If you are a Healthcare Professional (HCP) and are interested in getting up to speed on some advanced topics around the management of MS please take a look at the programme below. We converted our November meeting to be virtual, which has opened some spaces for more people to attend.
Mouse Doctor studied zoology and as a result, he tends to use animal analogies to describe various phenomena. In the past, he has been known to use his favourite invertebrates to describe some neurologists or even groups of neurologists. Why invertebrates? If anyone comes up with the correct answer I will send you an MRI scanner lego set as a prize.
Another animal he loves are lemmings, which he uses to describe the behaviour of pharmaceutical companies, i.e. they tend to follow each other by running off a cliff together. The question on everyone’s mind is how will the BTK (Bruton Tyrosine Kinase) inhibitor MS race turnout; will it be mass suicide with them failing as a class or will they usher in the next generation of innovative MS treatments?
Our interest with BTK inhibitors started about 5 years ago when the Mouse Doctor and I almost managed to get Abbvie to fund an investigator-led study of Ibrutinib in MS. However, it was not to be as Abbvie’s partner Janssen blocked the grant. Janssen was concerned that it was too risky to test Ibrutinib in MS because of the off-target effects of Ibrutinib and its potential for serious adverse events. I suspect they were right as Ibrutinib is a dirty drug and not a very selective BTKi as it also inhibits several other kinases.
Our hypothesis was simple; we wanted a CNS penetrant drug to target B-cells and plasma cells in the CNS of pwMS. We were buoyed by the observation that several people with CNS B-cell lymphomas were having dramatic responses to Ibrutinib. Although it was never to be we continued our search for a CNS penetrant anti-B-cell and anti-plasma cell agent and eventually, we managed to convince Takeda to fund a trial of their CNS penetrant second-generation proteasome inhibitor Ixazomib in MS. This study was meant to start earlier this year and has been unfortunately delayed by COVID-19 (we are now recruiting and are due to start very soon).
Despite our failure to get Ibrutinib, a first-generation BTK-inhibitor, into MS Pharma has taken up the challenge and there are now four companies with BTKi programmes in MS (Merck KGaA, Sanofi-Genzyme, Roche and Biogen).
BTKi’s will work in MS because they inhibit B-cell activation. There is phase 2 data for two of these agents confirming this (Merck and Sanofi-Genzyme). However, most people are not aware that BTKi also inhibits macrophage and microglial activation via the Fc receptor (FcR) signalling pathway. Therefore CNS penetrant BTK inhibitors, which applies to at least three of the four BTKi’s referred to above, will also target the so-called ‘hot’ or activated microglial response and test the hypotheses whether or not this response is favourable in MS.
The problem will be dissecting-out the anti-B-cell response from the anti-microglial response in terms of efficacy. Clearly, this will be important in view of some of the issues I raised yesterday around the ‘hot microglial’ response being potentially beneficial in the pathogenesis of MS. I envisage BTKi being very effective in stopping relapses and focal MRI activity the big question will be about the impact of BTKi on the smouldering component of MS. BTKi’s may have no effect on this component of MS, improve it or even make it worse.
I note that many of the phase 3 studies will be testing BTKi against teriflunomide. Clearly, BTKi’s are likely to beat Teri in terms of their impact on relapses and focal MRI activity, but Pharma (or the lemmings) may be taking a chance of beating Teri in terms of its impact on the end-organ or the smouldering component of MS. Don’t forget ofatumumab and teriflunomide had the same effect on brain volume loss when they were compared head-2-head in the ASCLEPIOS I and ASCLEPIOS II studies despite ofatumumab being clearly superior to teriflunomide in suppressing relapses and focal MRI activity.
It is clear to me that BTK is a very important treatment target in MS and the phase 3 trials will provide additional evidence beyond the B-cell on whether or not we should be targeting macrophage and microglial activation via their Fc-receptors. Whether or not this class of treatments will fail, i.e. fall of the cliff waits for the outcomes of the phase 3 trials.
For once I going to be an optimist and give this new class of treatment a 65% chance of success, mainly due to their anti-B-cell effects, and only a 30% chance of failure, due to their microglial inhibition and yet to be identified off-target effects. What is important is that we are testing a hypothesis about the smouldering component of MS, which I consider to be the real MS and why I am so excited to be part of the story.
CoI: I sit on two BTKi phase-3 trial steering committees.
