Ep 92 Multiple Sclerosis: Scarred nerves & skating saints

Summary

This Podcast Will Kill You

Episode 92: Multiple Sclerosis - Scarred Nerves & Skating Saints (March 8, 2022)

Hosts: Erin Welsh, Ph.D. & Erin Allmann Updyke, MD, Ph.D.
Theme: An in-depth exploration of Multiple Sclerosis (MS)—its biology, history, patient experience, and how our understanding (and treatment) have evolved.

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Overview

In this episode, Erin Welsh and Erin Allmann Updyke unravel the complex world of multiple sclerosis, a chronic autoimmune disease affecting the nervous system. Grounding the episode in the real-life experience of Nikki, who lives with MS, the Erins explore the science behind the disease, its history, epidemiology, challenges in diagnosis and treatment, its mysterious origins, and the extraordinary impact of advocacy.

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Patient Story: Nikki’s MS Journey

[Starts: 01:39]

• Diagnosis & Emotional Impact

  • Nikki was diagnosed with MS at age 27 after an incidental finding from an MRI intended for severe headaches.
  • Faced with her own mortality, she describes overwhelming fear and anxiety over her future and being able to “live the life that everybody gets to live.”

    “Now I'm thinking, I’m going to die, and I’m 27. I haven’t lived the life that everybody gets to live. ... What’s going to happen?” — Nikki [03:05]

  • The diagnosis process was long and grueling—four to five months, including a painful spinal tap.

• Years of Difficult Treatment

  • It took nine years to find an effective medication. Oral medications caused allergic reactions, and self-injections led to painful scarring and failed to halt her disease.
  • Eventually, Nikki started an infusion treatment which helped slow her progression, though the cost ($7,000/month) and side effects were daunting.
  • Infusions increased her risk for a potentially deadly brain infection (PML) due to JC virus reactivation.

• Symptoms and Daily Struggles

  • Nikki details constant symptoms: poor coordination, frequent falls, numbness, “band-like” tightness around her torso, fatigue, slurred speech, bladder issues, and worsening short-term memory.
  • She describes the social and mental challenges—misconceptions about her symptoms, embarrassment, fear of being a burden, and confronting the reality that MS isn’t fatal, but immune suppression could leave her vulnerable to fatal infections.

    "I'm scared as to how my final days will play out, because multiple sclerosis won't kill me, but the fact that I don't have an immune system will kill me." — Nikki [11:18]

  • Despite hardships, Nikki emphasizes gratitude for retained mobility and the importance of focusing on the present.

    "You can't focus on what could be coming. You have to just take every day as it is and be thankful that that's where you are at that moment." — Nikki [12:23]

Hosts React:

"As much as you can learn about the specific biology. ... it just doesn't fully encompass the experience of someone who is living with this." — Erin Allmann Updyke [14:18]
"MS, like many other diseases, are described by a series of signs and symptoms, but those signs and symptoms vary from person to person, and they don't capture the feeling..." — Erin Welsh [14:53]

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Key Concepts & Biology of MS

[Begins: 21:21]

What is Multiple Sclerosis?

• Definition: Chronic, autoimmune, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS).
• Main Pathologies:
  • Demyelination: The immune system attacks myelin (the insulation for nerve fibers), impairing nervous system signaling.
  • Gliosis (Scarring): Scar tissue forms where myelin is lost, disrupting nerve function.

    "You can think of [myelin] as like the insulation around an electrical wire." — Erin Allmann Updyke [23:21]

Disease Course & Symptoms

• Clinical Forms:
  • Relapsing-Remitting (RRMS): Most common (~90%). Flare-ups followed by periods of remission.
  • Primary Progressive (PPMS): Steady worsening from onset (~10%).
  • Secondary Progressive: Can follow RRMS, marked by continuous progression without clear flares.
• Symptom Diversity:
  • First signs can include optic neuritis (blurred vision, pain), limb weakness/numbness, muscle stiffness, bladder/bowel dysfunction, ataxia (coordination problems). Varies greatly because any CNS region can be affected.

    “Anything and everything is the real answer.” — Erin Allmann Updyke [24:22]

Progression and Pathophysiology

• Clinically Isolated Syndrome (CIS): First neurological episode, often resolves 80–100% with potential remyelination.
• Relapses: Over time, more relapses, more scarring, and accumulated disability.

