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Multiple Sclerosis Causality (science.org)
635 points by nabla9 6 days ago | hide | past | favorite | 243 comments

Here's a link to the article [0].

Just a bit of background - 95% of humans will experience infection with EBV at some point in their lives. Once you're infected, it remains latent, only flaring up in particular circumstances. MS is an autoimmune disease, like many others, and this paper does not imply that EBV directly causes MS. Obviously, as so many more people have EBV than have MS, EBV infection does not completely explain why people get MS.

Just to put a small caveat to the paper. The comparison is to EBV 'seronegative' population - this is a minority of people (i.e. people who do not have evidence of being infected with EBV). You could argue this is an 'unusual' population in the first place and there's something about them that provides protection from MS.

Another point is that EBV is a risk factor, there are other risk factors known too. I think the key to understanding a lot of autoimmune diseases is to understand how our adaptive immune system works. Our immune response is a very complex cell-to-cell interaction between millions of cells all with different roles, and how the immune system decides whether something is a threat or not is not, and how to respond to it, is not yet clear.

[0] https://www.science.org/doi/10.1126/science.abj8222

At least part of the adaptive immune system is implemented in the thymus. As an infant, the thymus makes examples of nearly every type of cell in the body and uses it as negative labelled examples to tune the false positive detector so it doesn't identify self as threat. From an information theory perspective, that's pretty extraordinary (you don't normally expect differentiated cells in an organ to act like cells from another organ).

Another part of the adaptive immune system randomly shuffles different regions of genes together to produce enormous diversity (searching for a rare example of something that "works"), then picks the proteins from those genes that work best and distributes them throughout the body.

Pretty amazing stuff.

Yes, it's really fascinating stuff. Just to add to that, cells must present a continuous sample of their proteasome on the cell surface in the form of a short peptide 9-12 amino acids long. T cells will recognise when the cell is producing protein it shouldn't be (i.e. because it became cancerous or infected with a virus), even if only one amino acid is incorrect.

It learns this in the thymus, which has a bizarre gene called AIRE which switches on genes from all over the body, essentially creating a representation of the entire body in the thymus gland as a sort of sandbox before they are let out.

However, we don't have enough T cells to recognise every possible sequence of 11 amino acids (which would weigh around 1.5 tons), so T cells must be so-called 'cross-reactive'[1]. And therefore other factors must go into how T cells respond to abnormalities.

[1] https://www.nature.com/articles/nri3279

yep, i was referring to AIRE without naming it. I saw a talk about it years ago and it blew my mind. In retrospect, it seems to just sort of fall out from the way you'd expect adaptive immunity to evolve, though.

I don't see many YouTube links posted here, but this Kurzgeasgt video blew my mind on this topic. Our immune system really is amazing.


I would have expected it to send out T-cells around the fetal body to pick up protein signatures. I'm surprised that it makes them all in one place.

Thanks, I had forgotten about this and had actually mixed parts of it up with in-thymic training

Why go samples all the files from all over the filesystem if they are deterministically created from a piece of code you've got a copy of?

To check for corruption, I suppose (validation).

Can't help but to highly recommend the recent book by Philipp Dettmer, Immune: A Journey Into The Mysterious System That Keeps You Alive. It's fantastic and very readable: https://www.amazon.com/dp/B08XTNHRR5/ref=cm_sw_em_r_mt_dp_FX...

What's the connection to information theory?

On information theory [unrelated to the discussion]: both digital information (stored in DNA --4-letters) and analog information (epigenome) can be manipulated for various effects e.g., "Lifespan: Why We Age—and Why We Don't Have To" by Sinclair https://www.amazon.com/dp/B07N4C6LGR/

sorry, I shouldn't have thrown that in there.

Where can I read more about this? Can you recommend a book or something?

I think this is may be one reason they used CMV infection as a control. Unless you think that the people who don't get CMV are not special, but the ones who don't get EBV are...

Yes that's a good point.

As someone with an autoimmune disease, is there anything I can do to prevent getting more? Iirc having one is a risk factor for others

I'm afraid this is out of my scope of understanding. Once the immune system determines something is non-self, the immune system can often self-propagate the response. It eventually enters a tolerance phase where it aims to just 'control' the threat.

There are some known modulators of the immune system, but the medical forms can be especially blunt tools (i.e. steroids). Locally directed treatment is better, and maybe in the future we'll have specially crafted cells that can inhibit a specific response for particular antigens.

There is a long and slightly-controversial link between stress (and lots of other environmental factors) affecting the immune system. I'm not familiar with the literature.

I recently learned (also from HN) that wild-type measles can often destroy your bodies pre-existing immunities to most past threats. I wonder if we will someday be able to trigger a similar effect with a synthetic virus, wiping the immune memory, then re-vaccinate to get back immunity afterwards. But it is practically just science fiction stuff now, as far as I know.

I had Ulcerative colitis for 20 years and managed to get rid of it by changing the diet. I used the carnivore diet, ie eat mostly meat, egg, fish (animal products). Cutting out processed foods, sugar (only 70% dark chocolate) and seed oils. I would recommend trying it for a couple of months and see if it helps, and if you do not notice any difference you have not lost anything. I lost 10% of my body weight without ever being hungry so that might be a nice side effect also.

