Early cladribine treatment prevents MS

Barts-MS rose-tinted-odometer: ★★★★★★ (6-star bull’s blood red #8a0303)

Yesterday’s post on using cladribine to prevent CIS from converting to MS and whether this is MS prevention or an MS cure generated a robust debate. Good, this was the purpose of the post; i.e. to get you thinking. 

As you are aware that as the diagnostic criteria for MS evolve many people diagnosed with CIS in the past actually have MS when the new diagnostic criteria are applied retrospectively. This then allows you to see how well cladribine works in preventing conversion to MS in the small subgroup of subjects who have ‘CIS’ and not MS when they were treated with cladribine. 

The subjects who were still CIS after applying the newer McDonald diagnostic criteria showed that cladribine’s treatment effect improved with a reduction in risk of conversion to clinically definite MS by 63% on low-dose cladribine and by 75% on high-dose cladribine compared to placebo. I am not sure the MS community has clocked how effective cladribine really is when used early. 

This post-hoc analysis also suggests that people with CIS treated with lower doses of cladribine actually do better than those on higher doses. The dose-effect is pretty clear when you look at the time to next attack or three-month confirmed disability worsening. Have we optimised the dose of cladribine? When you are trying to prevent/cure MS maybe not!

Any predictions? I predict that a proportion of patients with CIS treated early with cladribine may never go on to have a second attack or disability progression and hence are prevented from developing MS or cured of their MS, depending on how you define MS. Anyone taking bets? 

Freedman et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802.

Background: Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.

Objective: The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.

Methods: A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.

Results: Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001.

Conclusions: Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Prevention vs. cure

Barts-MS rose-tinted-odometer: ★★★★★ (a bright blue buzz – #0096FF)

I was at a mid-summer party last night when someone suggested that I should not waste my time trying to answer peripheral or trivial questions in relation to MS and focus on the really big questions. 

This got me thinking about which are the biggest MS questions in MS that I can try to tackle and answer. Apart from (1) MS prevention, i.e. does preventing primary EBV infection with a sterilizing EBV vaccine prevent MS, the next major question must relate to (2) curing MS

The BIG-C issue is one I have been exploring on this blog for several years but is hampered by defining what an MS cure looks like and then looking for it. The problem with the latter is the issue of smouldering MS, which clouds the definition of a cure. Even if you cure someone from the biological drivers of MS, if they have relatively advanced MS they may still get worse from downstream smouldering processes that become independent of the initial MS attack(s). So the only solution is to test the hypothesis of an MS cure is very early in the disease, i.e. at the RIS (radiologically-isolated syndrome) or CIS (clinically-isolated syndrome) stage. 

To cure MS what treatment strategy do you need to use?  I have made the point that we can only cure MS with an IRT (immune reconstitution therapy) and at present we only have three IRTs that are used routinely in MS., i.e. cladribine, alemtuzumab and AHSCT. It is clear that cladribine is the safest IRT and has the added advantage as being the most CNS penetrant, which I think is important. Cladribine levels in the spinal fluid of treated patients are high enough to have an effect on CNS resident T and B-cells. Cladribine is also the safest and easiest IRT to use and therefore the most likely to get widely adopted. I am convinced  that a proportion of pwMS treated early, within 12 to 24 months of MS diagnosis, with either alemtuzumab and AHSCT are cured. Despite the stunning results of this treatment approach the adoption of both alemtuzumab and AHSCT as a mainstream treatment for MS has been abysmal. I suspect cladribine as an early effective treatment would have a greater chance of being adopted. My conclusion then is that the IRT has to be cladribine and it has to be done evry early at the CIS or RIS stage. 

But this experiment has already been done. The ORACLE study below was of oral cladribine in CIS. So what has happened to these patients? We don’t know, which is why Merck is doing the CLASSIC MS study to try and find out what has happened to these patients with CIS. Wouldn’t it be brilliant if a significant proportion of the cladribine exposed patients have not developed MS compared to those in the placebo group? Would this be sufficient to convince the wider MS community that very early cladribine treatment cures a proportion of people with CIS, i.e. prevents them from developing MS?  I suspect not. This is why a new global RIS-CIS study will need to be done. 

Please note some people would argue that stopping people with CIS from getting MS is MS prevention, whereas others would argue, including me, that CIS is already MS and hence preventing CIS from becoming MS is an MS cure. This is not just semantics but challenges disease definitions and is an important philosophical debate. This is why I want to study medical philosophy to tackle some of these issues.

