Cells from the maternal circulation (your mother) cross the placenta into the foetal circulation (you) and set-up shop in your brain and body. This phenomenon is called maternal microchimerism and is very common and may be more common in people with autoimmune disease. The implications, or hypothesis, is that cellular autoimmunity may be transmitted in this way. Could this explain why MS occurs at more than twice the familial rate in children of mothers, when compared to children of fathers, with MS?
These maternal cells can be found in men by looking for female cells, i.e those that contain more than two X chromosomes.
The small study below does not show a difference between finding these cells in the brains of men with and without MS. Maybe the investigators’ should look in the immune compartment to see if maternal B- and/or T-cells could be found? Just maybe autoimmunity, or specifically MS, can be transferred from mother to child via the adoptive transfer of autoreactive B- and T-cells through the placenta? If this was the case then children born to pwMS on natalizumab may be more at risk? Why? Natalizumab is the one DMT that does not deplete the so-called peripheral autoreactive cells; in fact, natalizumab keeps them circulating in the periphery in high numbers hence making them more likely to cross the placenta in the foetal circulation.
The only way to find this out if children of natalizumab-treated pwMS are increased risk of getting MS is to start and run a pregnancy registry to collect data longterm and to follow-up all the children born to pwMS to see what happens to them in the future.
The good news is that Dr Ruth in our group will be doing just that a and will be launching a national UK pregnancy register with the aim of also collecting the outcomes of the children.
Another more sinister way to answer this question is via state surveillance, or Big Brother, which happens in Nordic countries. Sweden has probably the most mature system of state-sponsored surveillance and they could link all their databases to answer this question in the near future.
Maternal microchimeric cells (MMC) pass across the placenta from a mother to her baby during pregnancy. MMC have been identified in healthy adults, but have been reported to be more frequent and at a higher concentration in individuals with autoimmune diseases. MMC in brain tissue from individuals with autoimmune neurological disease has never previously been explored. The present study aims to identify and quantify MMC in adult human brain from control and multiple sclerosis (MS) affected individuals using fluorescent in situ hybridization (FISH) with a probe for the X and Y chromosomes. Post mortem brain tissue from 6 male MS cases and 6 male control cases were examined. Female cells presumed to be MMC were identified in 5/6 MS cases and 6/6 control cases. Cell specific labelling identified female cells of neuronal and immune phenotype in both control and active MS lesion tissue. This study shows that female cells presumed to be MMC are a common phenomenon in the adult human brain where they appear to have embedded into brain tissue with the ability to express tissue-specific markers.
The argument about whether or not MS is primarily a T-cell or B-cell disease is academic. Almost all the data suggests that both cell types are involved. Clinical trial data also suggests MS outcomes when it comes to end-organ damage (brain volume loss) is superior for therapies that target both T and B cells, i.e. alemtuzumab and HSCT over say mainly B-cell therapies (rituximab, ocrelizumab, ofatumumab and cladribine). I have posted on the latter topic in the past, i.e. see ‘Beyond NEDA’.
Another big clue is worsening MS and new-onset MS after the treatment of cancer with the relatively new class of treatments called immune checkpoint inhibitors (ICI). These drugs target cell surface receptors that inhibit T-cell activation. Remove the inhibition and you lower the threshold for T-cell activation. About 50% of patients treated with ICI develop immune-mediated complications including new-onset MS.
The study below identifies 14 cases of MS after ICI, which I suspect is just the tip of the iceberg. The type of MS induced by ICI appears to be much more aggressive in onset and disease course. Why? I suspect because the activated T-cells are not being regulated as a result of ICI treatment.
I am aware that some people argue that these cases don’t represent true MS, but a different disease. I don’t agree. Why? There is an increasing number of people with established MS who develop malignancies requiring treatment with ICI. In many of these cases, ICI triggers major relapses and rebound disease activity. The sceptics can’t really argue that these patients don’t have MS.