Crohn's sufferer here. I have lost track of the times people have said "I tried this diet, and then my Crohns / UC went away".. and then some time later their symptoms reappeared. My understanding (via own reading and discussion with my doctor) is that there is just as much evidence against as for a meat-based diet .... or any kind of diet.

As my specialist put it "if there was a common diet that cured people, we would know about it already". Anecdotally one never knows if their UC/Crohn's improves because of their diet or it's just part of the ups and downs of those diseases.

That said, I'm happy in general if I hear a fellow UC / Crohn's sufferer seems to have found something that works for them, especially something that is better for you than steroids and other treatments with severe side-effects.

Yeah, it's also my take that one should be careful correlating ups and downs to things eaten -- it might as well be stress or just bad luck.

That said, if I can get some placebo effect benefits from believing that reducing processed food helps, it might be worth doing -- if nothing else it reduces cancer risks :)

Well actually Dr. Borody discovered a treatment for Crohn that consists of long term abx. He says there are slow growing bacteria that causes it. https://youtu.be/crm4pKz6X2M

He is the inventor of the triple abx therapy for H.pilory so I would listen to what he says.

To be absolutely fair to readers: Please speak to your doctor before deciding on a diet to "cure" an illness, especially since fatty foods can trigger attacks for some folks. Ulcerative colitis has no actual cure, and this is one way one person has managed it a bit better. It might not be recommended for you.

(Sorry, i'm in this thread because I have MS, and there are lots of scam diets claiming to cure it. They don't - at all. They mostly just make folks feel like they have control).

Carnivore diet seems like a perfect excuse for people who don't want to eat their veggies. If you could provide any proven benefits of this diet that other diets don't provide, I'll change my mind.

As someone with an autoimmune disease I can say that this book https://books.google.it/books/about/An_Epidemic_of_Absence.h... Really helped me understand the complexity of what we are talking about. By the way he mention epstein Barr too, it seems that When you are infected is very important.

The prevalence of autoimmune diseases went up during a particular period of time while hygiene increased while other factors went missing that seems important for the regulation of our immune system.

[this is not medical advice] Some things that may modulate the immune system are: vitamin D3, intestinal worms, exercise, diet / fasting, and gradual stimulation of the immune response ("desensitisation").

Off-topic: interesting that we often see IANAL, but very rarely IANAD (I am not a doctor) around here. Either there's a lot of doctors here, or people are more comfortable giving medical than legal advice, which is weird, as medical advice can have very serious consequences.

I think it's just default recognised that you're not getting a doctor's medical advice, particularly not for you, through an internet forum. So, someone would have to tell you they are a doctor, and you'd still not get their medical advice unless you had a consultation with them. That last bit being similar to lawyers reminding people "IAAL but I'm not your lawyer".

Propolis and Cinnamomum verum are great immunomodulators for autoimmune diseases. Echinacea is sold as an immune system booster, and it is a firm nope.

Nope. Since we aren't certain what causes most things, we can't really prevent them. (This research isn't saying they know what causes MS, to be clear).

Realistically, the best thing you can do is basic health stuff. Get activity, eat a variety of healthy foods, and so on. As you can, anyway. Mostly because this stuff improves your outcome if you happen to get another (and probably helps with the one you have - I have MS, and this basic stuff tends to help outcomes)

Helminth therapy is supposed to help moderate it. I did it to get a handle on my asthma and allergies and it worked quite well. There's various websites and support groups which detail the process and why it works etc.

There's a bit of squick factor to get over but it is worth it for the relief.


Had a similar thought when reading the headline. It’s like saying drinking water causes MS.

100.0% of people consume H2O. There is no control group.

I guess titling the article "Multiple Sclerosis Causality" and then immediately going into EBV correlation seems like implication to me.

For anyone dealing with an acute bout of Epstein-Barr Virus, I used 3 teaspoons a day of monolaurin for three weeks to kick it. Research monolaurin, it's fascinating stuff as an antiviral and I can personally attest to its effectiveness.

Or get actual antivirals. IIRC the same thing that's prescribed for HSV works on EBV

Some people prefer God's medicine to man's medicine. To each his own

If God is what it says on the tin then man's medicine is God's medicine. In fact if anything in this world isn't God's then God isn't both omniscient and omnipotent.

Monolaurin is found in human breast milk and coconuts. Acyclovir and Ganciclovir were synthesized by humans in a lab

Human breast milk is also synthesised by humans!

But, more seriously, don't you believe human medicine to be inspired by God? What about other human activity?

Acyclovir is shown to decrease viral replication in vivo. There is no such evidence for monolaurin. So there’s that.

I never understood this argument. If God was against these medicines, why would He allow them to exist?...

I have MS and my first relapse was a pretty textbook case of transverse myelitis of the sort that the EBV can cause.

I know some people have been asking about why that might be the case when a ton of people have EBV, and I think the causality may go the other way: Those of us with something wrong are more likely to both have EBV complications and MS.

There are other viruses like this as well (ones that most people get/have but aren't dangerous). I was on one medication where I needed to be tested monthly because if I got one particular (normally harmless) virus, the suppression caused by the medication meant I would probably die.

There's pretty clearly some sort of relation between the state of one's immune system + how it deals with 'benign' viruses + auto-immunity, and I'm excited to see what the future holds, but for now it's a cool confirmation of something a lot of MSers have talked about amongst ourselves for a while.

