Happy dominos are the prettiest!

H

The prevalence of MS is not equally spread around the world, and is associated with latitude. Apart from some exceptions such as Sardinia, people living more closely to the equator are less likely to develop MS. Strikingly, when an individual moves before the age of 15 years old from for example Kenia (low MS prevalence) to the UK (medium MS prevalence), it will acquire the MS risk of his new home country. As the genetics of this individual obviously did not change, these migration studies are one of the most convincing arguments in favour of environmental factors as a trigger for MS. In addition, most countries have experienced a distinct increase of MS prevalence among women in the past few decades. This increase has been too fast to be explained by changes in genetic composition which take millions of years. Therefore, the increased prevalence of MS among women is likely to be explained by changes in lifestyle and environmental factors affecting women. Understanding environmental triggers is key in the light of MS prevention. 

http://cigarmonkeys.com/2020/02/01/audrey-hepburn-british-actress-film-and-fashion-icon-smoking-cigarette/

The usual suspects when it comes to environmental risk factors are:

  • Smoking (passive and active): The more you smoke, the higher your future risk of MS becomes. The underlying hypothesis is that smoking-induced lung irritation triggers aberrant immune responses. 
  • Low vitamin D levels: Low vitamin D levels are the consequence of insufficient sun exposure, which is – for obvious reasons – more frequent when moving further away form the equator. Vitamin D is known to have an immune-regulatory function and is thus able to tone down inflammation.
  • Adolescence obesity: The association is most strongest for a body mass index above 27. The most common explanation for this observation is the fact that obesity is characterized by a low-grade inflammation: increased levels of pro-inflammatory mediators are produced in fat tissue. 
  • Infectious Mononucleosis (caused by Epstein Barr Virus/EBV): Although EBV infection is very common in the general population, there is now more and more evidence that all pwMS have encountered the pathogen before ultimately being diagnosed. Some of the EBV proteins resemble myelin proteins leading potentially to aberrant immune responses. 

Importantly, all of these lifestyle and environmental factors can be traced to their effects on the immune system (similar to the genetic risk factors) which strongly supports the argument that the peripheral immune system (B cells, T cells) has a primary role in driving MS. In addition, you can imagine that when Audrey would move from Kenia to the UK at the age of 10, she would would be much more likely to have started smoking in her teens, more likely to have gained some extra pounds fuelled by ‘Breakfast at Dunkin’ Donuts’ and less likely to have played outside catching sunrays. “La vie en rose!” 

A new study from Xu et al. now adds another environmental risk factor to this list. In the walhalla of nation-wide studies Sweden, Xu et al. looked at whether any infection requiring hospital admission before the age of 20 years old would translate into a higher MS risk later in life. Interestingly, they found that only infections between the age of 11 and 19 years old conveyed into a higher risk of MS as opposed to infections before the age of 10. When analysing the infections according to site, especially infections of the central nervous system (e.g. meningitis) and respiratory infections (eg. pneumonia) could be linked to future MS risk. When analysing the infections according to the type of infection, especially bacterial infections and EBV were linked with future MS risk. 

These are very interesting observations. However, there is no explanation (yet) on why for example brain infections in early life would increase the risk for MS later onwards. Potentially, an inflamed, leaky blood brain barrier would facilitate immune reactions against brain constituents such as myelin. It’s also unclear why the risk is mainly apparent between 11 and 19 years old and not before. From a mechanistical point of view, this age difference is not logical. Potentially, there is a lower threshold to register non-specific infectious events in babies/early life? Most importantly, the study does not answer the question whether mild versus serious and single versus multiple infectious events matter when it comes to your future MS risk. Does your future risk of MS increase when you have multiple pneunomia admissions compared to a single one? Do you need to be infected with EBV (which triggers a pro-inflammatory immune state) before the risk-increasing effect of other infections becomes relevant? What about the additive effect of for example adolescent obesity? This is what we could call the environmental domino-effect, and refers to the cumulative MS risk if one environmental factor (e.g. smoking, EBV) would be required to open up your immune system to potential damaging effects of other environmental triggers (eg. infection)? And remember: happy domino’s are the prettiest! 

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Brain. 2021 Mar 9;awab100. doi: 10.1093/brain/awab100. Online ahead of print.

Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis

Yin Xu 1, Kelsi A Smith 2 3, Ayako Hiyoshi 1, Fredrik Piehl 3, Tomas Olsson 3, Scott Montgomery 1 2 4Affiliations expand

  • PMID: 33693538
  • DOI: 10.1093/brain/awab100

Abstract

The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections, such as of the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20 years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970-1994 were identified using the Swedish Total Population Register (n = 2,422,969). Multiple sclerosis diagnoses from age 20 years and hospital-diagnosed infections before age 20 years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11-19 years) and earlier childhood (birth-10 years) was estimated using Cox regression, with adjustment for sex, parental socioeconomic position, and infection type. None of the infections by age 10 years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21-1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06-1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11-3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13-1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30-1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections.

Keywords: CNS; Infection; adolescence; multiple sclerosis.

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Ide Smets

16 comments

  • Why is smoking still on that list? Smoking has been declining for quite a while now, so it can’t really explain the increase in MS numbers.

