Category: Causes

More women develop MS than men, why?

Yes, I agree the cause of MS has to explain the changing sex ratio of the disease. 



To prove that MS is caused by a single factor or the interaction of several factors, it has to explain everything we know about the epidemiology of the disease. In terms of EBV being the cause of MS, how does EBV explain why RRMS is becoming more common in women? In comparison, the incidence of PPMS seems to remain constant with an equal number of men and women affected.

One observation that has been noticed across several populations, but not all, is the increasing incidence of MS in women. Why is this occurring? Some of it may be due to the change in smoking prevalence amongst women, which has been increasing relative to males. An outlier here is Iran, which has a sex ratio of F:M of close to 5:1 and is one of the countries where less than 10% of women smoke. I am not convinced that smoking explains the changing sex ratio of MS incidence. 

Some blame cultural factors, for example, the addition of UV blockers in cosmetics over the last 20+ years and other cultural changes causing women to shun sun exposure. 

Others have suggested the use of oral contraceptive pill (OCP) or change in work environment. However, the change in sex ratio appears to go back to the beginning of the 20th century so it predates the change in work environment associated with World War II or the introduction of the OCP in the ’60s.

Please note the change is sex ratio is not universal; for example, it has not been noted in Sweden. What the changing sex ratio, or lack of change in some regions, is telling us that it must be driven by environmental factors and hence reversible. What we do know is the changing sex ratio is a proxy for a rising incidence and prevalence of MS. The changing sex ratio is also telling us that MS is preventable, which is why we at Bart-MS are working actively on trying to put in place a platform to do MS prevention studies. #PreventMS is one of our 2019 research priorities. 

Orton et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006 Nov;5(11):932-6.

BACKGROUND: Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change.

METHODS: Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset.

FINDINGS: The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada. Year of birth was a significant predictor for sex ratio (p<0.0001, chi(2)=124.4; rank correlation r=0.84).

INTERPRETATION: The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in the incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene-environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why the incidence of the disease is increasing are unknown, there are major implications for health-care provision because the lifetime costs of multiple sclerosis exceed pound1 million per case in the UK



Ramagopalan et al. Sex ratio of multiple sclerosis and clinical phenotype. Eur J Neurol. 2010;17(4):634-7. Epub 2009 Nov 24.

BACKGROUND AND PURPOSE: In a longitudinal population-based dataset of patients with multiple sclerosis (MS), we have previously observed a substantial increase in the female to male sex ratio in Canada over the last 50 years. Here, we aimed to determine whether this change in sex ratio is related to the clinical course of MS.

METHODS: We calculated sex ratios by birth year in 11 868 patients with relapsing-remitting (RR) MS and 2825 patients with primary progressive (PP) MS identified as part of the Canadian Collaborative Project on the Genetic Susceptibility to MS.

RESULTS: Year of birth was a significant predictor for sex ratio in RR MS (P < 0.0001, chi(2) = 21.2; Spearman’s rank correlation r = 0.67), but not for PP MS (P = 0.44, chi(2) = 0.6; Spearman’s rank correlation r = 0.11).

CONCLUSIONS: An increase in the number of female RR MS patients over time accounts for the increasing sex ratio of MS.



Kampman et al. Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway.J Neurol. 2013 Jan 6.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71°N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing-remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing-remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.



Background: Sex ratio in multiple sclerosis has been reported from several geographical areas. The disease is more common in women. In Europe, the female-to-male ratio varies from 1.1 to 3.4. A recent study from Canada has reported a significant increase, with time, in female-to-male ratio in multiple sclerosis over the last 100 years.

Objective: The aim of this study was to analyse any change in sex ratio in multiple sclerosis in the Swedish population.

Methods: Data from the Swedish MS Register and data from the Swedish National Statistics Office were used to estimate sex ratio by year of birth and year of onset.

Results: In the analysis of sex ratio by year of birth there were 8834 patients (6271 women and 2563 men) born between 1931 and 1985. The mean women-to-men ratio was 2.62. No clear trend was noted for the women-to-men ratio by year of birth (Spearman’s rho = 0.345, p = 0.298, n = 11). The number of patients analysed by year of onset was 9098 during the time period 1946 until 2005. The mean women-to-men ratio was 2.57. No significant change in women-to-men ratio (Spearman’s rho = -0.007, p = 0.983, n = 12) with time was observed.

Conclusion: There is no evidence for an increasing women-to-men ratio with time amongst Swedish multiple sclerosis patients.