> I think the causality may go the other way: Those of us with something wrong are more likely to both have EBV complications and MS.

I'm unsure, but it sounds like you're hypothesizing that EBV infections does not cause MS symptoms, and that instead some some third factor causes both, so that preventing EBV infection would not prevent MS. The paper being discussed specifically considers and rejects this possibility with pretty strong evidence. Indeed, that is the main contribution of the paper. (The fact that 99% of MS sufferers have EBV, way higher than the 90% baseline in the general population, has been known for a while.)

That's why I shouldn't read articles instead of taking a nap. Thanks!

There's other factors too.

All MS suffer-ers have low VitD.(as does just about everyone with an autoimmune issue).

They all have low uric acid too.

Almost all MS sufferers (same more most autoimmune) can also trace their disorder back to an extreme stress event too - divorce, loss of a loved one, falling into health anxiety, etc..

Are these causes or effects?

I'm guessing there's compounding factors.

Or that people who can't clear EBV may be unable to due to some deficiency that also cause them to get MS

Still a super interesting paper

> There are other viruses like this as well (ones that most people get/have but aren't dangerous). I was on one medication where I needed to be tested monthly because if I got one particular (normally harmless) virus, the suppression caused by the medication meant I would probably die.

For those curious, I’m going to guess and say this might’ve been Tysabri (natalizumab) and that the virus in question is JCV (John Cunningham virus). After approximately two years on Tysabri, people who test positive for JCV antibodies (approx half the population of the US) have an extremely high chance of developing an often-fatal brain infection called PML (Progressive Multifocal Leukoencephalopathy).

Tysabri was originally pulled by the FDA due to PML deaths back in the early 2000s, but later got reapproved after the link to JCV was discovered. Nowadays patients get tested for JCV antibodies every 6 months. The treatment is considered quite safe now, with the caveat that if you test positive you cannot get Tysabri anymore. Most people don’t switch from negative to positive, but it happens occasionally.

Source: my wife has a rare form of MS and has been on Tysabri for about 5 years now, relapse free. Modern MS drugs are a scientific marvel.

Monthly 3-4 day fasts - combined with a healthy diet in between (Mediterranean for ex) do wonders for autoimmune issues as well.

It was found fasting kills off old immune cells and activates stem cells to make new ones.





In plain English



Confirm. My brother is was on Tysabri for more than 5 and recently got confirmation of JCV. The checkup is however more regular. Blood test + MRI + symptoms check every three months, as if done less regularly would increase massively the risk. If JCV flare up is detected they’ll need to flush/wash the Tysabri away from his bloodstream.

He also got a severe mononucleosis infection before being diagnosed, and at that time we all thought that could have been the cause.


Well said. I said the immune system should be to blame in the previous thread and was downvoted to hell. But it’s true. What’s more, it’s highly under appreciated that the immune system is extremely ancient and it does a lot more than the typical things associated with it like destroying tissue. It pulls deep metabolic levers that can make critical cells, including brain cells, latent. It can do many amazing things. In the future, the immune system won’t be known for immunity — it will be known as something like the second nervous system and will be associated with the nth great wave of medical progress when we finally conquer it and all the hundreds of diseases it causes. Diseases we don’t even have a name for now, I know for a fact.

An immunological biomarker aasociated with MS had been discovered a few years back, but sadly nothing came of that research. https://www.nature.com/articles/s41598-017-04439-5

I think even if we find some markers it won’t be enough. It will take a full blown revolution in how we measure human anatomy in a clinical setting. That’s why it’s taken so long.

To be fair: I have MS. I've never had EBV with symptoms that I know of - which is absolutely normal. When folks catch it as children, there are generally zero to no symptoms. And I'm not alone, judging by activity on MS related sites.

I wouldn't take the word of "a lot of MSers" - I mean, there are folks that push the scam WAHLS protocol (diet) as a cure, too. Unless the folks are researchers, an MSer's thoughts about what causes the disease are often just as baseless as a non-MSer.

> I think the causality may go the other way

The whole point of the article is that this isn't the case.

What is interesting is that Epstein-Barr has been reported to be related to Multiple Sclerosis since the early 1980s.


It is great if there is new information and if this leads to knowledge on how to reduce the chance of getting MS.

Cause is still not well explained. EBV is such an ubiquitous virus, more than 90% of all adults worldwide have been infected with it. Most will never know. Why is that just a tiny percentage develop MS?

Good question, if I am correct there is also a higher chance to develop MS if you are a woman and if you live in the northern hemisphere and some parts of Australia and New Zealand.

Also if you are of Northern European descent the risk is higher if I remember correctly.

Possibly it's a mix of many things and you have to be one of the unlucky people where that mix triggers something in the immune system and the disease develops.

I am very unlucky in that regard.

According to my doctors the number of autoimmune diseases I have is rare in a single person.

I have a sysmetic autoimmune disease (Rheumatoid Artritis) and autoimmune diseases in my kidneys, liver,thyroid, skin and mouth.

So somehow multipe times there were events in my life where a mix of things caused my immune system to turn against me.

A little off-topic, but to give an impression of how that works out in daily life, in case you are also diagnosed with an autoimmune disease.

If you are lucky, there is good medication and you will hardly notice you're ill, except for the checkups with your doctor

I also know some autoimmune diseases can (become) pretty aggressive, but n=1, most people I know with autoimmune diseases have a decent quality of life.