Kaplan–Meier estimates of time to conversion to CDMS and McDonald MS in the intention-to-treat population during the double-blind period. Cumulative percentage probability of conversion to (A) CDMS according to the Poser criteria and (B) MS according to the 2005 McDonald criteria. CDMS=clinically definite multiple sclerosis. MS=multiple sclerosis. Figure from Lancet Neurol 2014.

Leist  et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

What is the most exciting MS research on the horizon?

I was asked about which paper I have written or co-written that has or will have the most impact in the field of MS. There is little doubt that it is our report of our 2017 workshop on “EBV Infection and MS Prevention”.

This report (see below) was the catalyst for creating the Preventive Neurology Unit (PNU), which is embedded in the Wolfson Institute of Preventive Medicine. The funding for the PNU allowed us to employ Dr Ruth Dobson to be the academic lead on the MS Prevention workstream in the PNU. All we need now is a sterilising vaccine against EBV, the necessary funding so that we can set-up an international anti-EBV MS Prevention study and support from the public to do this study. Once we have all these in place we will be a position to finally test the hypothesis that EBV is the cause of MS. There is nothing in the field of MS research that excites me more than testing this hypothesis. Do agree? What excites you? Any other recommendations?

#MSCOVID-19: how to prevent yourself from getting COVID-19 in your own home

What can do I to prevent myself from being infected with coronavirus if someone in my household gets COVID-19? 

This is a topic that I have not covered directly, but it is obviously very important and an oversight on my part. Apologies. 

The following advice is pretty intuitive and has been hacked from an amazing website, by the Univesity of Southampton, called Germ Defence. If you have the time can I suggest you ignore this post and go through Germ Defence’s short online programme? Although not COVID-19 specific it gives out generic and very sensible advice and only takes 10 minutes to complete. 

Image from Germ Defence, University of Southampton.

Ideally, the person who has COVID-19 should spending as much in their own space so that you are less likely to come in contact with them. This could be in their own room or a room in the house that other people should not enter. I am aware that this may not be feasible depending on your circumstances. 

It is important not to share a bed with the person who has COVID-19 or you think may have coronavirus.

Please open your windows and limit the amount of time you are in a room with the person who has COVID-19. Also, try to spend time outdoors if you can. 

If possible socially distance at home; i.e. try and keep 2 meters away from the person with COVID-19. 

Try and organise your home so that you have more space between seats. If it is possible arrange to use shared areas of your home, for example, the bathroom, at different times, so that only one person is in there at any time. 

Try and kill any viruses by frequent cleaning. It may be impossible to avoid shared areas of the home, such as kitchens and bathrooms, so keeping them clean, very clean, is important. Try and use a disinfectant to clean surfaces that the affected person may touch, e.g. taps, fridge, door handles, toilet seat, toilet handle, remote controls, computer keyboards, gaming consoles, etc. Wipe down surfaces such as tables, kitchen tops, fridge and freezer doors, seats, remote controls, keyboards, etc. 

Place bottles of disinfectant in key areas of the house so that they are quick and handy to use. 

Try to avoid sharing or touching things that other people have used, e.g. bottles, kettle, towels, fridge, taps, toothpaste, remote controls, telephone, etc., unless you know that they have been cleaned recently with disinfectant. 

It can take up to 3 days (72 hours) for the coronavirus to completely die on hard surfaces. So if there are things that you can’t clean, can you put them somewhere out of the way for 3 days before you use them. If 3 days isn’t possible, then aim for as long as possible. 

The person with COVID-19 should wear a mask. Similarly, if you need to spend time with the person who has COVID-19 then wearing a mask can stop you breathing any infectious particles that are spread through coughing and sneezing. 

Try and not touch your face, in particular your nose and mouth. This is very hard so you need to concentrate and train yourself to be aware of what your hands and fingers are doing. 

Try to limit the time you spend close to other people in the house as well. They may be incubating and shedding the virus asymptomatically. 

CoI: none

Smouldering away

As you are aware we, or I depending on your perspective, have recently have hit a brick wall trying to convince the MS community that the big unmet need in MS is smouldering disease.

The central hypothesis is that smouldering MS is the real MS. The following YouTube presentation summarises some of the main arguments for the hypothesis.

Your comments will help me make a decision to giving-up working on established MS and to focus on preventive neurology; in particular, preventing MS.

CoI: multiple

Could diet be the new add-on DMT?