Barts-MS rose-tinted-odometer: zero stars or one ★ depending on your disposition
I prepared this post not knowing that Prof. Laura Airas has submitted a guest post in response to a request from the Mouse Doctor. Before reading this post please make sure you read her blog post first. It provides an important counterbalance to my contrarian view below. Thank you.
More than 20 years ago, when I was a junior researcher, doing my PhD, I started a research collaboration with Dr Richard Banati, who worked in the Queen Square Brain Bank and the Imperial College PET imaging unit. Richard was investigating activated microglia in multiple sclerosis. The collaboration was very fruitful and led to the very first study of an imaging molecule called PK11195 that could label activated microglia.
In the study (see below), we elegantly showed that people with MS (pwMS) had widespread microglial activation in their brains. Their brains, in fact, lit up like Christmas trees with so-called ‘hot’ or activated microglia. The assumption, which is now dogma, from this and other studies is that these microglia must be bad for pwMS. This has led to many research and drug discovery programmes to find treatments to switch off hot microglia.
Now dial forward 20 years and finally, a follow-up study from Finland that shows that pwMS with a lit Christmas tree in their heads do worse in the longterm, i.e. pwMS with more microglial activation as determined by PK11195 staining had more disease progression that was independent of relapses. The implication is that PK11195 is a good marker of smouldering MS and if we switch off this marker we will improve long-term outcomes.
In an email exchange with colleagues, I challenged this thinking. Is the PK11195 signal, or hot microglial response, the chicken or the egg? The microglial response may not be causal but simply associated with a worse outcome in MS. Just maybe the microglia are responding to what is causing MS and are not the primary drivers of the MS pathology. Therefore if you switch off the microglial response you may not improve MS outcomes but actually make them worse.
I even provided some early odds of this happening. I predicted that a drug that switches off the microglial response had only about a 20% chance of improving MS outcomes. I balanced this by saying that I thought that a microglial inhibitor had about a 60% chance of actually making MS worse. I was then challenged that these odds were simply a guess; like an unskilled poker player. I disagree. Firstly, poker is a game of skill and the most skilled poker players make a relatively decent living from their skills. Secondly, there is a scientific process behind making accurate predictions (see post-script), which I try to apply. Finally, we need to apply science to the microglial prediction at hand.
The Science: In the smouldering or slowly expanding MS lesion the hot microglia are lined up like soldiers fighting an enemy at the edge of the lesion. They remind me of a Greek phalanx.
A Military Phalanx
These microglia are not malignant cells, which makes me think they are simply doing their job. Now what if these microglia are responding to something in the surrounding tissue, for example, a slow viral infection? Switching them off may actually make the slow viral infection worse. In addition, microglia have very important function clearing up debris in the nervous system and maintaining the health of synapses and neurons in general.
Figure 1 (from Frischer et al., Ann Neurol 2015): (A, B) Early active plaques (EAL) were defined by macrophages immunoreactive for minor myelin proteins (MOG positive macrophages right insert in A) as well as major myelin proteins (PLP positive macrophages left insert in A). (C, D) Smoldering plaques (also called slowly expanding plaques) typically showed a rather inactive centre with no or few macrophages, surrounded by a rim of activated microglia. Only few of these macrophages or microglia cells contained early myelin degradation products. Inserts depict plaque edge. (E, F) Inactive plaques revealed a sharp plaque border without or only few macrophages or activated microglia (insert). (G, H) Completely remyelinated plaques typically containing few macrophages without early myelin degradation products were classified as shadow plaques. Shadow plaques presented with a sharp plaque edge and were associated with fibrillary gliosis.
More Science: Importantly, defects in the signalling pathway of CSF-1 (colony-stimulating factor 1), which is also known as macrophage colony-stimulating factor (M-CSF), cause progressive dementia and disease of the cerebral white matter called a leukoencephalopathy. CSF-1 is a microglial stimulant. This is a warning that inhibiting microglia indiscriminately is unlikely to be good for the brain and particularly a damaged MS brain. This is why I have given greater odds to a microglial inhibitor making MS worse than making MS better.
I am also aware that there are different types of microglia, different types of microglial responses and hence we may have to be more selective in how we target microglia in MS. Despite this, I think we as an MS community need to take a step back and challenge the current dogma that the microglial response in MS is necessarily bad. If we don’t we may be unpleasantly surprised and disappointed with the outcome of clinical trials targeting hot microglia and smouldering MS.