Fortunately, in my case also for each disease there is medication that either supresses the inflammation or the protects my body against the effects of the auto-immune response.

So I take my pills and a bi-weekly injection with a biological and I can continue to live with a decent quality of life.

Except for one important thing, my main remaining symptom is that I have a lot less energy than most people and need much more sleep.

Despite that all inflammation parameters in my blood show no signs of inflammation or activity of the disease, my body somehow loses energy to something.

This seems to be a complaint of many autoimmune illness sufferers, no signs of activity of the ilness, but more tired than before the disease came into their life.

Hopefully there will soon be more developments in this area of medicine.

Yes, inflammatory signals can and do pull metabolic levers, something that is criminally under appreciated, and this can manifest as feeling tired somehow. There is absolutely a connection.

> if I am correct there is also a higher chance to develop MS if you are a woman and if you live in the northern hemisphere and some parts of Australia and New Zealand. Also if you are of Northern European descent the risk is higher if I remember correctly.

I believe this has been largely disregarded. The higher incidence rate in Europe/Anglosphere was a consequence of higher testing and accurate diagnoses, coupled with the ability to provide treatment.

EBV is associated with a lot of things that involve a tiny percentage of the population. Nasopharyngeal carcinoma, Hodgkin's lymphoma. Non-Hodgkin's lymphomas. Post-transplant lymphoproliferative disease. Burkitt's lymphoma. Oral hairy leukoplakia. Related viruses are associated with other diseases, e.g. HHV-8 and Kaposi's Sarcoma, primary effusion lymphoma, and Castleman's disease.

Is there an estimate anywhere of the total health burden of EBV, making reasonable assumptions about causality for the diseases you describe? Would be very interesting to know so you could compare it to the risk of a future EBV vaccine.

I calculated it on my blog a few months ago: Every year, it causes the loss of 4.6 million disability-adjusted life years due to cancers alone, and another ~2 million to autoimmune diseases like multiple sclerosis.


What are the reasonable assumptions about causality?

Welcome to the immune system :p

Most people don't develop food allergies. Especially most adults if they don't have a family history of it/didn't have any food allergies as children. Those that do typically only develop 1 or 2.

I can't imagine how infinitesimally small the odds of this happening to me are, and yet here I am, at age 31, with nearly 30 food allergies that all activated about a year ago, seemingly overnight. No known cause, and after a year of researching the immune system and just how depressingly little medical science knows about it, I doubt I'll ever know, let alone receive a treatment that will allow me to eat like a normal person again.

And that's just one way in which the immune system can go haywire. There's MS and all the dozens of other (auto)immune issues -- so many that some don't even have a name. It is truly baffling, but the immune system has gotta be one of the single most complex systems known to man. There's a whole lot of ways something like that can break.

Pardon my ignorance, does this mean you won’t have allergies if you take an immunosuppressive drug?

Why only a small percentage of those who contracted polio got paralysis? Interesting, but for now let's settle on eradicating ebv to hell

This question, though very worthwhile, doesn't necessarily need to be answered. Vaccines for EBV are under development. If we stop most EBV infections, we can stop most MS.

Doesn't help you if you've already got a persistent EBV infection though, and the host immune response to EBV may be something that you want to avoid stimulating if you've already got it in you and can't get it out.

Something like CRISPR/Cas9 editing may be the way to treat persistent EBV and other herpesvirus infections.

Maybe, though it appears that covid vaccines help clear long covid, so maybe not. Until we have a vaccine we cannot study this to see how or if it works.

Persistent EBV and long COVID are very unlikely to share any mechanisms, those are apples and oranges.

With little protein expression, training T-cells to identify viral MHC-epitopes is unlikely to ever clear something like EBV. There's no proteins, there's no virions, there's no proteases, the better target is the genome itself:


New vaccine to ebv targets also the proteins exposed during latent phase.

Yeah, but will the vaccines be effective? EBV is amazingly good at immune evasion. Prior antibodies don't protect against re-infection.

Vaccine is no guarantee though, just look at Covid. DW was recently covering breakthrough cases that led to Long Covid. You're speculating now.

Right but when was the last time anyone you know got polio? Vaccines aren't 100% effective but if we can get the average susceptibility to the virus in the population down far enough (even though it'll never be complete) there's a threshold where the virus can have a hard enough time hopping that it really makes a difference.

I don't see where gp assumed a vaccine will be effective. Note "if".

This study appears to suggest that MS is essentially "long Epstein-Barr." Terrifying if the same pattern holds for covid, given the number of people who have some sequelae (the most conservative estimates are 2-5% for "serious" post-viral symptoms, which would be hundreds of millions of people worldwide). There will be an extraordinary amount of suffering, not to mention radical shifts in economic and public policy.

There's another paper from June of last year[0] that proposed a long COVID explanation: Epstein-Barr reactivation. I haven't seen any follow-up work yet, but if both that and this paper have any predictive power to them[1] we might start seeing a cohort of "long long COVID[2]": people who got COVID, didn't recover, and then progressed to MS.

[0] https://pubmed.ncbi.nlm.nih.gov/34204243/

[1] I'm particularly worried about the "EBV reactivation" theory as COVID-related studies have been used as a vehicle for many medical frauds.