  "Every attack results in like, 80 to 100% recovery... but as these relapses accumulate, the recovery is further and further from the initial baseline." — Erin Allmann Updyke [36:00]

• Fatigue: Extremely common and poorly understood; not just a single nerve malfunction but possibly generalized disrupted signaling.

Diagnosis

• MRI: Detects characteristic lesions/scars in the CNS—key for diagnosis.
• Other Tests: Lumbar puncture (to detect immune changes in CSF), bloodwork, testing for other causes.

  “...For a really long time, it was the case that you could really only make the diagnosis of MS if somebody had a recurrent CIS, and that would then lead you to the diagnosis…” — Erin Allmann Updyke [32:47]

Treatment Advances

• Early and aggressive use of disease-modifying therapies (DMTs), especially B cell–targeting drugs, can reduce relapses and slow progression.
• Symptom management requires multidisciplinary care.
• Primary progressive MS has fewer treatment options.

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The Mystery of Causes: Why and How Does MS Develop?

[41:20]

Genetics & Environmental Factors

• Genetics: Multiple gene variants associated with immune function contribute risk, sometimes overlapping with other autoimmune diseases like lupus or type 1 diabetes.
• Environment:
  • Low Vitamin D/sunlight—suggested increased risk, but evidence is “mediocre.”
  • Smoking—associated with higher risk.

Epidemiology

• 3x more common in those assigned female at birth (not always the case historically).
• Striking variation globally: high rates in North America and Western Europe, lower in sub-Saharan Africa and Asia.

Epstein-Barr Virus (EBV) Link

[43:41]

• Major Discovery Highlighted:
  • Groundbreaking 2022 studies suggest EBV infection is a necessary precursor to MS—raising the risk 32-fold.

    "This paper... showed that infection with EBV increases your risk of MS by 32 times." — Erin Allmann Updyke [47:21]

• How? EBV infects B-cells, and in susceptible people, triggers autoimmunity against myelin. A second paper found cross-reactive antibodies between EBV and proteins on human nerve cells.

  "...They found antibodies that were produced in people with MS that bind to a specific EBV viral antigen and cross react on a specific human cell surface protein that is associated with autoimmune demyelination." — Erin Allmann Updyke [49:25]

• Not everyone with EBV gets MS: Requires other risk factors (genetic, immune).
• Potential for prevention: development of EBV vaccines, using mRNA technology from COVID-19 research.

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The Elusive Origins and History of MS

[56:13]

Searching for Origins—Why Only Humans? Why Now?

• No definitive answer. Humans may be predisposed due to heavily myelinated brains.
• Onset often coincides with the period when myelination ends (~20s), fitting the typical age of MS onset.

Noteworthy Historical Cases and First Medical Descriptions

• Saint Ludwina of Schiedam (1380): Chronic disabling illness after a fall, considered by some as a possible early MS case.
• Augustus d’Este (1822): Kept detailed diaries describing recurrent neurological symptoms now recognized as classic MS.

  “Sitting produces a numbness all down the back part of my thighs and legs… When standing or walking, I cannot keep my balance without a stick…” — Augustus d’Este (via Erin Welsh) [63:15]

• Jean-Martin Charcot (1868): French neurologist who defined MS as a distinct disease by identifying characteristic plaques during post-mortem studies.
  • Early theories linked MS to stress, “illegitimate pregnancy,” and other social factors—a legacy of bias and misunderstanding that contributed to misdiagnosis as “hysteria,” especially in women.

Evolution of Diagnosis and Perception

• Over time, MS shifted from being classified as paraplegia, neurosyphilis, or “hysteria” (wastebasket diagnoses) to a defined neurodegenerative disease as clinical neurology advanced.
• The advent of MRI in the late 1970s revolutionized early diagnosis and validated patient experiences.

Patient Advocacy and the National MS Society

• Sylvia Lawry (1945): Frustrated by her brother’s illness, she posted a New York Times ad, which sparked the formation of the National MS Society and later the International Federation. Her advocacy fostered collaboration, research funding, and celebrity-driven awareness.

  "She brought over 20 leaders in the field of neurology together to try to set objectives for an organization that was dedicated to understanding the disease and finding a cure." — Erin Welsh [82:15]

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MS Epidemiology and Today’s Landscape

[88:47]

• Global Prevalence (2016): 2.2 million+ cases, with highest rates in North America (164/100,000) and Western Europe (127/100,000).