P.S. If you are interested in reading about the science of prediction I would recommend ‘Superforecasting: The Art and Science of Prediction’ by Dan Gardner and Philip Tetlock; a remarkable book that provides important insights and lessons to avoid unconscious biases and it teaches you a little poker as well 😉
Sucksdorff et al. Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis. Brain, awaa275, https://doi.org/10.1093/brain/awaa275 Published: 02 October 2020.
Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.
This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.
The reason why so many people are coming down with COVID-19 and the second-surge is truly surging is the observation that three-quarters of people who are actively shedding SARS-CoV-2, i.e. have positive tests, are asymptomatic at the time of testing (see the latest study below).
In summary, having symptoms suggestive of COVID-19 is a very poor marker of whether or not you are infected with the virus and shedding. Therefore the only way to reduce the spread of the virus in the community is to assume that everyone who you come in contact with is infected and shedding. Therefore social distancing, masks, handwashing, avoiding high-risk environments, etc. becomes critical in slowing down the spread of the virus.
Saying that there are many scientists and probably most politicians who are actively supporting the spread of the virus in low-risk communities, for example, University students, as an attempt to increase herd immunity. The danger of the latter is that it is very difficult to contain the virus in these low-risk communities and as a result, it is already spreading into high-risk groups which is why we are beginning to see an increase in hospital admissions and deaths from COVID-19.
It is clear that we have many months still to run with this pandemic and sadly many more lives will be lost. On a positive note, the observation that many people in the general population and probably in the MS population as well, seem to have pre-existing cross-reactive immunity to the virus and hence seem to be resistant to infection. This means that we may get herd immunity at a population level much quicker than we expected.
The latter may explain why the second-surge is not nearly as bad in London compared to some of our Northern cities, for example, Liverpool, Manchester and Newcastle. Many more people were infected in London in the first-wave, i.e. we have more herd immunity, which is acting as a firebreak and slowing down the spread in London.
To paraphrase Robert Frost, we have many miles to go before we sleep. There is little doubt that 2020 is going to be a long hard year. We have just had to cancel our travel plans for Christmas; a small price to pay for being healthy and alive. Please try and stay positive things will get better; time is a great healer.
Stopping by Woods on a Snowy Evening BY ROBERT FROST
Whose woods these are I think I know. His house is in the village though; He will not see me stopping here To watch his woods fill up with snow.
My little horse must think it queer To stop without a farmhouse near Between the woods and frozen lake The darkest evening of the year.
He gives his harness bells a shake To ask if there is some mistake. The only other sound’s the sweep Of easy wind and downy flake.
The woods are lovely, dark and deep, But I have promises to keep, And miles to go before I sleep, And miles to go before I sleep.
Background: To reduce transmission of SARS-CoV-2, it is important to identify those who are infectious. However, little is known about what proportion of infectious people are asymptomatic and potential “silent” transmitters. We evaluated the value of COVID-19 symptoms as a marker for SARS-CoV-2 infection from a representative English survey.
Methods: We used data from the Office for National Statistics Coronavirus (COVID-19) Infection Survey pilot study. We estimated sensitivity, specificity, the proportion of asymptomatic cases (1 – sensitivity), positive predictive value (PPV) and negative predictive value (NPV) of COVID-19 symptoms as a marker of infection using results of the SARS-CoV-2 test as the “gold standard”.
Results: In total, there were 36,061 individuals with a SARS-CoV-2 test between 26 April and 27 June 2020. Of these, 625 (1.7%) reported symptoms on the day of the test. There were 115 (0.32%) with a positive SARS-CoV-2 test result. Of the 115, there were 27 (23.5%) who were symptomatic and 88 (76.5%) who were asymptomatic on the day of the test. Focusing on those with specific symptoms (cough, and/or fever, and/or loss of taste/smell), there were 158 (0.43%) with such symptoms on the day of the test. Of the 115 with a positive SARS-CoV-2, there were 16 (13.9%) reporting symptoms. In contrast, 99 (86.1%) did not report specific symptoms on the day of the test. The PPV for all symptoms was 4.3% and for the specific symptoms 10.1%. The specificity and NPV of symptoms were above 98%.