[2] As per ISO standards long long COVID must have an infection duration represented with at least a 64-bit machine integer

That sounds unlikely. Epstein-Barr is a herpesvirus, and it's persistent - once you catch it, it stays latent in your body and you'll shed it through your saliva periodically for life.

As far as I can find, coronaviruses have no way to pull that trick. Once your immune system gets rid of it, it's gone and not coming back unless you're infected again by a sufficiently unrecognizable relative.

Like my uncle, Oscar? He looks nothing like anyone else in the family and looks out of place in family photos. I’m pretty sure he is antivax, too.

Coronaviruses do a weird thing where their viral RNA persists in cells long after the initial infection. [1] No one knows if this has a bearing on long COVID or not.

[1] https://www.nature.com/articles/s41592-021-01145-z

Yeah, I don't trust the viruses not to do sneaky shit. Not at all.

It's not a terribly weird thing for a virus to do, but as far as I know (just an interested amateur) coronaviruses can't use this to stay latent.

We don't really know. A recent manuscript submitted to Nature shows minute persistence in various tissues as long as 230 days or more post-infection. [1] RNA is fragile, if the infection is completely cleared or not integrated into the genome in some way we would not expect it to persist.

[1] https://assets.researchsquare.com/files/rs-1139035/v1_covere... (Figure 1)

I would be hesitant to generalize from existing coronaviruses to SARS-2. As the sibling comment points out, SARS-2 has been shown to persist in every organ of the body well after initial infection.

The study really doesn't suggest that. All it suggests is that EBV seropositive people are much more likely to develop MS than the seronegative minor population.

As for long COVID, the data quality is very variable. I'd like to see a controlled study that compares recovery from COVID vs. other respiratory viruses.

It's pretty clear that the causal explanation is the only reasonable one here. (Besides, at least for covid, not everyone who contracts the virus develops antibodies for it: https://journals.asm.org/doi/10.1128/Spectrum.00904-21 )

There's a reason I quoted conservative estimates of long covid. The 2% is from this ONS study: https://www.ons.gov.uk/peoplepopulationandcommunity/healthan.... The high end of estimates is 10-30%, which would mean the end of our current era of civilization.

There are lots of viruses that persist forever. You can get chickenpox as a kid then die of shingles as a retiree. Measles might give you only mild symptoms then 6-15 years after reactivate and cause Subacute sclerosing panencephalitis (SSPE), a fatal brain inflammation with all the interesting symptoms that implies (starting out with mood swings progressing into dementia, muscle spasms and blindness).

Think of this the next time some brain dead person starts talking about the "unknown long term effects of the vaccine" - we know what has long term effects, and it's freaking live viruses!

Terrifying - I was EBV positive 4 years ago. It does not mention an association between EBV severity and MS, but I was very symptomatic and had post viral fatigue for around a year. I had no idea about the MS association!

> According to epidemiological studies, the EBV is estimated to be positive in more than 90% of the world's populations

- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008310/

> A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population)

- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720355/

Given that you have EBV, I guess you're in the unlucky 90%, increasing your odds from 359 in a million to a ...whopping... 399 in a million.

Since the risk for the non-EBV group is 32x less, you'd be increasing your odds from like 11 in a million to 399 in a million no?

If you knew you were negative yes, if the status was unknown then not.

Calm down... from the article:

"Note, though, that EBV would then be in the "necessary but not sufficient" category. There's something about the interaction of particular human immune systems with EBV infection that pushes things over into the pathological state of multiple sclerosis, and we don't really know how to identify these people. But that fits with what we know about infectious disease in general - everyone's different. The situation with Guillian-Barré is similar - a small number of people tip over into neurological pathology, for reasons unknown, and that one also often seems to follow some sort of viral infection."

That's a good quote, thank you.

About the use of "calm down" as an instruction: while your sentiment is good (to reduce another person's anxiety), it's not always possible for someone to follow that when it is received as an instruction. It's tricky to estimate other people's emotional state based on text, and for them to infer your tone. I'm overexplaining and sure that you probably understand all that; but it feels worth mentioning.

> About the use of "calm down" as an instruction: while your sentiment is good (to reduce another person's anxiety), it's not always possible for someone to follow that when it is received as an instruction.

this is a pet peeve of mine. something i picked up when i was a counselor at a special needs camp was the idea that everyone (regardless of where you lie on any spectrum) has a unique sensitivity to criticism. it's important to NOT treat people how you would like to receive criticism, but to assess how you think they would best consume and digest it. obviously, this is extremely difficult on the internet and i'm just nitpicking but i had an altercation with my sibling earlier when they told me to 'calm down' so i'm still on edge about it.

i'm sure OP doesn't need to hear this but typically i find that a good alternative is to nudge someone into rationality. not to say that the parent comment is irrational, but when you simply show someone why they may be overreacting, they may very well 'calm down' all by themselves. if said person refuses to acknowledge your rationale, it's likely they aren't welcome to any criticism at all and won't be 'calming down' in any capacity.

True. My first reaction to the directive, was that it was rude. Reading more of the context attenuated that impression, but I still think it could have been phrased less ... paternalistically?

You could be onto something there, yep.

Communication is hard.

It is, but there are some easy heuristics before you get to the hard stuff.

One is that telling people how they should feel about things is usually irritating.

It certainly is.