  "It is the most common non-traumatic cause of neurologic disability in young adults." — Erin Allmann Updyke [88:55]

• Latitude Effect: Higher rates further from the equator, supporting (but not proving) environmental factors like sunlight/vitamin D deficiency.

  • But, variations within groups (e.g. low rates among some northern indigenous populations) suggest a multifactorial cause.

• Immigration Patterns: First-generation migrants retain MS risk of country of origin; their children’s risk matches their new home.

• Increasing Prevalence: Diagnosed earlier, treated better, people live longer with MS.

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Memorable Quotes & Insights

• On the complexity of MS:

  "As much as you can learn about the specific biology... it just doesn't fully encompass the experience of someone who is living with this." — Erin Allmann Updyke [14:18]

• On historic misdiagnosis and stigma:

  "MS is not that difficult to diagnose. But there are a lot of misdiagnoses, with doctors most commonly confusing it with hysteria." — Maya Dusenberry, quoted by Erin Welsh [78:36]

• On the future and hope for prevention/treatment:

  "These new studies really showing that EBV is likely... a necessary precursor to the development of MS, meaning that MS is like viral sequelae of infection with this virus. That means that we could prevent MS... if we could prevent infection with EBV." — Erin Allmann Updyke [95:53]

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Notable Timestamps

• 01:39 – Nikki’s MS journey and firsthand symptoms
• 14:53 – Discussion on how standard descriptions fail to capture lived experience
• 21:21 – Biological breakdown: definition, forms, symptoms
• 36:00 – Explanation of how relapses and scarring lead to permanent disability
• 43:41 – EBV breakthrough: recent science summary
• 56:13 – Historical mysteries: why MS? why humans?
• 61:33 – Historical case of Augustus d’Este and earliest clinical accounts
• 73:25 – Changing theories: bacteria, viruses, the “hysteria” era
• 82:15 – Sylvia Lawry: patient advocacy and the National MS Society
• 88:47 – Modern prevalence, latitude patterns, and the current state of MS

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Final Thoughts

The Erins emphasize hope: major progress in the science of MS, the massive new focus on EBV as a key trigger, promising vaccine trials, and a robust culture of patient advocacy. But there is a clear acknowledgment of the ongoing challenges—both scientific uncertainty and the crucial need for compassionate, patient-centered care.

“We are now so much better than we used to be in our knowledge about multiple sclerosis. But at the same time, there are still so many unanswered questions. Why? First and foremost, because without a why, it’s going to be nearly impossible to find a cure.” — Erin Welsh [88:08]

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Resources Mentioned

• National MS Society: Comprehensive resource for symptoms, support, research (https://www.nationalmssociety.org)
• Book: Multiple: The History of a Disease by Jock Murray

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For more about EBV and new science, check the follow-up bonus episode with Dr. Mika Luftig on EBV.

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End of Summary

Transcript

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My name is Nikki, and I was diagnosed with multiple sclerosis in 2007 when I was 27 years old. The silver lining to my diagnosis is that I was lucky enough that my GP found it when she did because it was by complete, pure accident. Had she not discovered it when she did, I probably wouldn't have shown any symptoms for about a decade later, and my condition would have been obviously worse than it was at that time. I was just having horrible headaches, which is not. Has anything to do with ms, so. So she sent me for an mri and I did the test, and she called me the very same day. And the fact that she called me the very same day, I was like, oh, God, what's happening? Something really bad is going on. And she's like, best case scenario, you might have migraines. She goes, worst case scenario, I think you might have multiple sclerosis. So now I'm really panicking because I'm 27 years old. I don't know anything about multiple sclerosis. I know it exists from the media and the famous people that you hear have it now. I'm thinking, I'm going to die, and I'm 27. I haven't lived the life that everybody gets to live. Am I going to be able to get married. What's going to happen.

Then? To determine whether or not I really had multiple sclerosis, I went through a battery of tests over probably the next four or five months.