Barts-MS rose-tinted-odometer  ★ ★★ ★ ★

I gave my first on using diet as a potential symptomatic and disease-modifying treatment for MS and as a preventative therapeutic strategy in MS, last night.

The symptomatic part of my talk was about food coma and using diet to prevent or reduce the impact of food coma. We are still studying why pwMS are so susceptible to food coma. I suspect it is because they have less cognitive reserve and food coma may interact with other medications to make it such a problem.

The really interesting part of my talk was using caloric restriction (CR), intermittent fasting (IF) or ketogenic (K) diet as a DMT. I suspect the mode of action of all these diets is via ketosis and inducing high levels of circulating β-hydroxybutyrate one of the ketone bodies. Ketone bodies are the source of energy the body uses when we have depleted our sugar stores (glycogen) and are fasting or not absorbing sugar from the gut.

Interestingly, β-hydroxybutyrate works via the hydroxycarboxylic acid receptor 2 (HCA2), which is also known as niacin receptor 1 (NIACR1) and GPR109A. Why is this so important? This is the same receptor that fumaric acid works on. Yes, ketosis works at a cellular level in the same way that dimethyl fumarate (DMF) and diroximel fumarate work, i.e licensed MS DMTs.

Yes, CR/IF/K diet may induce a metabolic pathway that is known to be disease-modifying in MS.

There is an extensive literature, which I discovered about two years ago, showing that β-hydroxybutyrate works via NRF2 and downregulates NFKappa-B, the master inflammatory transcription factor. In other words ketosis, in particular β-hydroxybutyrate promotes programmed cell survival via the NRF2 two pathway and is also anti-inflammatory. β-hydroxybutyrate may even be better than the fumarates as a treatment for MS because it is likely to penetrate the CNS better than oral fumarates.

The corollary of the above could also explain why a processed and ultra-processed high carbohydrate diet is pro-inflammatory. Most people put it down to the pro-inflammatory signals from adipose tissue, but it could be related to the fact that carbohydrates, via insulin, inhibit ketosis and suppress β-hydroxybutyrate levels in the body.

Another nugget of information I found is that metformin also works via NRF2, but not via the HCA2 receptor. This may explain why metformin promotes rejuvenation of oligodendrocyte precursors and is being explored as a potential remyelination therapy in MS.

I have also discovered whilst reading the NRF2 literature that some statins, including simvastatin, activate NRF2. Could this be a potential mode of action of simvastatin in MS?

I didn’t have time to discuss MS prevention last night. However, we think that about 10-20% of the increase in MS incidence may be caused by childhood and adolescent obesity. This is why we are pushing for policy on sugar and a national campaign to tackle this problem.

So when I say I have declared war on sugar, I mean it in more ways than you realise.

Despite observational evidence showing that pwMS do well on CR/IF/K diets, the studies show that they are generally safe. However, we need controlled evidence before promoting these pwMS as a potential adjunctive treatment for MS. The good news is that there are ongoing studies looking into this. The one below is actually using MRI to see if a ketogenic diet has an impact on MRI activity, i.e. the inflammatory component of MS.

Are you up for biohacking your metabolism as a treatment for your MS?

Bahr et al. Ketogenic Diet and Fasting Diet as Nutritional Approaches in Multiple Sclerosis (NAMS): Protocol of a Randomized Controlled Study. Trials, 21 (1), 3 2020 Jan 2.

Background: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression.

Methods: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed.

Discussion: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS.

Trial registration: ClinicalTrials.gov, NCT03508414.

CoI: multiple

The war on sugar (more posts below today)

Barts-MS rose-tinted-odometer ★★★ 

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?

Jacobs et al. BMI and Low Vitamin D Are Causal Factors for Multiple Sclerosis: A Mendelian Randomization Study. Neurol Neuroimmunol Neuroinflamm, 7 (2) 2020 Jan 14.

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

Pathways to Cures

Barts-MS rose-tinted-odometer ★★★★★ 

I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me. 

As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people. 

Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences. 

So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me! 

If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease? 

Sonia Vallabh. The Patient-Scientist’s Mandate. N Engl J Med 2020; 382:107-109.

Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.

There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease. 

My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS. 

Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with. 

In the area of MS prevention, it will take more than a  patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.

My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?

Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there. 

On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.

For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold. 

I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.

My prevention hat

About three years ago I started wearing another hat; a preventive medicine hat.