Conclusion: COVID-19 symptoms are poor markers of SARS-CoV-2. Thus, 76.5% of this random sample who tested positive reported no symptoms, and 86.1% reported none of those specific to COVID-19. A more widespread testing programme is necessary to capture “silent” transmission and potentially prevent and reduce future outbreaks.
Since my rather neutral “#DIETSPEAK: IS THERE AN IDEAL MS DIET?” post last week, in which I refuse to support any particular MS diet I have had a torrent of social media abuse about my position. Intriguingly, many people out there have bought into the falsehood that saturated fats are bad for you and some commentators even believe that saturated fats cause MS. The evidence is clearly to the contrary for the former and for the latter the evidence is just not there to draw any causal inferences. In fact, as saturated fat consumption has gone down the incidence and prevalence of MS has increased. This alone indicates that saturated fat consumption cannot be the cause of MS.
John Maynard Keynes, the famous British economist responsible for ‘Keynesian economics’, is often quoted as saying: “When the facts change, I change my mind. What do you do, sir?”.
The claim that saturated fat is bad for health was promoted by the now-discredited physiologist and nutritionist Ancel Keys. His theory was based on his ‘Seven Countries Study’, which has now been discredited with several commentators suggesting that some of the data was made up. There is evidence that of 22 countries that he had data for, he cherry-picked 7 countries so the data would fit and prove his hypothesis. Despite this, he and his collaborators managed to change the dietary guidelines of the world, recommending a low-fat diet to counteract the cardiovascular disease epidemic. Tragically, the rest is history.
The low-fat diet, in particular the low-saturated fat diet, resulted in a caloric switch to carbohydrates, which has seen obesity rates soar and contrary to what was expected cardiovascular disease rates have increased. It is now clear that Ancel Keys was heavily conflicted and was supported by the food industry. Yes, the food industry managed to influence a change in dietary guidelines that have killed tens of millions of people prematurely. I predict that when the dust settles on this issue the food industry will be judged to have behaved much worse than the tobacco industry.
The good news is that the facts have changed and several recent meta-analyses have been unable to find any evidence that saturated fats are bad for you (please see review below). The studies showing saturated fats are associated with poor health outcomes are confounded by other factors for example the consumption of processed carbohydrates.
To address the point that saturated fats cause MS you need to go back to causation theory and apply epidemiological principles. I have addressed this topic several times in the past on this blog, mainly in relation to EBV as a potential cause of MS. To prove or disprove causation you have to satisfy as many of the following nine criteria as possible.
1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS 2. STRENGTH OF ASSOCIATION 3. TEMPORAL SEQUENCE 4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP) 5. SPECIFICITY 6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE 7. BIOLOGICAL PLAUSIBILITY 8. REASONING BY ANALOGY 9. EXPERIMENTAL EVIDENCE
When you apply these nine criteria to saturated fat consumption none of them is fulfilled. I, therefore, can conclude that saturated fat consumption is not the cause of MS. On other words, the data disproves the hypothesis.
Another perspective that you can use to tackle this problem is an evolutionary medicine perspective and to look at how our ancestors evolved and what diets they ate. It is clear that our ancestor’s diets were high in saturated fats and as the history of MS suggests it is a relatively new disease it cannot be caused by saturated fat. In fact, if you want to finger a dietary factor you would point at sugar and processed carbohydrates rather than saturated fats.
The recommendation to limit dietary saturated fatty acid (SFA) intake has persisted despite mounting evidence to the contrary. Most recent meta-analyses of randomized trials and observational studies found no beneficial effects of reducing SFA intake on cardiovascular disease (CVD) and total mortality, and instead found protective effects against stroke. Although SFAs increase low-density lipoprotein (LDL) cholesterol, in most individuals, this is not due to increasing levels of small, dense LDL particles, but rather larger LDL particles, which are much less strongly related to CVD risk. It is also apparent that the health effects of foods cannot be predicted by their content in any nutrient group without considering the overall macronutrient distribution. Whole-fat dairy, unprocessed meat, and dark chocolate are SFA-rich foods with a complex matrix that are not associated with increased risk of CVD. The totality of available evidence does not support further limiting the intake of such foods.
I had to have a detailed discussion with a patient this week about starting ocrelizumab during the COVID-19 pandemic. This patient was concerned about (1) the data showing an increased risk of COVID-19 in anti-CD20 treated patients, (2) an increasing number of cases not seroconverting when being infected with the coronavirus and (3) she will not be able to have a coronavirus vaccine when one emerges.