If you've never had a spinal tap, let me tell you, they are the world's worst creation. There's nothing positive I can say about spinal taps. I hope nobody ever has to have one. But after all that was said and done, it was pretty much 100% certainty that I had multiple sclerosis. And so I kind of had to digest that and face my own mortality. It's hard to kind of grasp the concept that your lifespan is going to be shortened. We all know we're going to die, but we it's off in the far, you know, future and we don't think about it on the day to day. We don't grasp it. It's not something we worry about. But at that point my death seemed to be right around the corner and it was very scary and feelings of depression and helplessness kind of took over and I was just not in a good place in my head just thinking about how all of this was going to play out. But I did end up finding a fabulous multiple sclerosis specialist and he is the best thing that I could have ever hoped for. And honestly I can say without him, I would not be here talking with you today. So over the next nine years, it took that long to find a medication that I would respond to. We tried everything. My body will either reject or not respond to lots of different medications. So with the oral medications, I just went into complete allergic reactions on every single one and it was just not going to be able to happen to stay on it. So then there's the self injectable medications, but they would burn when they would go in and I ended up creating a lot of scar tissue around my body from where I had to inject because there's only so much skin areas you can put them into. But when we were doing MRIs because each drug that you go through you have to wait about six to eight months to see if they actually work. The self injectable medications did not stop any of the progression of the disease at this point. Like I said, it had been nine years and I was just still progressing and falling down this horrible whole. And my prognosis was really grim at that point. We didn't really know if I was going to respond to anything or if I was just needed to prepare myself and get my affairs in order type of thing. But God love my specialist because he did not give up on me. And there are infused medications. So I've actually been on an infused medication now for five years and it is working, which is fabulous. It really has slowed the progression of the disease. The downside of my infusions, one is the cost. My infusion is about $7,000 a month and had I not had insurance, there would be no way for me to receive this medication that would save my life. I, I would have to just die because you can't afford $7,000 a month. Also with my medication, I get very tired. Like the day before and the day of I'm tired and sort of the day after I'm tired. So it's good like 48 hours to 72 hours where I'm kind of just have to be still and relaxed. My body just doesn't function. And the last thing that's kind of scary about my infusions is it interacts negatively with something called the JC virus, which we all have, most of us have in our brains, but nothing really happens with it because it's never really activated. But this drug will activate it. And when it is activated and you're on this medication, your risk for PML goes right up, which is a really long medical term. But basically it's a brain infection that can cause death. So that's kind of scary. Every time I sit in the chair once a month going, is this the day? I don't know. Since it took such a long time for me to find the medication that would help me, I had gone from the beginning stages of Ms. To the secondary stages of Ms. What that means is I don't have flare ups anymore. My conditions and my symptoms are with me every day, all the time. Nothing changes. So my motor nerves are what's mostly affected. And so my coordination's off, my balance is off. I trip and fall a lot. And a lot of people get uncomfortable when that happens because I don't think a lot of people are used to seeing someone just fall flat on their face and start laughing. So I definitely was a klutz before ms, but now have really shined in that area. I also have a lot of numbness and tingling in my hands and my feet, they shake sometimes. Sometimes the numbness gets so bad I have to look down at the ground to actually make sure that I'm standing. I can't feel it or I have to look down at my hands to see if I'm holding something because I just can't feel the nerve endings at the end of my fingers, it just isn't there. I get tired a lot. I lose motivation to do things just because my, my body is so exhausted. Recently, I've started slurring my speech a little because my tongue just can't keep up with my brain impulses. So it sort of sounds like I'm drunk and trying to explain to people that I'm not drunk when they think I am. They don't really list it because they're like, yeah, no, you're just wasted. I'm like, no, it's 2 o' clock in the afternoon. I'm just trying to explain to you what's happening. But I would have to say the most humbling symptom that I have with my multiple sclerosis is the loss of bladder control. That is an incredibly embarrassing sort of dejecting thing to experience because it makes you feel like you're incapable as an adult. You know, you've gone back to being a child and not being able to make it to the bathroom on time. Recently, my short term memory is abating me. I need sticky notes to get through my day, otherwise I don't know where I am. Sometimes I'll be in the car, I'll be driving, and I have completely forgotten where I'm going. But even after all of that, I'm still one of the lucky ones who have multiple sclerosis because at this point, I don't need any assistive devices to move around. I don't need a cane yet or walker. I do know, though, that in the future I will most likely be confined to a wheelchair. I'm not thrilled about that, obviously, but I'm sort of resigned to it. My worry is that as my disease progresses, I'll become a burden on my loved ones that will have to take care of me because I won't be capable of doing that. And I'm scared as to how my final days will play out, because multiple sclerosis won't kill me, but the fact that I don't have an immune system will kill me. So I don't know if it'll be pneumonia or some sort of sepsis or at this point, Covid, it's, it's like a grab bag. And so that sort of fear of the unknown really just overwhelms you at times, and you just want to sit on the couch and say, well, what's, what's the point? But at the end of the day, you just have to do your best and get up and try to keep going.