Trojano et al. Geographical Variations in Sex Ratio Trends over Time in Multiple Sclerosis. PLoS One. 2012;7(10):e48078. doi: 10.1371/journal.pone.0048078. Epub 2012 Oct 25

BACKGROUND: A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out.

OBJECTIVE: In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas.

METHODS: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births.

RESULTS: Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS.

CONCLUSIONS: Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.

CoI: multiple

What have poppies and fields got to do with the cause of MS?

It took a while for me to truly understand why the poppy is so important to people living in the UK. The poppy is a symbol of remembrance, i.e. to observe and never forget. 



 Why are fields and poppies relevant to MS? 

The study below supports anecdotal clinical evidence of many of my clinical mentors and, now as I have gotten older, my own clinical experience; if you have an MS relapse, or attack, in one particular area of the brain or spinal cord you are more likely to have subsequent attacks in this area. I refer to this as the so-called field effect, i.e. something locally in a specific anatomical area triggers recurrent attacks in the same site. 

 What underlies the field effect? One explanation is that the area that is damaged by the initial attack is more likely to trigger autoimmune responses in future as a result of the local up-regulation of so-called second, or danger, costimulatory signals. The latter occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated they need an antigen-specific signal via the T-cell receptor and additional signal via co-stimulation.


Another hypothesis, which I favour, is that there is something in the field that triggers relapses. Possibly a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when MSers were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS. 

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear the field of the offending agent. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response to the virus that causes MS.

 Another observation comes from serial MRI studies that have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology is something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. I think the best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post on the subject.



Epub: Willis et al. Site-specific clinical disease onset in multiple sclerosis. Eur J Neurol. 2014 Sep 8. doi: 10.1111/ene.12564.

BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.

METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.

RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.

CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.

Proving EBV is the cause of MS

There is some healthy scepticism about my comment that I think we have found the cause of MS and it is EBV. 




What should we do about it?




I gave the Charcot lecture earlier this year at the NIH. In the lecture, I made the point that the epidemiology and biology of MS are coming together around the B-cell and EBV and that it is looking increasingly likely that EBV is the cause of MS. 


Although my slides tell the story it is important to stress that proving causation is a complex process and the only way to prove that EBV is the cause of MS is to prevent EBV infection and see what happens to the incidence and prevalence of MS over time. This hypothesis is based on many epidemiological studies, but the most compelling piece of data is the observation that people who are EBV negative are protected from getting MS. Yes, protected from getting MS.


One hurdle we have at the moment is that we don’t yet have a good sterilising vaccine to prevent EBV infection. The latter is a technological challenge and there are very good vaccinologists working on bivalent and trivalent vaccines as we speak. Let’s hope they are safe and effective.



Some of you may know that I now wear two hats. My new hat is that I am a co-director of the Preventive Neurology Unit within the Wolfson Institute of Preventive Medicine and one of the diseases we are focusing on is MS. This is one of the main reasons I left Queen Square to move to Barts and The London; I wanted to work on EBV and MS. 


In October 2016 we held a task force meeting on EBV as a cause of MS (see PDF below). The conclusions of the meeting was a unanimous yes; we need to go ahead and design and perform EBV vaccination trials to try and prevent MS. The latter is easier said than done, but that is our direction of travel, with ‘many miles to go before we sleep’. 


There will be a lot of naysayers along the way but to quote Arthur Schopenhauer, ‘All truth passes through three stages; first, it is ridiculed, then it is violently opposed and finally, it is accepted as self-evident’.


Is it time to reunify MS as one disease?

I am just about to leave Berlin tired but content that the MS world is finally beginning to acknowledge that #MS_is_1_and_not_2_or_3_diseases. We have covered this topic extensively over the last 4-5 years and I did so again in my talk as part of the Roche satellite symposium.



I have also uploaded all my other ECTRIMS-related slides and posters to my new SlideShare site for download.



CoI: multiple

ECTRIMS 2018: will MS become one again?

I arrived in Berlin yesterday and already I am seeing ECTRIMS 2018 turning into a battle between the lumpers and splitters, i.e. is MS one, two or three diseases. 
Making Berlin one again

Roche, who has ocrelizumab licensed for relapsing and primary progressive MS want MS to be one disease. On the other hand, Novartis who have just submitted siponimod to the FDA for SPMS want it to be at least two diseases. This new battle helps nobody. We have been running the #MS-is-1-not-2-or-3-diseases for several years on this blog and I am not going to change my position on this.