The use of ICI in patients with established MS is creating a treatment dilemma. They clearly need the ICI to treat their cancer, but how do you manage their MS during the high-risk period when they are on ICI?
I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The potential downside of this strategy is that if she had occult secondaries in her CNS and gut, areas of the body that natalizumab reduced lymphocyte trafficking, natalizumab will prevent her activated T-cells finding and clearing cancer cells in these organs. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking.
The last update I had about this patient was that she was doing well from the MS perspective (natalizumab is a very effective DMT), but she was not doing that well in relation to her bowel cancer. She, unfortunately, had liver metastases that had not responded as hoped to the ICI.
I am also sure that natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab? I have informed Biogen about this possibility.
So in conclusion, don’t let anyone try and convince you that MS is only a B-cell disease. It is a T-cell and B-cell disease and we are really lulling ourselves into a false sense of security by thinking anti-B-cell monotherapy is sufficient to treat MS. The anti-B-cell therapies may appear very effective and safer in the short term, but as a class, their impact on brain volume loss (end-organ damage) is just not good enough for me (see NEDADI post). This is why we need to think about using anti-B-cell therapies differently, i.e. as part of an induction-maintenance strategy or in combination with other therapies that target other disease processes.
Introduction: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.
Methods: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.
Results: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors.
Conclusions: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.
As you know high-dose simvastatin 80-mg per day is being tested in a phase 3 trial in the UK (MS-STAT2). I have referred several patients to participate in this study. Despite this, there has always been a worry about this treatment strategy because statins have been associated with changes in cognition, which is why I have always said that if I needed a statin I would take one that was non-CNS penetrant, for example, pravastatin.
The publication below is reassuring in that it shows that statin therapy in a population of elderly Australians was not associated with any greater decline in memory or cognition over 6 years compared to non-statin users. In fact, statin usage actually attenuated the decline in specific memory test performance in participants with heart disease and the genetic dementia risk factor apolipoprotein Eε4.
You may ask what has this got to do with MS? I think a lot. One of the theories of delayed or late worsening in MS is related to early ageing mechanisms. This is why it will become important in the future to tackle ageing as a potential add-on treatment for MS (please see my previous blog post, ageing, on this topic).
Background: There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline.
Objectives: This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined.
Methods: Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors.
Results: Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users.
Conclusions: In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.
Just back from the NMSS ‘Pathways to Cures’ meeting in Washington DC during which we pledged to STOP, RESTORE and END multiple sclerosis.
The END refers to prevention. We discussed at the meeting modifiable risk factors that could be tackled to reduce the incidence (new cases) of MS and one risk factor childhood and adolescent obesity. One theory has been that obesity affects MS risk by interacting with vitamin D (vD); either by lowering levels due to the breakdown of vD in fat or secondary to systemic inflammation associated with obesity.
In this genomics study below it is clear that obesity itself increases your risk of MS and is independent of vD levels.
So how do we tackle obesity and the obesity epidemic? It is clear that obesity is caused by sugar and the change in the dietary guidelines that occurred in the 1970s and 1980s when governments launched a war on fats and started to promote a low-fat diet as being ‘heart-healthy’. We now know that the low-fat diet was wrong and that what was driving heart and vascular disease was processed carbohydrates, in particular, sugar consumption, and not saturated fats. Fortunately, the world is now beginning to acknowledge that saturated fats are healthy and that processed and ultra-processed foods, which are largely made up of carbohydrates and polyunsaturated fats are unhealthy culprits and are what is causing the obesity epidemic.
This graph shows you the strong association between per capita sugar consumption and obesity. It is extraordinary that politicians are not doing more to tackle global sugar consumption.
Another factor driving obesity is our sedentary lifestyle and reduced exercise.
To tackle obesity we need governments to declare ware on sugar and the food industry and to put in place national policies to tackle our sedentary lifestyle. This is easier said than done. Politicians are not as powerful as they used to be; most of them rely on lobby money to get elected and once elected they represent the vested interest groups that got them elected. Sadly this often includes sugar money.