And see the Lucky side, the bright side, that I still can walk on my two legs and I still can have a full life where I walk my dogs or drive a car. So as much as the dark thoughts want to take over, I have to try and really stop and remind myself that is a day by day, you can't focus on what could be coming. You have to just take every day as it is and be thankful that that's where you are at that moment. And that's my story.

Sam.

Wow.

[B]

It's just. There's just. There's just so much.

[A]

Yeah.

[B]

Thank you so much, so much, Nikki, for taking the time and being willing to share your story with us.

[A]

Yeah, thank you. We really appreciate it.

[B]

Yeah, we do. Hi, I'm Erin Welsh.

[A]

And I'm Erin Allman Updike.

[B]

And this is. This podcast will kill you.

[A]

Today we're talking about multiple sclerosis.

[B]

We are.

This is a very complicated topic.

[A]

It is. It's complicated in so many ways. And I. I want to say thank you again, Nikki, for sharing your story. I think, especially for a topic like ms, it's so important to be able to hear from people that are living with this disease, because as I think we'll kind of see in the biology section, as much as you can learn about the specific biology of what underpins this, it just doesn't fully encompass the experience of someone who is living with this, you know? You know?

[B]

No, exactly. That's something that I came across a few times, too, in the history research, is that, like, ms, like many other diseases are described by a series of signs and symptoms, but those signs and symptoms vary from person to person, and they don't capture the feeling of someone. Like, how does it feel to, you know, experience this symptom or this sign? And so it just. I think that it really shows how inadequate our, you know, diagnostic criteria are. Not even diagnostic criteria, but how inadequate our definitions of disease really are.

[A]

Yeah. And our. And our measures of things, too, because, you know, we can measure, like, life years lost or. Or disability scales and things like that, but that doesn't encompass, like, so many other parts of your life.

[B]

Yeah, no, absolutely. So.

[A]

So, yeah, I think it. That's very true for a lot of the chronic diseases that we've covered on this podcast, like sickle cell. I feel like that a lot. With cystic fibrosis, I felt like that a lot. So I very much appreciate you, Nikki. Thank you so much.

[B]

Yeah.

[A]

Well.

[B]

Well, is it quarantini time?

[A]

It is. It is. After that, it's quarantining time.

[B]

What are we drinking this week?

[A]

We're drinking Sylvia's Sour.

[B]

This is named for Sylvia Lowry, who I'll talk a lot more about her later. But basically she was an incredible person who essentially like founded the National Multiple Sclerosis Society and also helped found the Multiple Sclerosis International Federation. It's just like she did such an incredible amount of work to raise awareness and research funds and support funds for people living with Ms. So we wanted to honor her with a quarantine drink.

[A]

So Erin, what is in Sylvia's Sour?

[B]

It is orange and mango and rum and lime juice and some mint and yeah, I don't remember fully, but I will post the full recipe on our website. This podcast will kill you.com along with the non alcoholic placebo Rita recipe and I will also post both on our social media pages, Twitter, Facebook, Instagram, etc. So check it out there on our website.

[A]

This podcastwithkilly.com you can find Anything that you've ever wanted to find in relation to this podcast would kill you. You can find our merch, which we have some pretty incredible merch. You can find a bookshop.org affiliate. You can find transcripts of all of our episodes. You can find links to the sources that we've used in every single episode. You can find Bloodmobile who provides our music. You can find a Patreon page. You can find everything, anything.

[B]

Lots and lots of stuff. I actually wrote it down on a post at this time, but I left it upstairs.

[A]

Well, there you have it.

[B]

Do we have any other business or should we get into the episode?

[A]

I think we should get into the episode right after a short break.

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Multiple sclerosis, or ms, is an autoimmune, inflammatory, chronic, demyelinating, neurodegenerative disease of the central nervous system.

[B]

That's a lot of adjectives there.

[A]

It's a lot. It's a lot of words. I know, and we'll get into all of them and what all of those things mean. But there are basically two major processes at play in the pathology of Ms. Demyelination, which occurs in an autoimmune fashion. So our own immune system attacking our nerves along with inflammation, and then scar formation or gliosis that then results in nerve damage. So those are kind of the two big picture things that are happening.

[B]

Okay.