Here's a (probably totally unrelated) comment that I think is good food for thought: https://news.ycombinator.com/item?id=29917158



There is one more condition you may be interested in: CFS/ME. It manifests itself primarily as a chronic fatigue and is believed to onset after a trigger event: virus, intoxication, hypoxia, stress, and the like.

I talked to some people with MS and most of them told me the same story: the trigger event, followed by some time, then onset of a full-blown MS.

I wonder: are those diseases really different? Or maybe this is the very same disease but with a bit different outcomes: myalgic encephalopathy vs sclerous plaques. Both are driven by the inflammation, both have the same initiating sequence.

What leads me to strongly suspect that it may be just different manifestations of the same disease is the involvement of mitochondria in both MS and CFS/ME.

And along with CFS/ME, also look up POTS, MCAS/MCAD, and EDS. My wife had a very bad bout of mono in late high school and 15 years later developed POTS, MCAS, and what the rheumatologist called "unspecified connective tissue disorder," which seems like a mild case of EDS. After 10-15 years of trying treatments, she's significantly worse off. :-/

There are tons of people (mostly women) out there with this set of conditions, and they're only starting to be taken seriously. It's a set of life-altering conditions and dealing with the medical system when you have it can be infuriating and exhausting. I hope you don't have any of these things.

My wife also has MCAS, POTS, and a connective tissue disorder that is not at the level of EDS. Was diagnosed about 4 years ago and is on treatments to suppress some immune responses, that has been helpful at taking the edge off some symptoms. It was like tumblers clicking into place when she saw a specialist and got the diagnosis, so many rather disparate, long-term symptoms all from the same cause.

POTS, MCAD-like (hyperlipidemia) and inflammatory conditions are triggered by CFS/ME as well.

I am really puzzled: are we dealing with the same thing but under different names?

For reference, NSAIDs combined with high-dose vitamin therapy help to resolve those conditions in people with CFS/ME.

In Bergen in Norway we had a big outbreak of Giardia parasite and a lot of people got CFS/ME after that. The Giardia was big because the parasites came into the drinking water from one of the water sources. I myself had this for of this for many years afterwards but one do not notice it since before you get rid of it. I was able to function normally but totally lacked energy, and everything was a chore. It was like the feeling the first time one drinks coffee and experience the way the fog clears up.

Conclusion. The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study.


Also very impressed with google when searching for: giardia leads to CFS

I have this pet theory that CFS/ME is what a lot of long-covid patients are suffering. I knew a few people who have been affected by it, and it really limits them. Just as long-covid seems to.

I came to the same conclusion as well. Moreover, I was somewhat successful in healing post-viral CFS/ME using the therapy targeted at mitochondria with large doses of B1 and B3 vitamins [1].

[1] https://news.ycombinator.com/item?id=29138006

Its worth noting that 80% of those the develop post viral conditions just recover, we don't know why. It is unlikely your intervention is the reason you recovered, the majority of people do even if they do nothing at all. We do know that those that rest and stay below their energy budget have a better chance but that is about it, nothing else has shown efficacy.

Intervention was only applied to people who did not recover by themselves. But almost all of them recovered after intervention which leads me to believe that we are onto something here.

> using the therapy targeted at mitochondria with large doses of B1 and B3 vitamins

commercially available under the brand names... "Red Bull" and "Monster"

Nope. They do not contain the key element - vitamin B1 which is also called thiamine. Instead, they do contain large doses of caffeine which is known to abruptly inhibit thiamine absorption in the body leading to mitochondrial ETC inhibition when a person has deficit.

Then comes sugar - those drinks contain too much of it causing the unneeded insulin spikes. Sugar free variants are even worse - they (esp. aspartame) cause the insulin spikes as well but lead to insulin resistance progression much faster [1]. By the way, Insulin resistance and hyperlipidemia are hallmark signs of mitochondrial dysfunction.

Yes, they do contain some 10-20 mg of B3 (nicotinamide) and that's it. Not enough for the treatment; other key elements are missing.

That's why people with CFS/ME condition do not feel better after energy drinks, usually they feel even worse.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014832/

Super interesting thank you!

They already have B3 B6 B12 (my mistake about M1)

So the energy drinks should contain B1 or be taken with B1, is that what you say? If they don't already have B1, why is it so given the other vitamin B? Could it be for a good reason?

About insulin resistance, Monster contains sucralose and acetasulfame. It's not clear if the effect reported with aspartame also happen with these. Still, a super interesting thing to check - one of the many reasons I love HN!

I guess they do not include B1 because caffeine blocks its absorption anyway. Which is bad.

It is better to have B1 in everything that involves energy instead of caffeine. But B1 will hardly be noticed by the general public while caffeine is addictive for many. Energy drink producers clearly maximize for profits and not for health.

Back in 1980s, there were proposals for a "chronic mononucleosis" or "chronic mononucleosis syndrome" as a diagnosis / standard disease. There were very comprehensive studies trying to investigate the patients who had chronic fatigue and other long lasting debilitating symptoms. After a good decade of studies, the research community found that this group of patients is very consistent (their complaints, symptoms, etiology), but failed to prove EBV as a cause (although the studies did not disprove it either) or at least come up with a clear serological diagnostic criteria. So, in 1990s they decided to define a generic Chronic Fatigue Syndrome (CFS) as a standardized disease. Other viruses and pathogens can cause CFS/ME and a broader definition would sometimes include even psychosomatic patients, so as a result CFS/ME has been quite discredited.