The sugar industry is heavily subsidised, which keeps the price of sugar artificially low. Sugar subsidies interfere with the global market and have resulted in a sugar glut. This is one of the reasons why junk food is so cheap and real-food is so expensive.
Obesity is not only a risk factor for causing MS it also affects people with established MS. Obesogenic diets cause a metabolic shitstorm that impacts on MS indirectly. Obesity causes metabolic syndrome (hypertension, insulin resistance, glucose intolerance, diabetes and dyslipidaemia) and a systemic inflammatory syndrome that worsens MS. Therefore, there is a good reason why, if you are obese you should consider doing something about it.
I recommend you read “Why we get fat and what to do about it”, by Gary Taubes or you can watch one of his lectures on YouTube. Understanding the metabolic issues that underlie obesity will allow you to understand what to do about it.
Then there is the responsibility you have to your siblings, children and relatives. If you have MS your direct family are at increased risk of getting MS and you should get them to modify their risk factors, i.e. make sure they stay slim, or if they are obese they need to lose weight, get them to exercise and to start taking vD supplements. Tell them about the link between smoking and MS; they should either stop smoking or get them to pledge not to start smoking in the future.
MS prevention is about education, education, education and education begins in the home. We estimate that ~15-20% of new cases of MS could be prevented by preventing childhood obesity and smoking. This is why we need to declare war on sugar and smoking as part of our END MS campaign. Do you agree?
Objective: To update the causal estimates for the effects of adult body mass index (BMI), childhood BMI, and vitamin D status on multiple sclerosis (MS) risk.
Methods: We used 2-sample Mendelian randomization to determine causal estimates. Summary statistics for SNP associations with traits of interest were obtained from the relevant consortia. Primary analyses consisted of random-effects inverse-variance-weighted meta-analysis, followed by secondary sensitivity analyses.
Results: Genetically determined increased childhood BMI (ORMS 1.24, 95% CI 1.05-1.45, p = 0.011) and adult BMI (ORMS 1.14, 95% CI 1.01-1.30, p = 0.042) were associated with increased MS risk. The effect of genetically determined adult BMI on MS risk lessened after exclusion of 16 variants associated with childhood BMI (ORMS 1.11, 95% CI 0.97-1.28, p = 0.121). Correcting for effects of serum vitamin D in a multivariate analysis did not alter the direction or significance of these estimates. Each genetically determined unit increase in the natural-log-transformed vitamin D level was associated with a 43% decrease in the odds of MS (OR 0.57, 95% CI 0.41-0.81, p = 0.001).
Conclusions: We provide novel evidence that BMI before the age of 10 is an independent causal risk factor for MS and strengthen evidence for the causal role of vitamin D in the pathogenesis of MS.
CoI: this work was done by our Preventive Neurology Unit
I am at the NMSS’ Pathways to Cures think tank where exercise is a major theme in terms of restoring lost function. A lot of discussions have been about how we motivate and get pwMS to exercise. Some suggested using motivational interviewing techniques and behavioural psychology to motivate and nudge pwMS to exercise. The elephant in the room is that some people simply don’t like exercise. Are you one of them?
Not many people know that your participation in exercise is largely driven by genetics. It is clear from the twin study below that genetic variation is important in relation to individual behaviour when it comes to exercise. Heritability of exercise participation in males and females was similar and ranged from 48% to 71%; this may explain why you love or hate exercise. At the moment we don’t know what this heritability in relation to exercise is due to. As the investigators’ point out in their conclusion that it may ‘involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality’.
One of the other aspects of exercise that was discussed was its biology, in other words how does exercise work. If we can work this out we could potentially explore drugs to mimic exercise. The problem with this reductionist approach is that exercise is very complex and hence likely to be very dirty. For example, exercise can be aerobic (oxygen) or anaerobic (lack of oxygen) and can involve resistance. Then there is intensity and duration. Is HIIT (high-intensity interval training) better than aerobic exercise? What about movement? Does exercise require you to move; is a treadmill run equivalent to an outdoor run? How important is exercise frequency; is daily better than 3-4 times a week versus the weekend warrior’s activity on Saturday and Sunday?