[A]

Ms. Has several different classifications, and we'll go through them all in a bit. But the relapsing remitting form of ms, which is often called RR or rms, is the most common. I think most sources I found said up to 90% of cases are the relapsing remitting form. And then there's the primary progressive form, or PPMS, which is less common, about 10%, and then a secondary progressive that can result from the relapsing remitting form.

So in terms of the pathology, at its core, what's happening in Ms. Is that our neurons become demyelinated. We've talked about myelin, I think, before on this podcast, but I can't remember what episode. And I tried to look through my notes and I couldn't find it. But anyways, myelin is the sheath. It's the outer layer of our nerve axons. It's like an insulating layer that surrounds our nerve fibers. You can think of it as like the insulation around an electrical wire.

[B]

That's exactly how I was thinking about it.

[A]

Yeah, that's how it's most often described.

[B]

Oh, yeah.

[A]

So without this, you know, insulating sheath, nerve impulses can't travel. Either they can't travel as quickly as they're supposed to, or they can't travel the way that they're supposed to. Or sometimes they can't travel at all. They just simply can't make the jumps they need to make. Hmm. So as this process of demyelination, which literally just means, like, the myelin sheath is going away. As this myelin sheath becomes destroyed, nerve impulses aren't traveling from our brain to whatever target organ they're supposed to.

And then this can lead to any and all different kinds of neurologic symptoms because of this lack of signal transduction. And so that's what the kind of symptoms can look like. What does that actually mean in terms of disease? Let's talk about it.

[B]

Anything and everything.

[A]

Anything and everything is the real answer. So Ms. Often starts with what is called a clinically isolated syndrome or a cis. This is, and I think, like 85% of cases, the very first manifestation of Ms. And it can be almost anything that's neurologic. And it just depends on where in the brain or the spinal cord this demyelination happens. So let me give you an example. One relatively common presentation that happens in about 20% of people as the first sign of Ms. Is something called optic neuritis. This is when the demyelination and this inflammation happens to affect the optic nerve, which is our second cranial nerve. Optic neuritis, when it's like this presenting sign of Ms. Usually happens as a pretty abrupt onset of blurry vision or loss of color vision or complete loss of vision in one eye, or sometimes the presence of like a black spot or a scotoma in the middle of your vision and pain with eye movement because of this inflammation that's happening in the nerve.

[B]

Okay, why is this one of the first signs?

[A]

Great question. It's just a common place that Ms. Affects is the optic nerve in your brain. And so.

It'S just a common place that you will then have Ms. Presenting. And I know that's not a very satisfying answer.

[B]

Well, there's not a lot of satisfying answers in I think this episode, probably.

[A]

Yep. Yeah. But this optic neuritis doesn't occur exclusively in Ms. It can occur in other disorders as well. But usually in Ms. It happens just on one eye rather than both eyes. Though in theory it could happen in both. And in other disorders it might be more common to happen in both eyes at the same time. But that is sort of just one very small example. This type of demyelination and inflammation can happen in any part of the white matter, which is where the myelin containing nerves are in our brain or our spinal cord. So some other common presentations of this clinically isolated syndrome or this first time presentation of what will then be Ms. Could be weakness in one or more of your limbs.

It could be spasticity on the flip side, which is where, you know, the muscles become very either flexed or they get stuck in an extended position. And that can be very painful.

You can have abnormal sensation like numbness or tingling in the arms or legs, or even one that kind of comes up commonly is like a band, like sensation of like a squeezing band feeling around the rib cage.

[B]

Hmm.

[A]

If the autonomic system, the autonomic system parts of your brain are what's affected. You can have bladder or bowel incontinence or loss of function. If it's the cerebellum or parts of the brain stem that are involved, then you can have difficulties walking, like we've talked about on this podcast before, ataxia, where you just can't coordinate your movement so you gait difficulties. So the list of possible symptoms is very, very, very long.

[B]

And it just depends on like where the demyelination and inflammation is happening.

[A]

Exactly. Right.

[B]

So I have a question about the demyelination. What is that? Like, how fast of a process is that? And I mean, and maybe this is like, way looking ahead to the future. But is like, when does myelination in general happen? And is there any possibility for, like, remyelination?

[A]

Yeah, yes, we'll talk all about that. Okay.

[B]

Yes.