All of these three concerns are not black-and-white, but very grey, and need explaining.
1. The increased risk of COVID-19 and severe COVID-19 on anti-CD20 therapy
This finding has been reported by the Italian register, the Iranians, the Swedes and the MSIF’s Data Alliance initiative. There is also a similar signal in the US data and French data. However, despite the increased risk of COVID-19 it is not associated with increased mortality. In the Italian data there is a weak signal that the longer you have been on an anti-CD20 therapy, particularly more than 3 years, the greater the risk of COVID-19.
One issue that is not adequately addressed is reporting bias, i.e. more severe COVID-19 cases get reported and the less severe ones don’t because they are not registered as having COVID-19. Reporting bias is likely to affect DMTs that require patients to attend hospitals, i.e. treatments that bring them into contact with HCPs and hence they have a chance to report symptoms, and those DMTs that are the most widely prescribed. It is clear that both of these factors play a role in anti-CD20 therapies. One clue in support of this is the fact that there is a similar signal of a greater COVID-19 and severe COVID-19 signal emerging with natalizumab, i.e. another DMT that requires frequent hospital visits (reporting bias) but is less prescribed than anti-CD20 so the signal is not quite significant yet.
One way to address this issue is to study non-biased trial populations, which has to be the data gold-standard. Roche presented 51 COVID-19 cases in over 4,000 ocrelizumab exposed trial patients (1.3%) (see presentation below). There was clearly no link between COVID-19 and treatment duration (slide 6). Three patients out of 51 patients died (5.9%). The numbers are too small to make a call on whether this represents a higher mortality than the background rate. Another important factor is that COVID-19 was not linked to hypogammaglobulinaemia. This ‘gold-standard’ data challenges some of the dogma that has emerged around CD20 therapies and COVID-19 and alters my interpretation of the Italian data.
(2) An increasing number of ocrelizumab-treated cases not seroconverting when being infected with the coronavirus
Although there are several cases of SARS-CoV-2 positive COVID-19 cases on ocrelizumab who have been reported that have not seroconverted (detectable antibodies) there are many more normal people who have have COVID-19 who haven’t seroconverted as well. Whether this observation is assay dependent, i.e. insensitive assays that don’t detect low level antibody, or true biology needs further investigation. The fact that these people, ocrelizumab-treated or normal people, recover from COVID-19 is telling us that an antibody response is not necessary to clear the virus and for recovery from COVID-19. It is likely these patients have very good cellular immune responses that will protect them from reinfection in the future.
These observations have implications for vaccine responses and hence we may have had the wool pulled over our eyes focusing on the easier to measure antibody responses. I suspect, as do many others, that it is not humoral, but cellular, immunity that will be important for protective immunity against SARS-CoV-2. I am not saying antibody responses won’t be important, but it is likely the dominant protection will come from cellular immunity.
(3) Not being able to have a coronavirus vaccine when one emerges
This is clearly not correct. Patients on ocrelizumab will be able to have DNA, RNA and component coronavirus vaccines. The only vaccines they may not be able to have are live attenuated vaccines and potentially vaccines using a live viral vector to deliver the immunogen. The question is whether or not ocrelizumab-treated patients will be able to mount an adequate protective immune response to these vaccines is a moot point, which is why I have been urging Roche to plan and set-up registry studies to see if ocrelizumab-treated patients develop adequate immune responses to these vaccines. It is important that these studies are well designed and include both antibody or humoral and cellular components.
Another thing to remember is that no vaccine is likely to be 100% effective. Even if the vaccine is only 60% to 70% effective it will be sufficient to create herd immunity and stop the spread of coronavirus. Vaccines are about population health and not necessarily about individual health, which is why regulators are fixated on safety.
I also told this patient that there are many other factors at play. For one the death rate or mortality from COVID-19 is falling. This is happening for several reasons. Firstly, we now have approved treatments for COVID-19 and the circulating strains are likely less virulent than the initial strains. Based on simple evolutionary principles the more benign strains are out competing the virulent strains. Another factor that I have commented on before is that we may be nearing herd immunity in some areas of the country, for example in London. This is based on the observation that many people have cross-reactive cellular and humoral immunity, presumably from other coronaviruses, that are protecting them from getting COVID-19. Therefore the risks of getting COVID-19 are falling. Add to this sensible personal hygiene and social distancing and the risks remain low. The second surge is really happening in areas of the country with low herd immunity and amongst care-free populations who are not being adherent to the government’s guidelines; for example, University students.