The bottom line is that we know exercise works for some pwMS. However, as always we have many unanswered questions. One that Robert Motl, the doyen of exercise research in MS, raised with me in one of the coffee breaks is that we don’t know if exercise may have negative effects in certain groups of pwMS. For example, during a relapse or in more advanced MS. Is flogging a dying horse, i.e. making people with walking impairment exercise their lower limbs, potentially bad for them in that overuse of the pathway through exercise is speeding up its degeneration? We need to be careful in not making pwMS feel guilty about not exercising when we don’t have a mature evidence-base to recommend it or not.
Background: A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used.
Methodology: Self-reported data on leisure time exercise behavior from Australia, Denmark, Finland, Norway, The Netherlands, Sweden and United Kingdom were used to create a comparable index of exercise participation in each country (60 minutes weekly at a minimum intensity of four metabolic equivalents).
Principal findings: Modest geographical variation in exercise participation was revealed in 85,198 subjects, aged 19-40 years. Modeling of monozygotic and dizygotic twin resemblance showed that genetic effects play an important role in explaining individual differences in exercise participation in each country. Shared environmental effects played no role except for Norwegian males. Heritability of exercise participation in males and females was similar and ranged from 48% to 71% (excluding Norwegian males).
Conclusions: Genetic variation is important in individual exercise behavior and may involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality. This collaborative study suggests that attempts to find genes influencing exercise participation can pool exercise data across multiple countries and different instruments.
By definition an immune reconstitution therapy (IRT) for MS is given as a short course, i.e. as a one-off treatment in the case of HSCT or intermittently as in the case of alemtuzumab or cladribine. IRTs are not given continuously and additional courses of the therapy are only given if there is a recurrence of inflammatory activity. IRTs have the ability to induce long-term remission and in some cases potentially a cure.
Immune reconstitution simply refers to the restoring of a competent immune system after a cycle, or cycles, of depletion. Immune competence in the context of an IRT refers to the ability of the immune system to respond to infection, in particular, opportunistic infections, mount an antibody response to vaccines and to perform normal systemic tumour surveillance.
Immune reconstitution has been best shown in the context of hematopoietic stem cell transplantation (HSCT). In the case of an IRT, for example, alemtuzumab or cladribine, which are given as short courses breakthrough disease activity can be used as an indicator to retreat rather than to necessarily switch therapy. Therefore, there a rebaselining MRI should be delayed until after the final initial course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered
A major concern in relation to the wide adoption of IRTs is the uncertainty about the duration of their effectiveness and the concern that disease activity may reoccur at a level below the clinical and MRI monitoring thresholds used in routine clinical practice. If disease activity does reoccur will it cause irreversible end-organ damage? In addition, some IRTs, in particular, alemtuzumab and HSCT, are associated with a high rate of secondary autoimmunity and rarely with early and severe rebound disease activity.
One strategy we are exploring is to use an IRT as true induction therapy and then maintain the treatment effect with safer maintenance therapies. In the case of alemtuzumab and HSCT, certain maintenance therapies could potentially prevent secondary autoimmunity and early rebound disease activity.
We are in the process of preparing a grant application to explore the safety of an induction-maintenance treatment. Would you be interested in helping by completing the following survey?
One of my colleagues, with whom I was co-authoring an editorial on smouldering MS, demanded I delete the section on premature ageing being a factor driving delayed worsening of disability in people with MS (pwMS). I refused so we had to pull the editorial. The fact that he is quite old and doesn’t like the hypothesis of brain & cognitive reserve being neuroprotective explains his position. He criticised my theory for being ageist.