[A]

So in general, to be classified as, like a clinically isolated syndrome, these symptoms come on anywhere from over a matter of hours to a few days. So they happen kind of gradually. So this demyelination is like, it's a process. It's not just like. And all of a sudden the myelin's gone.

[B]

Okay. It's like an unraveling almost.

[A]

Right, okay. Yeah. But it does happen relatively quickly. So they come on within hours to a few days. To be classified as a clinically isolated syndrome, the symptoms have to last for at least 24 hours. So we're not talking about, like, numbness that comes on and lasts just a few hours and then disappears. This is something that comes on, lasts at least a day, but usually for days or weeks, and then does resolve. And generally, especially with a clinically isolated syndrome or a first time presentation, people do tend to recover to about 80 to 100% capacity. So in the case of something like optic neuritis, you have loss of vision or drastic change in your vision, it lasts for at least 24 hours, and then it gradually improves back to pretty close to or at your baseline level of vision. And that happens with essentially remyelination of your nerves.

[B]

And then how does that happen?

[A]

Oh, Erin.

We'Ll have to get into all of it.

[B]

Okay. Okay.

[A]

Sorry. You're okay. It's good questions. There's just too much.

Okay, but. So that's the symptoms.

One of the key things, because obviously all of those symptoms are incredibly broad. And it's not just Ms. That can cause any of those symptoms.

[C]

Right.

[A]

They're not specific in and of themselves to Ms. Necessarily. So one of the key things to discern, especially with a first time presentation of an isolated neurologic symptom, is whether or not there are associated MRI changes. So MRI magnetic resonance imaging is a type of imaging that's really good at looking at soft tissues and our nervous system. And there are a number of different MRI changes that you can see on different, like, types of MRI imaging, which I am not a radiologist, so I'm not about to get into.

But there are a number of different findings on MRI that Can be relatively specific to Ms. Right. So if you have these symptoms consistent with a cis, a clinically isolated syndrome, and you have these typical findings on mri, you are very likely to then go on to develop Ms.

[B]

Okay.

[A]

And with new diagnostic criteria, if you find more than one of these MRI findings that are separate in time and space. So either like two symptoms with two different lesions on mri, or maybe you have lesions without symptoms, but you have lesions in different stages of healing in different places in your brain and spinal cord that together can lead to a diagnosis of Ms. Even with a first time presentation. Does that make sense?

[B]

I think so. So basically, like, if you go to a doctor and you say, okay, I have a loss of vision in one eye and I have tingling in my hands, and then you get an MRI and they see two separate lesions associated with those two symptoms, then you get a diagnosis. Potentially.

[A]

Potentially, yeah. But it even could be that if you just had loss of vision and that was your only symptom, you could still have brain findings on MRI even without having clinical symptoms.

[B]

Right, okay.

[A]

And that is kind of a really big deal, because for a really long time, it was the case that you could really only make the diagnosis of Ms. If somebody had a recurrent cis, and that would then lead you to the diagnosis of the relapsing, remitting type of Ms.

There are other, like, things that you can do. You can do lumbar punctures to look for findings that are indicative of Ms. So there's a lot of different, you know, kind of things that you can put together to try and make an earlier diagnosis of Ms. Now than we ever used to before, which is a big deal, as we'll talk about later, when it comes to, like, starting early treatment.

[B]

Right.

[A]

So, but then what tends to happen with ms, especially without treatment? In the most common form, the relapsing remitting form, is that after this first cis, this first presentation, there are recurrent relapses or attacks. And generally, especially early on in the course of disease, between the relapses, people tend to not have symptoms. But over time, as these relapses occur, and remember, each one of these could be any of those neurologic presentations. One time it might be my hands are tingling. Another time it might be I can't move my legs at all. Another time it might be I go blind in one eye. It could be any of those or any combination thereof. And over time, as these relapses recur, they result in progressive worsening of disability, progressive loss of. Of neuronal function. Because what happens is that every time this demyelination process occurs, not only do you have acute inflammation and a lot of immune reaction in that area, but then there is damage to the underlying nerves, and that's difficult to repair. So our brains and spinal cord can repair the myelin sheath. We have cells that. Their job is to make myelin, and they can do that. But as part of our body's natural repair process, there's scarring that happens in the brain. We call this gliosis. And this scarring then leads to progressive disability over time.

[B]

Right. So is that just because, like, the myelin sheath can't be fully repaired or can't function the way it used to.

