could they have gingivitis or periodontitis? Sinusitis?

Is this patient exercising enough? I suspect not. The drop off in the walking distance could be deconditioning, i.e. losing fitness because of lack of exercise. In this particular patient, I suspect this, however, is unlikely because deconditioning is unlikely to result in a dragging leg on walking a mile.

What medication is this patient on? Are they are on an anti-spastic medication or anticholinergics for their bladder problems? Both these class of drugs affect cognition and may explain the memory loss and brain fog. I have commented on baclofen being particularly problematic in the past.

How well is patient Y? Patient Y seems to have become socially isolated and withdrawing from having social interactions with their work colleagues. The patient has stopped gardening, which helps improve mental health. What about the home environment? Is patient Y’s relationship with the family stable, etc? What are this patient’s finances like? Are they in debt? Are they struggling economically?

Could this patient have smouldering MS? Does this patient need an MRI of the spine and a lumbar puncture to measure CSF neurofilament levels? We know that brain MRI will not pick-up all disease activity. Does this patient need to start a DMT or have a DMT switched and escalated? I would be very interested to know how this patient’s cognitive function is and whether or not they have a swiss cheese brain (lots of black holes) and brain volume loss. Having this information makes a diagnosis of SPMS and/or smouldering MS more likely.

How old is patient Y? If they are over the age of 50 we may be seeing early ageing.

Making a diagnosis of SPMS is not simple and most neurologists would prefer not to do it. However, if we are to improve the lives of our patients we need to take a holistic approach to the management of MS. Clinical practice must not be a box-ticking exercise. We need to provide our patients with the tools to self-monitor, self-diagnose and self-manage. We need them to become partners on a life-long MS journey that will result in better outcomes and happier and more content MSers and HCPs.

To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together”. This case vignette illustrates this very well.

I hope this post motivates you to start self-monitoring and to start preparing for your consultations with your HCP. You need to have a list of questions to ask. Don’t let your neurologist or HCP fob you off. You know yourself better than they do; please don’t forget this.

CoI: multiple

Why is everyone drinking anti-CD20 kool-aid?

Prof G will ocrelizumab and rituximab prevent SPMS?

Just back from the COMBAT-MS stakeholders meeting in Pasadena with the Kaiser (Kaiser Foundation Research Institute) and Swedish (Karolinska Institute) trial teams, PCORI (Patient-Centered Outcomes Research Institute) and many brave an wonderful people with MS and their families.

The COMBAT-MS study (NCT03193866) is recruiting well and is on schedule to deliver very important comparative data on the effectiveness of rituximab in real-life. The full title of the study is ‘COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient’s Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis’. In short, COMBAT-MS will be comparing Rituximab with Natalizumab, Fingolimod, Alemtuzumab, Interferon-beta, Glatiramer acetate and Dimethyl Fumarate. Because the use of alemtuzumab seems to be quite limited in Sweden, with the majority of patients going onto rituximab, the study will not have enough power to compare rituximab with alemtuzumab. This a great pity because the real question I have is how does anti-CD20 therapy compare to our top-guns, i.e. alemtuzumab and HSCT. This question is becoming a priority for me.

We had a comprehensive safety update from the COMBAT-MS trial team, which will be presented later this year. However, the safety profile of rituximab is broadly in keeping with what is seen in rheumatology, with a few interesting exceptions. However, the overall safety profile will help with the adoption of rituximab as a treatment of MS in resource-poor environments.

I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. Yes and no. It may be a secondary progressive disease, but the pathology driving smouldering MS (microglial activation, slowly expanding lesions, subpial cortical lesions, intrathecal immunoglobulin production, demyelination, mitochondrial toxicity and energy failure, oxidative damage, delayed axonal loss, synaptic pruning, premature ageing, etc.) are all present at the very earliest stages of the disease, even the asymptomatic stage of the disease, i.e. radiologically isolated syndromes. This is why I don’t think SPMS really exists and why MS is one and not two or three diseases.

The construct that MS has distinct phases, an early inflammatory and a delayed degenerative phase, is artificial and comes from the Pharma industry’s need to get interferon-beta licensed under the orphan drug act, i.e. MS had to have a prevalence of fewer than 200,000 affected people for the orphan drug act to apply. The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases, i.e. RRMS, SPMS and PPMS. Later on, a fourth category, CIS (clinically isolated syndrome) was added. However, CIS has largely disappeared as a category because of diagnostic creep and the earlier diagnosis of MS with the evolving definition of MS based on the newer versions of the McDonald criteria. Having looked hard I can find no scientific justification for making SPMS a different disease.

In my opinion, smouldering MS and the pathologies driving it do not seem to be anti-CD20 responsive. If they were then we would see a much better impact of anti-CD20 on brain volume loss, disease improvement and the slowly expanding lesion. What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS. Can I please urge you to re-read Stephen Hauser’s case report below. You may argue that one swallow doesn’t make a summer, but Stephen Hauser implied two year’s ago in a response to a question at ECTRIMS that anti-CD20 was not the panacea everyone wants it to be and that a lot of his long-term rituximab-treated patients were now secondary progressive, i.e. they had smouldering MS.

The concept of smouldering MS is a difficult one for people in the field to grasp. Why? It is because NEDA-3 has become de-facto what defines MS. We need to move beyond what we can see and measure and focus on end-organ markers of disease activity, i.e. whole brain and regional or grey matter volumes, the expanding MS lesions, neurofilament levels and more sensitive clinical outcomes. An EDSS view of the world is simply too narrow. We need to look at cognition, visual function and more sensitive functional tests of different neuronal systems. One of the attendees was horrified when I said that the best thing that could happen to the field is if we could automate the neurological examination using a validated technology platform. The idea of using a neurologist to assess eye movements and balance, when it can be done so much better with eye tracking systems and balance sensors, shocked this individual. Bring on the robots and maybe our worldview of MS, in particular, smouldering MS, would change.

I was also able to deliver good news about our WHO Essential Medicine List (EML) application that includes ocrelizumab as one of the three drugs and rituximab as a suitable replacement for ocrelizumab if access to ocrelizumab is a problem. If our EML application is successful this will allow us to pressurise governments to prioritise the treatment of MS in low prevalence countries. I explained to the group that what had started out for me as an ‘Essential Off-label DMT list’ in 2014, may become an official WHO-backed Essential DMT list in 2019. I am holding thumbs we get MS onto the EML, it needs to be there for many reasons.

I also covered in my talk alternative hypotheses, i.e. that MS may be due to a virus and that our current world-view of MS being an autoimmune disease driven by T and B-cells may be wrong. I briefly presented the B-cell-EBV hypothesis and our proposed EBV vaccination trial. I stressed that we need to use anti-CD20 as a tool to explore the EBV hypothesis and the good news is that Fredrik Piehl is going to explore EBV biomarkers as part of the COMBAT-MS study.

I used my lecture to represent my ‘marginal gains’ philosophy as it applies to treating MS and how we need to manage MS holistically and focus on the small things that may make a big difference to MS outcomes in the future. This is only the second time that I have presented this concept to my peer group, but it is something that still needs work to make it sticky.

The following are my slides from the meeting, which you can download from my slide sharing site.

I would like to thank PCORI and the Kaiser team for including me in this study and for your wonderful hospitality. I have little doubt that the COMBAT-MS study is going to help change the way the MS community treats MS globally. I would also like to thank the MSers who attended and spoke at the meeting; you are are the reason why we are doing what we do.

von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Ann Clin Transl Neurol. 2016 Dec 20;4(1):46-52.

A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.

CoI: multiple