I am more convinced than ever that premature ageing is a big driver of delayed worsening in MS.
A few years ago I was asked to see a patient from the North of England who has presented in her early 60’s with SPMS. She had had three spinal cord attacks in her late teens and had been in remission until her late 50’s when she noticed increasing weakness in her weaker leg with foot drop. In the intervening 40 years since her last attack, she had been relapse-free and fully functional apart from mild persistent weakness in her one leg that prevented her from running.
As part of her work-up, I repeated her MRI of the brain and spinal cord and we performed a lumbar puncture. Her CSF showed local synthesis of oligoclonal IgG bands consistent with her diagnosis of MS and her neurofilament levels were low. Her MRI showed no active or new lesions and apart from some brain and spinal cord atrophy, there was nothing extraordinary about her imaging. When I saw her in outpatients I explained to her that she did not have active MS and that her diagnosis was now non-relapsing or inactive secondary progressive MS; I now refer to this as smouldering MS.
She then volunteered that she didn’t think her worsening was due to MS, but rather ageing. I couldn’t disagree with her and explained that her previous MS attacks had probably reduced the number of axons or nerve fibres in the motor pathway to her leg, which was now ageing as the surviving nerve fibres were gradually dying off she was seeing increasing weakness in the leg. This is called the premature ageing theory of progressive MS. Is there any proof for it?
We know from other neurological diseases that ageing can cause delayed worsening. The most well know one is post-polio syndrome. This is when people who have had polio notice increasing weakness in previously affected muscles decades later as they start to age. In HIV we see age-related neurodegenerative diseases present decades earlier than one would expect. The theory being that HIV infection of the brain reduces reserve and triggers premature ageing mechanisms. Even with Alzheimer’s disease factors that are associated with reduced brain reserve result in an earlier age of onset of dementia.
I suspect MS is not and exception and that ageing, or premature ageing, is part of the disease. The problem we have is that disease duration and disability are strongly correlated with ageing. This makes it difficult to unentangle ageing from disease duration. One way to look at this is to use biomarkers of ageing. As you get older the ends of your chromosomes or telomeres get shorter. Telomere length is used as a biomarker of physiological and not chronological ageing. By using telomere length instead of your age we may be able to unpick the impact of ageing on disease worsening.
In this study below there was a clear gradient in terms of disability and telomere length. Shorter telomere length was associated with disability independent of chronological age, suggesting that biological ageing is contributing to neurological injury in MS.
The implications of this are enormous and imply that we should be targeting age-related mechanisms as a therapeutic strategy in MS. This is why I also include ageing in my holistic management of MS talks and why focusing on all of those lifestyle issues and comorbidities is so important in MS. Interestingly, I made this a major theme in my talk at ACTRIMS last year when I had to predict what was going to happen in MS in 5 years time (slides below).
So the time for biohacking (diet) and aggressive lifestyle interventions have arrived in the MS space. The million-dollar question is how to we get the MS community to buy into this as a therapeutic strategy.
Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).
Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.
Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).
Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.
This blog post explains why blood neurofilament level monitoring is not ready for primetime and may never quite replace CSF NFL monitoring in pwMS.
Although blood neurofilament light chain (NFL) levels are a promising biomarker for monitoring MS inflammatory disease activity there are issues that need to be resolved.
We and others have shown that blood levels correlate with spinal fluid levels with a correlation coefficient of ~0.7. This translates to an R-squared value of ~0.5 and tells us that only 50% of the blood levels can be explained by what is detected in the lumbar CSF. We have many examples of patients low NFL levels in the CSF with high blood levels and the converse, i.e. high CSF levels and low blood levels. I think the discrepancy in these individual cases may indicate real biology.
CSF is an admixture of fluids derived from the (1) choroid plexus, where most of the CSF is made, (2) the so-called interstitium or substance of the brain and spinal cord, (3) the meninges and (4) the blood vessels that traverse the subarachnoid or CSF space.