The bottom line is that if you are low risk of getting COVID-19 and you double that risk the risk remains low. I would also only cross the vaccination bridge when it arises. Trying to preempt when and what vaccine will emerge first is really a guessing game. What is not a guess is that this patient has active MS, with a relatively poor prognostic profile (spinal cord disease) and needs treatment. She does not have highly-active MS therefore the only high-efficacy DMT available to her first-line on the NHS is ocrelizumab. She could select a platform therapy, which has also been offered to her, and to then see how she does, but as she is very well informed and understands the concept of ‘flipping the pyramid’ and that ‘time is brain’ doesn’t want to take a chance on a lower efficacy DMT. The outcome from our discussion is that she has decided to go ahead with ocrelizumab after she has had her pneumococcal and seasonal influenza vaccines.
As you can see the COVID-19 anti-CD20 data is quite complex with a lot of nuances, which makes it difficult to communicate to patients. But if you take time to explain it to patients, not only do you allay their fears, but you end-up with a well informed patient who knows what they are signing up for.
Wear a mask, don’t travel if you feel unwell, and limit carry-on baggage. Keep distance from others wherever possible; report to staff if someone is clearly unwell. If there is an overhead air nozzle, adjust it to point straight at your head and keep it on full. Stay seated if possible, and follow crew instructions. Wash or sanitize hands frequently and avoid touching your face.
I am always being asked about what is the ideal diet for someone with MS. The simple answer is there is no ideal MS diet. What you eat is about personal choices and has to be compatible with your cultural background and your social circumstances. There is so much more to eating food than what you actually eat. I have written a piece on Medium called ‘Diet as a Philosophy’, which provides some context to this statement.
In short, my diet philosophy recommends that anyone with MS should eat socially, i.e try not to eat alone and make your meals a social occasion. To eat real food, i.e. avoid processed and ultra-processed food. To try and eat locally-produced food that is seasonal; I am aware that this easier said than done, particularly for economic reasons. Finally, it would help if you eat mindfully, in other words, think about what you are eating, why you are eating it and what impact it is having on the world.
The question about diet being an actual treatment for MS is a different question. Here I would support a ketogenic diet and intermittent fasting and I have written extensively on the science behind these diets and why I think these two diets may be disease-modifying for people with MS. At present, the evidence base for these diets working in MS remains weak and exploratory, but the good news is there are ongoing studies looking at these diets in pwMS. Despite this, the basic science on these diets from animal studies is so compelling that if I had MS I would be ketotic and fasting intermittently (5:2 or 16:8 diet).
Please note ketogenic diets and intermittent fasting are not incongruent with my diet philosophy.
I also don’t support one diet over another. The reason I don’t support a specific diet is simple; the evidence-base for anyone diet being better than another is weak and a lot of diets are not based on science. Yes, science. As scientists, we should be following the science. For example, the study below is interesting in that they flipped the question and looked at the metabolic responses to food and its influence on cardiometabolic disease. You may say what has this got to do with the central nervous system, but I believe in the aphorism ‘that what is good for the heart is good for the brain’.
What this study showed is that person-specific factors, such as gut microbiome, had a greater influence than the diet in relation to metabolism and that genetic variation only had a modest impact on the metabolic responses to food linked to cardiometabolic disease. The only metabolic output that was influenced by diet was blood glucose or sugar levels, which is dictated by carbohydrate intake and the type or quality of carbohydrates we consume.
In summary, apart from carbohydrate metabolism, it is horses for courses and personal factors (gut microbiome and genetics) which dominate how your diet impacts on your metabolism.
The good news is you can manipulate your carbohydrate metabolism; it is relatively simple. Both ketogenic diets and intermittent fasting reduce your sugar intake and blunt or flatten your blood glucose levels and the subsequent downstream insulin response, which is clearly the bad guy in driving cardiovascular risk.
Based on the above I hope you have enough information at hand for you to make an informed decision about your diet without having to ask me next time 😉
Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.
“Did you hear that Professor Giovannoni dropped dead after attempting to complete the virtual New York Marathon trying to raise money for a multiple sclerosis research project?”