Diagnostic techniques evolved and research progressed. In the recent decade, new studies are very close to proving that EBV is indeed a likely cause of CFS/ME (well, one segment, as there are other causes too). Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/

One important thing to note is that EBV is extremely prevalent. Almost everyone gets it eventually and very few of those people develop MS.

But a lot of people don't really develop severe symptoms either, right?

When I had it, my doctor said that if I was a professional athlete, the standard outcome would be to just consider the current season lost and switch focus to getting well again in time for the next.

I was relatively useless for two weeks and then spent the next four months getting back to my normal energy levels. "Severe" is a question of definitions, I think. I wouldn't consider that kind of illness severe, but it certainly put a dent in things for a while. Properly inconvenient, I'd say. I think this degree is pretty common.

Some develop no noticeable symptoms and many develop mainly annoying ones for a few weeks to a few months. I had the misfortune to develop symptoms from infectious mononucleosis shortly after minor surgery. My GP and surgeon kept giving me antibiotics and sending me back to uni. Finally after several months of fatigue, nausea, and depressed appetite I wandered into campus health jaundiced with a 104º F fever and a temporarily enlarged liver. I ended up withdrawing from that semester and retroactively from the previous one. I was ordered into a month of bedrest and half a year of decreased physical activity while recovering. So I guess we could say there's a wide range of severity, partly depending on how soon it's addressed.

Many if not most folks dont' even realize they get it because they catch EBV as a child. In children, it generally causes no symptoms or symptoms so mild that they are dismissed as a normal childhood virus. You know, the sort you miss 2 days of school for and then go on. This is the reason most folks don't know they've had it.

When we get older - teens and adults -, we are more likely to have it develop into mono or other things that realistically make your life difficult for a while.

If you're EBV-positive, you're in good company... It infects something like 90% of the human population.

Makes me wonder how many virii are out there that haven't been identified by modern medicine because their spread vector is so low-impact that they never even trigger symptoms. A virus like that would become real indistinguishable from "behavior of the human body" in not very much time if its infectivity was high.

> A virus like that would become real indistinguishable from "behavior of the human body" in not very much time if its infectivity was high.

My weird theory: how can we know then if aging (or its acceleration or the diseases usually linked to it) isn't the result of some infection that's super contagious and infects 100% of the people,

It's not weird, it's the same idea I had back in the 1970s, but at that time things like retroviruses weren't known or understood.

Now we know about endogenous retroviruses, and yes, they have infected everyone (going back millions of years) and yes, they do become more active in aging and are responsible for cancers and causing cellular senescence via DNA damage through retrotransposon activity.

You can inhibit them with some of the same anti-retrovirals that work on HIV. Or nutritionally what may work is: high doses of cyanidin plus NAD precursors to stimulate SIRT6, which normally prevents at least one of these endogenous retroviruses, LINE1, from being expressed.

Super interesting. Please tell me more, like what you are taking besides that.

I find it especially interesting how some multicellular macro organisms like jellyfish (one of the oldest ancestor of all non insect animals) have no aging, while humans and most other animals do.

Could it be that their immune system or simply their evolutionary path prevented them from being exposed to such endoviruses, that may simply be too omnipresent (or long integrated) in about every other species to be selected out? (They could also present an advantage at the population scale, by ensuring a quick turnover and therefore more genetic evolution simply by filtering out not just the unadvantageous gene but the older adults, thus offering more opportunities for the new generation to replace them faster)

This could be supported if jellyfish had less requirements for evolution, like a stable ecological niche - something I have no idea about!

Because it's very unlikely the same pathogen or disease would affect shrimp and humans in the exact same way.

Great question. A related question: how many undiscovered viruses exist that are beneficial to the host?

There's the anelloviruses which are at least as prevalent and nobody really knows what they do.

If you're going to develop MS as an adult after getting EBV mononucleosis, it's likely that it will be soon (5-10 years) after you have the initial infection as an adult. There's only a long delay in children according to one study. [1] Every passing year the probability of getting MS should decay after that.

Female sex and EBV mononucleosis during adolescence are the biggest risk factors.

[1] https://nn.neurology.org/content/4/3/e308

Scores of folks with MS never had mono. I'm one of those. It isn't mono that is the risk factor, but EBV itself.

Interesting. My sister and I both had mononucleosis before puberty, and she was diagnosed with MS in her late twenties.

The article says EBV is prevalent and is probably necessary but not sufficient for MS. If I was in that position I would look at my gene test results for any markers that correlate with MS. The more of those markers, the more intensely I would prioritize following relevant interventions.

What are the relevant interventions? Which genes correlate with MS?

That's the independent study part. I wish I could be more help but that research is time and money intensive, and not guaranteed to be fruitful. It also involves review of multiple studies, sometimes several dozen. Then it's about seeing which ones are relevant to an individual's specific genetic mutations.

I'm currently going through dozens of reports from SelfDecode, and that's after massive amounts of work on their end. I think I'm out a few hundred bucks so far, but it is an amazing service. I will soon seek their genetic consultation service, which is about $1k, and their lab testing service.

Genuinely curious, what's your ultimate goal here? What do you optimize for? Total life-years, sum quality-of-life, etc.?

Seems like picking out the diseases you don't want to get/die from is a way to go nuts; curious how you're thinking about this.