The typical volume of CSF in adults is 125–150 ml. This turns over approximately four times a day, i.e. the daily volume of CSF produced is approximately 600 ml. CSF production and flow are subject to diurnal variation; flow rates of ventricular fluid can vary by as much as a factor of 3.5, with minimum CSF production occurring around 1800h (12±7 ml/h) and a maximum at approximately 0200h (42±2 ml/h).
The integrity of these barriers and the flow of CSF determine the content of CSF protein. The CSF constituents are not uniform and depend on the site from which the CSF is sampled. There is a head-to-tail concentration gradient for total protein along the axis of the CNS, with the lowest concentrations in ventricular fluid and the highest concentrations in the fluid from the lumbar-sacral sac from where the CSF is sampled during a lumbar puncture.
Physical activity influences the CSF protein concentration; subjects who have been lying down for prolonged periods have higher CSF protein concentrations than active subjects. It is important to consider this when interpreting the results of CSF analyses from subjects who have been on their backs for more than 24 hours.
The lumbar subarachnoid space is a cul-de-sac. CSF obtained from lumbar punctures does not necessarily provide accurate information on inflammatory or pathological events in the brain that occur beyond the CSF outflow pathways of the fourth ventricle, i.e. events in relation to the surface of the brainstem, cranial nerves and cerebral hemispheres. In addition, the extracellular space of lesions deep in the brain may not necessarily communicate with all parts of the free CSF space.
For these reasons, spinal NFL levels are more likely to represent spinal cord disease and not brain pathology. In comparison, blood levels are more likely to integrate what is being produced from the whole CNS and the peripheral nervous system. Yes, NFL is not specific to the CNS. Therefore NFL from peripheral nerve disease will affect blood levels.
Another issue is that some pwMS mount an autoantibody response against NFL proteins. These antibodies may reduce the circulating NFL levels and hence may affect peripheral blood levels by artificially lowering NFL levels. The anti-NFL antibodies tend to occur in people with more advanced or progressive MS and hence may explain why peripheral blood NFL levels are so low in people with progressive MS.
Another factor is the circulating blood volume; the study below shows the larger your blood volume the lower your peripheral blood NFL levels will be. Height and body size will need to be taken into account when interpreting blood levels.
A critical factor that needs to be determined is how long does NFL circulate in the periphery and what is the mechanism of its clearance and breakdown. Without knowing the latter we will continue to have difficulty interpreting what peripheral blood NFL levels mean.
Could peripheral blood levels increase as part of normal biology? I was recently told at a meeting that peripheral blood NFL levels increase as a result of running a marathon (unpublished data). Why? Could this be due to microtrauma to peripheral nerves or the neuromuscular junction? Or due to increased release from the brain? We know that minor head injuries raise NFL levels. Could the excessive bobbing around of the brain in the skull during marathon running result in a small NFL leak? Marathon running also affects peripheral fluid balance; the increased NFL levels could be related to an alteration in blood volume or the breakdown and clearance of the NFL in the periphery.
So switching from CSF to peripheral blood monitoring of NFL levels is not going to happen until we have answered some of these questions. In addition, it is unlikely that we are going to make treatment decisions based on isolated peripheral blood NFL measurements. NFL levels will be one of many factors that will need to be taken into account when making clinical decisions. Serial or longitudinal NFL measurements with an area under the curve analysis will be more valuable than a single peripheral blood measurement.
These are some of the reasons why peripheral blood NFL levels are not quite ready for primetime and clinical practice. Do you agree? This is why we at Barts-MS will continue to do lumbar punctures and CSF measurements of NFL in our patients for the foreseeable future. So if you come to see us in our clinic we may offer you a monitoring lumbar puncture.
In addition, to NFL levels there are many other biomarkers that can be measured in CSF that will provide us with information on smouldering MS disease activity. This is why Barts-MS is ideally positioned to tackle the challenge of defining and studying smouldering MS.
Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals’ Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.