Our MS as a length-dependent axonopathy hypothesis makes a strong case of MS being one disease, which is why we are arguing that advanced MS (formerly known as progressive MS) is modifiable. This principle underpins our #Chariot-MS and the #Oratorio-Hand studies and explains the positive low-dose oral methotrexate and ASCEND (natalizumab) trials. If we had interpreted the results of the low-dose oral methotrexate progressive trial from over 20 years ago correctly we would have had licensed therapies for progressive MS decades ago; yes, decades ago.

In reality, the salami slicing-up of MS into relapsing and non-relapsing forms, and of chronic progressive MS into primary and secondary progressive MS, was driven by money. When the interferon trials started it was important to make MS an orphan disease, i.e. to having fewer than 200,000 patients classified as having the disease. Being an orphan disease allowed Pharma (Bayer-Schering) to access the market with one pivotal trial, gave them market exclusivity and allowed them to charge much more for their product. The consequences of this is that we have divided MS into being many diseases, which is to the detriment of people with MS. The consequences of this are not trivial. Being diagnosed as having MS is bad enough, but then being diagnosed as having secondary-progressive disease is like getting another disease. The latter is still interpreted by most people with MS as now having a disease that is not modifiable. For example, in the NHS we are meant to stop DMTs in patients who develop SPMS. There are also many other reasons to avoid a diagnosis of SPMS.

An analogy to the RRMS vs. SPMS dichotomy is being diagnosed with a low-grade tumour, that on average is quite indolent and slow growing, however, after time the tumour mutates to become highly-malignant, life-threatening and often terminal. Just as people fear their tumour mutating, and becoming ‘terminal’, people with relapsing MS live in fear of developing progressive MS.

Recruitment for our PROXIMUS trial, which is now closed and being analysed, has been a victim of MS being two and not one disease. We made the mistake of calling it a secondary progressive trial. Very few of my colleagues referred patients for this trial simply because it meant diagnosing their patients as having early SPMS. Almost every neurologist I know avoids making a diagnosis of SPMS as long as possible because of the repercussions it has for their patients.

I think we need to turn the clock back and get rid of arbitrary, non-science, based definitions of MS. They don’t help us clinically. MS begins long before the first clinical attack. Similarly, progressive MS is present from the start of the disease. There is simply no magic point in time when you become SPMS. Dividing MS into relapsing and progressive phases may have helped Pharma get interferons licensed under the orphan-drug act, made them lots of money, but it is now doing the field of MS a major disservice. 


Now that there are marketing reasons to keep MS sliced-up as multiple diseases I can only imagine the Pharma shenanigans that will emerge. ECTRIMS-BERLIN 2018 is witnessing the first shots of this epic battle. Who will win? At least this new battle buries the dogma that advanced, or progressive, MS is not modifiable. We have won one battle only to replace it with another one. 

I am determined to remain an optimist and view this change in perspective as being positive for the field; at least both sides believe progressive MS is now modifiable.  

CoI: multiple 

Has your neurologist discussed HPV vaccination with you?

What to advise MSers about the HPV vaccine?



You may be aware that for almost a decade young girls living in the UK have been offered the HPV vaccine at ~12-14 years of age. The HPV vaccine is to prevent infection with the sexually transmitted human papillomavirus (HPV) that is known to cause cervical cancer and several other cancers. The current issue is that innovation never stands still, technology moves on and society changes its behaviour. All of these are coming together to create a perfect storm that has major implications for MSers. 


The innovation: The current NHS funded vaccine (Gardasil) covers only 4 strains of HPV and reduces the risk of cervical cancer by ~67%. The newer more advanced HPV vaccine covers 9 HPV strains and reduces the risk of cervical cancer by over 90%. The problem is the Department of Health are not yet prepared to pay for the more expensive vaccine that covers 9 strains. It is important to realise that the newer vaccine also covers more strains of HPV that cause warts, in particular, genital warts. Is this important? Yes, it is. If you decide to go onto an immunosuppressive therapy, in particular, an immune reconstitution therapy or IRT, then suppression of your immune system allows the virus to escape and to start replicating. I am aware of two cases at other centres who have had alemtuzumab only to see their genital warts become a major problem. I am also aware of a patient who developed a problem when her common old garden variety of cutaneous warts spread post-alemtuzumab. These anecdotal cases are very important and I now view warts, be they genital or cutaneous, as a relative contraindication to IRTs, particularly the non-selective IRTs such as alemtuzumab and HSCT. 