I did accidentally traumatize myself by focusing on one marker that basically said "You have an increased risk for degenerative disease x". I had a full-blown psychosomatic attack, and I convinced myself that I was going to die in 5 years. After I calmed down I realized it was probably anxiety. I learned a little bit more about statistics in medicine and realized that my layman's understanding of chance is probably way different than what genetic markers point at (I have no idea what the actual numbers are, but maybe they consider 1 in a million an increased risk, for example).

My ultimate goal is to address some weird ADHD-style issues and an autoimmune disease, holistically. When I go to a stomach doctor he gives me stuff for my stomach, but never asks about how my brain feels, about fatigue, about my skin, etc. I don't blame doctors for specialization.

I've given up on expecting them to be able to "fix my car". That would be silly to ask of an actual mechanic. What I'm doing instead is studying, tweaking and fixing what I can through lifestyle and careful supplementation. Basically, I'm starting with filling the tires with air, changing the oil, etc. Then once I realize my car is still violently wobbling, I'll have a list of what I've fixed myself, and the mechanic can focus on more complex wobble factors.

Thanks for the response, that seems like a healthy way to look at it. I’ve avoided touching any of self-genetics, for fear of finding out I’m going to die of something terrible, thanks for the point about medical stats being nuanced .

EBV causes more severe symptoms the older you are. So everyone here who remembers getting it and it being terrible? That's because you got it as an adult. If you get it as a kid, it can be asymptomatic.

I got it at 36 and had a fever that leveled me for 3 weeks. Between "wait 1 week before bothering your doctor" and multiple rounds of tests, they didn't even diagnose it as EBV until the 3rd week.

I got at 21 IIRC and I was in bed for a few weeks and the doctor started fearing I had a blood cancer or something given how abnormal the tests were until he finally got the idea to test for EBV and it came back super positive.

Never before was I so happy to get tested positive for something lol

It's been a few years and I think I'm fine but due to hedonic adaptation etc maybe for all I know I operate at like 70% of my previous capacity and don't even realize it

So I'm super interested in all that new research and I can't wait until we get mRNA vaccines against EBV!!

How do you even test for EBV? The GP I asked laughed it off when I was living in Canada basically saying I am already positive and no need to test.

If you want to test whether you already had EBV, then it would be a test for Immunoglobulin G (IgG) antibodies to the EBV viral capsid antigen (VCA). It shows whether the virus has established the latency in your body. Most laboratories would just label it as "EBV IgG", so just ask for that.

If you are in your 30 or older, then you most likely have had it already.

thanks for sharing.

does this test for EBV in both latent and lytic phases?

EBV seems very adept at evading the immune system. does this also impact our ability to perform accurate detection (i.e., could current methods yield false negatives)?

EBV VCA IgG antibodies remain present for the rest of your life, as your immune system maintains certain antibody levels to keep the virus in check (it's a delicate host-virus balance).

EBV VCA IgM indicates a primary EBV infection and these antibodies remain for a few months, until seroconversion happens. They might not necessarily be present immediately. During the primary infection, the virus is in active lytic replication which can accurately be shown by an EBV PCR test.

Once the virus establishes latency, EBV PCR will be negative. It may occasionally become positive when EBV reactivates, but it may also reactivate in other compartments i.e. it infects more than just B-cells and the standard PCR test wouldn't show that. There are more antibodies involved and the whole thing is more complex than just the lytic and latent cycles.. the immune system is very complex.

thanks! this answers many questions already. a few more if you don't mind:

1. if VCA IgG antibodies persist for life, how does EBV reactivate?

2. when you say, "may also reactivate in other compartments," this implies that standard PCR tests only verify infection in b-cells? what tests verify infection/activity in epithelial cells?

3. are you on social media? would love to follow you.

4. does VCA IgG detect EBNA2?

They have like 2 separate tests: one for old EBV (IGG) and one for new EBV (IGM or maybe it's the other way around?)

IDK about false positive though

This was a study conducted by the military on soldiers. They all contributed three blood samples over a period of time that were tested for a large number of conditions. EBV was the only one that contributed to MS.

There are at least two tests for it, or at least there were in the mid 1990s. One's a quick clinical test with lots of false negatives than can be done in-office but unless it's a campus healthcare clinic at a university they probably don't bother. The other is a more sensitive lab test that takes a few days. If you're having a really serious set of symptoms they may test to confirm it's not something else. If it's a minor case, two weeks of bedrest fix a lot of issues in a young adult and you do probably already have it anyway.

You can test for pretty much anything in a research setting.

In a clinical setting, doctors will rely a lot on heuristics and practical considerations, and there may not be any clinical testing available.

Even if there is a test, sometimes it is insanely expensive and so they won't give it if they can find any other way to decide.

Wow, I was also EBV positive ~4 years ago (45 months), was symptomatic and I had post viral fatigue for around a year. It was 12 months before I could do light physical training and it was around 2.5 years before I could train physically at high intensity.

Do you have a baseline to compare or are you only relying on your memory?

I got it at 21 and now I fear I may operate at a lower overall potential since I don't have a baseline to compare to

Possibly a co-factor, since many get EBV and few MS.

Found this in my news feed, so this timely. Good news I guess!


Is there any evidence that the vaccine wouldn't also cause MS? From my understanding, MS is caused by the immune response, and the vaccine would trigger a similar (or same?) immune response.

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