You know something is happening when it gets its own review article in the New England Journal of Medicine. The review article in last weeks issue covers the science and medicine around intermittent fasting (IF) and its effects on health, ageing and disease. The article even includes a few lines on IF and its potential impact on MS.
In my ‘2020 Vision’ post yesterday under #ThinkMetabolic I glibly made the comment that ‘we are our metabolism and that MS is first and foremost a metabolic disease’. I truly believe this. Let me tell you why.
MS is a complex disease due to an interaction between the environment (macro- and micro-environment) and our genomes (DNA code, epigenome or DNA modifications, and our metagenome or microbiome). Studying each component in isolation is difficult. However, the complexity comes together in the metabolome or our metabolism, i.e. in how the body and its organ systems function on a day-to-day basis. Similarly, when we treat MS we modify our metabolism. So the way to integrate all influences on the body is to study our metabolism.
Your metabolism is a great integrator.
The question I pose is can we hack our metabolism in a way that will improve MS outcomes? I am sure we can and one way of doing this is through diet. There is mounting evidence that caloric restriction (CR), intermittent fasting (IF) and ketogenic diets (KD) does this, which is why if I had MS I would be exploring these as potential complementary treatment options.
Common to caloric restriction (CE), intermittent fasting (IF) and ketogenic diets (KD) is a metabolic switch that triggers anti-inflammatory, neuroprotective and antiageing mechanisms. The body responds to these diets by an adaptive stress response that leads to upregulation of antioxidant defences, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation. Animals maintained on intermittent-fasting regimens show improved function and resistance to a broad range of stressors.
Ketosis alters cell signalling mechanisms and increases the nuclear factor erythroid 2–related factor 2 (NRF2) transcription factors, which are part of the programmed cell survival pathway. Interestingly, this pathway is the one that dimethyl fumarate works via. In fact, many of the metabolic changes that are seen with ketosis are similar to that which are seen with DMF. Similarly, metformin the antiageing diabetes drug triggers a similar metabolic switch to ketosis. Could DMF and metformin be mimicking IF or ketosis? I say yes!
Similarly, IF and KD trigger antiageing mechanisms and potentially rejuvenate senescent cells. The recent observation that CR and metformin rejuvenate senescent oligodendrocyte precursor cells and augmented remyelination in older animals suggests that these mechanisms are inter-related.
There are several dietary trials in MS exploring IF and KD as a potential DMT. Some of the preliminary results are very interesting. I suspect interesting enough for many of you to have already adopted IF or ketosis as a treatment option. So if you are wanting to hack your metabolism you may want to read the NEJM review; figure 4 from the article gives some advice on how to incorporate IF patterns into your daily life.
Figure 4. Incorporation of Intermittent-Fasting Patterns into Health Care Practice and Lifestyles. As a component of medical school training in disease prevention, students could learn the basics of how intermittent fasting affects metabolism and how cells and organs respond adaptively to intermittent fasting, the major indications for intermittent fasting (obesity, diabetes, cardiovascular disease, and cancers), and how to implement intermittent-fasting prescriptions to maximize long-term benefits. Physicians can incorporate intermittent-fasting prescriptions for early intervention in patients with a range of chronic conditions or at risk for such conditions, particularly those conditions associated with overeating and a sedentary lifestyle. One can envision inpatient and outpatient facilities staffed by experts in diet, nutrition, exercise, and psychology that will help patients make the transition to sustainable intermittent-fasting and exercise regimens (covered by basic health insurance policies). As an example of a specific prescription, the patient could choose either a daily time-restricted feeding regimen (an 18-hour fasting period and a 6-hour eating period) or the 5:2 intermittent-fasting regimen (fasting [i.e., an intake of 500 calories] 2 days per week), with a 4-month transition period to accomplish the goal. To facilitate adherence to the prescription, the physician’s staff should be in frequent contact with the patient during the 4-month period and should closely monitor the patient’s body weight and glucose and ketone levels (from NEJM).