We started the Preventive Neurology Unit within our medical school focusing on MS, Parkison’s Disease and all-cause dementia. The unit is growing rapidly and gaining momentum. It was with great pride that I was able to attend and speak at first symposium. I have uploaded my slides for anyone who wants to download them for personal use. 

It is clear that we have an obligation to the next generation of pwMS. The study below shows that young people with MS take a massive cognitive hit. The study shows that at a presentation about a quarter of young people with MS have cognitive impairment at baseline and ~15% had a measurable decline over the next 2 years. In a world where our self-worth is largely defined by our cognition, these figures are scary. The observation that MS is a dementing disease is not new and goes back many decades. 

The willingness of the MS community to accept this is worrying; they say calling MS a dementing disease is stigmatising. Yes and no. Yes, if you want to put your head in the sand and no if you want the MS community to do something about it. It is clear that the dementia is preventable; i.e. the less brain damage that you allow to accumulate the less cognitively impaired the pwMS will become. This is the message behind our treat-early treat-effectively campaign and why we need to flip the pyramid. Access to the most effective treatments early on is the only way to really prevent end-organ damage. 

More importantly, is the observation that MS is preventable. We estimate that by tackling childhood and adolescent obesity and smoking may reduce the incidence of my MS by ~25%. Vitamin D supplementation may reduce the incidence by a further 40%. Preventing EBV infection with a vaccine strategy may prevent the majority of people developing MS. May be admitting how bad MS is at a personal and population-level will get funders to put more money and resources into prevention. 

I think we should call a spade a spade and forget the rose-tinted world most people like to live in. We need to take MS prevention seriously; we owe it the next generation of people who are destined to develop MS. Wouldn’t it be nice if they didn’t get MS? 

Wallach et al. Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline. Mult Scler. 2019 Nov 28:1352458519891984.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS.

OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors.

METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free.

RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT.

CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

CoI: multiple

The cause of MS

When I posted the link to our EBV and MS meta-analysis on social media yesterday I was taken to task because of the slow progress we have made in MS prevention. 


Can I remind you that science moves steadily and slowly and the biggest problem we have is the slow adoption, or rejection, of innovations or new ideas. 

“The human mind treats a new idea the same way the body treats a strange protein; it rejects it.”
Peter Medawar, Nobel prize laureate, in Physiology or Medicine, 1960.

I was convinced by the evidence already back in 1999 that EBV was the likely cause of MS. I have been working on EBV ever since and the progress has been very slow. The main reason I left the Institute of Neurology (Queen Square) was to move to a multi-disciplinary institute, that would allow me space and time to work on EBV. However, it takes more than just moving to a new research environment to build momentum around a new research hypothesis. 

I have had more grant applications rejected around the viral hypothesis of MS than I care to count. It is very depressing. Despite this, we are pushing on slowly with our plans to create a trial-ready cohort of people at high risk of MS for exploratory MS prevention studies. Dr Ruth Dobson is doing quite an amazing job at getting this off the ground. We are also pushing forward with our ideas around treating MS with antivirals that target EBV. To say that the funding for doing these trials has been difficult is an understatement, but I am hoping if we can get pilot data we can convince the sceptics to fund definitive trials. 

We are also not the only team working on the EBV hypothesis of MS. Michael Pender in Brisbane, Australia, is doing great things and Atara Bio has taken up the baton in industry. I have recently posted on their preliminary results that were presented at ECTRIMS.

I spend most of my waking day doing MS and a large part of that is thinking about EBV and MS prevention. The main strand of MS prevention is an EBV vaccination study. The vaccine is not in our hands, but the capable hands of Jeff Cohen at the NIH, and hopefully a deep-pocketed Pharma company to commercialise it. Even if we get an effective EBV vaccine developed and launched we will still have to overcome the public resistance to vaccination and to convince public health officials that this is a worthy idea. 

The battles ahead are numerous, but we will get there in the end. We have to. We don’t want the next generation of MSers asking us why we haven’t done anything to prevent MS given the current state of knowledge.

EBV is almost certainly the cause of MS. What are we doing about it?  

Jacobs et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors. https://doi.org/10.1101/19007450

Background: EBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. 

Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. 

Methods: Pubmed was searched using the terms multiple sclerosis AND Epstein Barr virus, multiple sclerosis AND EBV, clinically isolated syndrome AND Epstein Barr virus and clinically isolated syndrome AND EBV. All abstracts were reviewed for possible inclusion. 

Results: 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10-4; RERI 3.84, p<5×10-3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. 

Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

CoI: multiple