Social changes: There are public health issues that are as relevant to MSers as the general population. HPV is not only a problem for women. HPV is a well-established cause of penile and anal cancer and causes a small proportion of throat and oesophageal cancers. Therefore it makes sense for males to be vaccinated against HPV as well. In the UK boys who have sex with boys and are prepared to admit it can have the HPV vaccine. But what about men? The rationale for targeting the general population is to reduce the pool of susceptible people and thereby reduce the spread of the virus. Epidemiologists call the latter herd immunity. For herd immunity to be effective you typically need over 90% of the population to vaccinated.


The epidemiology of HPV infection is also changing. People are becoming infected later in life and are spreading the virus. Social media and dating apps have revolutionised the dating world and many older people are becoming promiscuous in older age and are having unsafe sex. As a result of this, there has been a large increase in the incidence of sexually transmitted diseases in older people, including HPV infections. This has prompted some commentators to suggest that public health officials extend the HPV vaccine to all women and possibly all men. Why wouldn’t you want to reduce your risk of getting cervical cancer? Isn’t prevention better than having to treat HPV infection and its downstream effects, i.e. premalignant cervical lesions or cervical cancer?


As a result of these trends, an increasing number of MSers are asking about the HPV vaccine. Similarly, when I go to meetings neurologists are asking me for advice or what to do about vaccines, in particular, the HPV vaccine There are several questions that HPV vaccination raises that are directly relevant to MSers.


Question 1: If I have been vaccinated with the older quadrivalent vaccine could I receive the new vaccine to cover the other strains of the virus?


Yes, there is data that shows that the previous vaccination against HPV doesn’t stop your immune system from responding to the components cover the new strains.


Question 2: As I am on a DMT can I have the HPV vaccine?


This all depends on the DMT you are on. For the non-immunosuppressive immunomodulators such as interferon-beta and glatiramer acetate vaccination is not a problem. These agents do not blunt immune responses to vaccines. For the other DMTs to story is not that clear. Fingolimod and ocrelizumab are known to blunt vaccine responses. Vaccine responses to component vaccines on dimethyl fumarate have been studied and were normal. However, I am not aware of any specific studies looking at the HPV vaccine. I would, however, think it would be fine to receive the HPV vaccine if you are on DMF. Teriflunomide is similarly unlikely to blunt the immune response to HPV, but we don’t have specific data on the HPV vaccine and teriflunomide Natalizumab mode of action is unique and is unlikely to affect peripheral immune responses. For the IRTs (alemtuzumab, cladribine, mitoxantrone and HSCT) vaccination should be delayed until after immune system reconstitution.


Question 3: I need to start a DMT, but I want to have the HPV vaccine or extend my cover with the new polyvalent vaccine, how long will I need to wait before I can start treatment?


The polyvalent vaccine at the moment requires 2 or 3 doses with the last dose given at 5 or 6 months. Ideally, to give your immune system a chance to respond to the vaccine you will need to wait until 4 weeks after the final booster, i.e. 6 or 7 months.


Question 4: Should I delay starting DMTs to have the vaccine?


There is no simple answer to this question. You have to balance the risks and benefits of having the vaccine against the risks of untreated MS. In relation to the IRTs, I would suggest going ahead and starting the IRT and delaying the vaccine until you have reconstituted your immune system. Delaying starting an IRT to have the vaccine does not make immunological sense in that the memory responses you have just made to the vaccine could potentially get depleted and depending on the intensity of the immunodepletion may not recover. For maintenance DMTs, in particular, fingolimod, dimethyl fumarate and ocrelizumab, you should probably delay starting treatment to have the vaccine.


Question 5: If I want the new polyvalent vaccine will the NHS cover it?


At present, the answer is no. Public Health England cover the quadrivalent vaccine under the national vaccine programme. If you want to be vaccinated against HPV you will have to cover the costs of the vaccine yourself. This is not too dissimilar to what happens with travel vaccines.


As you can see HPV vaccination is one of those factors that have to be put in the mix when deciding which is the correct DMT for you. It is not a major factor but is an important factor nevertheless. At the moment I don’t routinely advise my patients on this topic, but it is something that has future health implications, be they sexual, so maybe we need to do this routinely. What is your view on this? Do you think healthcare professionals should be obliged to discuss issue around vaccination before the start of a DMT?

CoI: multiple
Exit mobile version
%%footer%%