If you have given CR, IF or KD a try please let us know how they make you feel. It is clear from our ‘Food Coma Survey‘ that many people with MS and food coma are already using dietary manipulation to manage their symptoms.
Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
An intermittent fasting or calorie restriction diet has favorable effects in the mouse forms of multiple sclerosis (MS) and may provide additional anti-inflammatory and neuroprotective advantages beyond benefits obtained from weight loss alone. We conducted a pilot randomized controlled feeding study in 36 people with MS to assess safety and feasibility of different types of calorie restriction (CR) diets and assess their effects on weight and patient reported outcomes in people with MS. Patients were randomized to receive 1 of 3 diets for 8 weeks: daily CR diet (22% daily reduction in energy needs), intermittent CR diet (75% reduction in energy needs, 2 days/week; 0% reduction, 5 days/week), or a weight-stable diet (0% reduction in energy needs, 7 days/week). Of the 36 patients enrolled, 31 (86%) completed the trial; no significant adverse events occurred. Participants randomized to CR diets lost a median 3.4 kg (interquartile range [IQR]: -2.4, -4.0). Changes in weight did not differ significantly by type of CR diet, although participants randomized to daily CR tended to have greater weight loss (daily CR: -3.6 kg [IQR: -3.0, -4.1] vs. intermittent CR: -3.0 kg [IQR: -1.95, -4.1]; P = 0.15). Adherence to study diets differed significantly between intermittent CR vs. daily CR, with lesser adherence observed for intermittent CR (P = 0.002). Randomization to either CR diet was associated with significant improvements in emotional well-being/depression scores relative to control, with an average 8-week increase of 1.69 points (95% CI: 0.72, 2.66). CR diets are a safe/feasible way to achieve weight loss in people with MS and may be associated with improved emotional health.
Some of our readers are not satisfied with the Swedish Gothenburg 50-year follow-up data on MS outcomes, I presented yesterday; they make the comment that the data is out of date. However, there are very few databases that have 50+ year follow-up data; one of them is the Swedish National MS Register.
The following is the latest Swedish registry data that has recently been published on long-term outcomes. Please note the Swedish register includes over 98% of pwMS living in Sweden so it is arguably the best population-based MS database that exists.
As you can see from figure over 90% of people in the registry with relapse-onset MS develop SPMS and over 90% eventually need a walking aid 50 years after clinical disease onset. This population includes pwMS from the pre-DMT era and post-DMT era. So the rosy-looking Gothenburg data loses it rosy-tint and becomes very grey when diluted out with the remainder of the country’s data.
Background: The course of multiple sclerosis (MS) has been studied in several cohorts; however, results have varied significantly.
Objective: To describe the clinical course of MS in a nationwide cohort of patients.
Method: Data from the Swedish MS register (SMSreg) were used to estimate the median time to the sustained Expanded Disability Status Scale (EDSS) scores 3.0, 4.0 and 6.0, onset of secondary progressive multiple sclerosis (SPMS) and death using Kaplan-Meier method. A possible effect of first-line treatments on age at EDSS 6.0 and SPMS was estimated.
Results: In all, 12,703 patients were included. Median ages at EDSS scores 3.0, 4.0 and 6.0 were 55.4 (95% confidence interval (CI): 54.8-55.8), 60.7 (95% CI: 60.1-61.2) and 64.3 (95% CI: 63.6-64.7), respectively. Median age at SPMS was 57.4 (95% CI: 56.9-57.9). The median age at the time of death was 80.5 (95% CI: 79.9-81.1). Males and progressive-onset patients showed higher risks of disability worsening. On average, treated patients gained 1.6 years (95% CI: 0.2-3) to EDSS 6.0 as a result of treatment.
Conclusion: Ages at disability milestones in this population-based cohort were higher than previously described in clinic- and regional-based samples. Nevertheless, MS patients die at younger age and live at an average almost 20 years with moderate and 30 years with severe disability.