“Prog G finally throws in the towel and arranges to see an orthopaedic surgeon about his failing right hip. His attempt to complete a marathon to raise money for MS research was one run too many.”
“Prof G’s kidneys finally pack-in after excessive use of non-steroidal anti-inflammatories in his futile attempt to complete a marathon and raise money for MS research.”
These are some of the comments I am getting back from my colleagues, who are concerned about my potentially foolish attempt to run a marathon. Please don’t be concerned about me I wouldn’t be taking on this challenge if I didn’t think I could complete it. As proof that I am getting close, I managed to complete a 20-mile run on Sunday; all I need to do is extend that by 6.2 miles in a few weeks time.
The reason for taking on this challenge is to raise money to complete a very time-sensitive research project that is very relevant for people with MS. We have developed an ultrasensitive GloBody assay to detect antibodies against coronavirus that can be run on blood spots that are collected at home and posted to our laboratory.
Our preliminary data indicates that our assay is more sensitive than the two commercial assays (Roche Diagnostics and Abbott laboratories) that are currently available via the NHS. The GloBody assay is detecting antibodies in people who are ‘antibody-negative’ on the commercial assays. This finding may be very important going forward and to help pwMS come to terms with their risk of getting COVID-19 and potentially help to detect antibody responses to any future coronavirus vaccine.
To borrow a metaphor we have an oven-ready study that needs to be done in the next month or two. We lost our funding when the charity that was funding this project realised they had a funding shortfall due to COVID-19. Prior to hearing this bad news, we had already been given the green-light by our research office and ethics committee to proceed with the study; this is why the study is oven-ready.
As our assay is now running and is closed to being validated would you be interested in getting yourself tested for a small amount? The result will then be sent to you and we would use the money collected from providing a service to pay for the service and to support the costs of the laboratory component of the MS seroprevalence study. Your thoughts, please?
If you haven’t done so already we would appreciate any microdonations so that we can start the study as soon as possible.
At Barts-MS we spend a lot of time teaching people about MS. It is not only important to generate new information (ideas, testable hypotheses and research), but also to disseminate knowledge (teaching). However, with the COVID-19 pandemic and the resultant social distancing, almost all teaching has gone online and that does not make for very engaging and interesting. Most of us are webinar-ed or Zoomed-out. I wrote a piece on Medium that I titled Zoomed-Out addressing this exact point.
Can we make teaching the next generation of potential MSologists more interesting? I think we can. The following is an example of case-based teaching we are trying out at our first MS Academy Basecamp in a few week’s time. Let’s hope it works and it encourages more junior doctors, nurses, therapists and other allied HCPs to plan a career in multiple sclerosis.
Scenario 1: You are called to see a case with double-vision due to an internuclear ophthalmoplegia (INO) in casualty and an abnormal MRI suggestive of MS.
How are you going to confirm the location of the lesion?
How do you diagnose MS?
What MS mimics do you need to exclude?
How do you profile the patient’s prognosis at baseline?
Is the patient eligible for DMTs?
How do you de-risk the DMTs?
Scenario 2: Your consultant asks you to see a young woman of 26 with her partner. She is coming for a scheduled follow-up appointment after a diagnostic work-up for MS. The consultant tells you she has MS.
How are you going to confirm the diagnosis of MS before seeing her?
How are you going to tell her the diagnosis?
How are you going to counsel her about her future disease course?
She asks if she can have a family. What are you going to tell her?
What is active MS, highly active MS and rapidly evolving severe MS?
What is the difference between maintenance-escalation and immune reconstitution therapies? How are you to explain the difference to them between these two treatment options?
Scenario 3: You are asked to do an MS follow-up clinic for your consultant neurologist?
How are you going to prepare for the clinic?
What information are you going to record in the medical notes?
How are you going to investigate and manage an MS-bladder?
How do you manage MS-related fatigue?
Should you routinely screen for and manage MS-related cognitive impairment?
Scenario 4: You attend your departments, MS Research Day, for patients with MS and are asked to prepare a teaching session for the attendees.
How do you explain the cause of MS to the attendees?
What are the latest treatments available for progressive MS?
A woman attendee asks you about the risks of her children getting MS. What do you tell her?
An attendee asks about stem cell therapy; how are you going to counsel her?
What would you want us to teach the next generation of MSologists and how?