    • Yes, on a population level smoking has become less frequent, but at sex level it has become increasingly more common for women to start smoking compared to a couple of decades ago.

  • I wonder sometimes whether the messages about covering up with suntan cream is part of the cause of the recent increase in MS.
    Now school children are encouraged to wear it every day. I don’t ever remember wearing suntan cream as a child in the 70s & 80s in the uk. After my first child was born, I used SPF 50 on him – and consequently myself (no point getting 2 different bottles) when we were outside. I wonder whether that reduced my vitamin d exposure & tipped me over the edge 5 years later into “getting” RRMS.
    After diagnosis, I had my children coming home from school saying they must wear sunhats and suntan cream to go to school, and having to go and see their teacher and say I was balancing the sun exposure v vitamin d risk, so I wasn’t always going to apply suntan cream. I only hope I have been balancing the risks correctly 🤞

    • Absolutely, Chris, you are raising a very important point here. Making official recommendations for sun exposure is difficult because excessive exposure to sun indeed increases the risk of developing skin cancer, which is probably more harmful than low vitamin D levels on itself. However, a modest exposure to sunlight seems fair to recommend, and especially sunburn should be prevented at all cost.

      • I have also pondered this since diagnosis in 2015.
        I lost a friend to melanoma, after which I plastered myself with Factor 50 day in and day out, all year.
        I know I had glandular fever as a teenager and recognise this is likely the driving cause, but lack of VitD may well be another. Like Chris I wonder if there’s an imbalance to the current advice on sun protection.

  • I’ve always been borderline underweight, that might be an issue, as being underweight can make us more prone to infection…

    • Personally, I think if you are healthy otherwise and have a stable weight there is no harm in being a little underweight, and I guess it’s probably less harmful than overweight.

      • I’m not at all sure, from my point of view… I’ve always been borderline underweight, a high output type who has no problem going without eating because I’m too busy, i.e. unintentional fasting. Never more so than when my first symptoms of PPMS appeared. I think better is to eat plenty, lots, but of the right things. Pack in nutrients but not calories.

  • I have a question for Ide Smets. Since EBV seems to be a prerequisite for ms how ( I don’t know if this is the case or not ) are you trying to make the research move into clinical trials in regards to testing antivirals for EBV to treat ms ?

    • We are still not sure whether EBV is a necessary event to develop MS, but more and more evidence is pointing in that direction. Importantly, EBV infection will only lead to MS in susceptible individuals, meaning that their immune system is irrespective of EBV more likely to reside in a less regulatory, mildly inflammatory state.

      https://multiple-sclerosis-research.org/2020/04/ebv-and-ms/

      Prof G is already trying for years to get research funded to test the efficacy of treatments that reduce EBV shedding in pwMS, and I can assure you he is not planning on giving up. For example teriflunomide, an MS drug, is known to reduce viral shedding, but we don’t have the evidence yet that this drug would impact on the disease course and reduce for example accrual of disability in pwMS.

      https://multiple-sclerosis-research.org/2020/10/blackswan-anecdotal-evidence-we-cant-ignore/

      • Thank you for your response I appreciate it. 🙂 Also I was wondering how can I help move these trials forward regarding antivirals for EBV into clinical trials how can I help ? 🙂

  • How about ”toxins” in general so : Through diet, polluted air, solvents/cleaning agents and of course self-care products which women use a lot of?

    Is there good research on how these ‘Toxins” increase your chance of getting MS?

    • Regarding toxins, there is some evidence that exposure to organic solvents such as painting products and varnish increase future MS risk. The underlying theory is that different sources of lung irritation may contribute to induce an immune reaction against certain proteins in the brain and promote MS development in people with a genetic susceptibility to the disease.

      Regarding diet: Alcohol and coffee did not turn out to increase MS risk. I have not read anything about other toxins. Shift work has also been linked with an increased MS risk.

  • If the atmosphere were free of clouds, every place on earth would receive the same amount of sunlight in a year. The degree of UV irradiation is influenced by the angle of sunlight, but less so than by cloud cover. Some of the highest annual rainfall totals are recorded near the equator; cloud cover is present on most days in these locations. Lima, Peru, gets little rainfall, but on most days the sun is fully or partly obscured by cloud. Arctic regions endure days-long storms, but the worst occur in the winter under already-darkened skies. The “midnight sun” at the height of summer is legendary.

    Meanwhile, supplementation with Vitamin D (and other nutrients) has been popular in some temperate and subarctic regions for decades. As a child in Toronto in the 1950s I was given my daily treat of cod liver oil, at first in liquid and later in capsule form. Vitamins A and D have been added to the milk supply in Canada for several generations. Supplementation may not be as good as UV rays, but that hasn’t prevented its near-ubiquitous inclusion in treatment guidelines and clinical recommendations.

    So the links between Vitamin D, sunlight hours, latitude, and MS prevalence have never seemed to me to be as straightforward as is commonly supposed. The factual construct is a proxy for the indicator that would clad the theory in steel: low early-life serum Vitamin D levels accompanying suspect genetic and infection factors in people who later develop MS.

    Can pwMS and healthy controls whose early Vitamin D levels were recorded for other purposes be recruited to enable direct investigation of the proposed association? I’m sure this question has been asked but I haven’t found such a study.

    As always, thanks for listening.

By Ide Smets

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