[A]

Or it's both a process of damage to the underlying NER nerves underneath that myelin sheath. Right. So you have direct damage to the nerves. You also have inflammation causing damage to the cells that are repairing the myelin. Right. To the cells that are responsible for making the myelin. And then as part of our repair process, like, there's different kinds of repair in our bodies. There's regeneration, and then there's, like, repair with fibrosis and scar formation, and that's part of our body's natural repair process. But that scarring then leads to neuronal damage.

[B]

I see.

[A]

So you can kind of think of it as. Sometimes the statistics say that every attack results in, like, 80 to 100% recovery. So if you think of it as 80% recovery and scar formation and then 80% recovery and 80% recovery, as these relapses accumulate, the recovery is further and further from the initial baseline.

[B]

Mm. Yeah.

[A]

So over time, especially without treatment, relapsing, remitting Ms. Can lead to what's called secondary progressive ms, which is where instead of seeing these discrete relapses of, like, new symptom onset and then recovery, you just now have, like, a progressive accumulation of neurologic dysfunction and disability. Gotcha.

[B]

I have a question about one of the symptoms that's often reported.

[A]

Yeah.

[B]

And so, you know, you talked about how. Well, the. The symptom that you feel is related to where the demyelination and inflammation is happening, which completely makes sense. But fatigue seems to be. So, like, what is the. What is the basis of fatigue? Like, obviously, it's a very real thing, but, like, where is that happening and how is that happening?

[A]

It's such a good question, Aaron. I don't know. I don't think we understand at all fatigue. It's a. It's a huge part of ms, especially as it progresses, but it can also just be an initial presenting sign. Right, okay. And we, we don't know, we don't understand, I think enough about fatigue and. Because it's not, it's not like a tingling in your hands. Right. It's not one specific nerve. And so I think like I said, how you can have radiologic findings on MRI that maybe don't correspond to a specific symptom, but maybe lots of little demyelination events in various areas can then result in these more generalized symptoms like a fatigue or etc.

[B]

Right. It's like many different signals are getting lost or being slowed down other than one specific one.

[A]

I do know that there is some. I saw a paper, but I didn't have time to read through the whole paper that was trying to get at more specifically the mechanisms of Ms. Related fatigue. So I'll put that on our website so if people are interested, they can read more.

[B]

Yeah, I mean it seems like it would have huge implications for many other.

[A]

Right.

[B]

Things like chronic fatigue syndrome, like so.

[A]

Much of Ms. That is applicable to so many other things. But yeah, yeah, I digress. So the other form of Ms. Is when this progressive worsening of neurologic function happens initially rather than the relapsing remitting happening first. And this is called primary progressive Ms. And happens in about 10% of cases. Interestingly, this type of Ms. Tends to be diagnosed in older individuals over age 40, whereas relapsing remitting tends to be diagnosed between ages 20 and 40 most commonly. So they seem to be a little different. But there's also so much overlap between these two that there's also some question whether they truly represent two different, you know, phenotypes of this disease or not.

So when it comes to ms, there's a lot of questions, but there are two big kind of separate but very related questions that full disclosure, we don't fully have answers to. And that is what is the ultimate cause of Ms. And what is the underlying mechanism of damage? So the underlying mechanism of this damage is still not entirely clear. There are a number of papers that I will point listeners to with a lot of like really immunology geek heavy details on like what specific immune mediators, inflammatory markers, etc. Are involved. We know that especially B cells and to a lesser extent T cells and self reactive antibodies, AKA autoimmunity is heavily involved in the, in the mechanistic underpinnings of Ms.

And we know that it's a combination of this immune response and inflammation that results in the destruction and damage to the myelin sheath and then those cells that produce it, and then that's what makes it more and more difficult to recover, et cetera. Right, right.

[B]

Because if it's an autoimmune thing where your cells are attacking yourself, then it's just going to be better and better at recognizing it and it's going to be more and more damage accumulates.

[A]

That makes sense.

[B]

Okay.

[A]

Yeah. So now to the question of what ultimately causes Ms. And this is one that has been up for debate for. I'm guessing you'll tell us how long, Aaron? It's been up for debate.

[B]

160 years or so.

[A]

Okay. All right.

[B]

Maybe not quite that. Yeah, yeah.

[A]

The bottom line is we technically still don't know.

But we know a lot. So there are a number of different genetic polymorphisms, genetic changes that have been associated with an increased risk of Ms. Most all of these are either near or in regions that are in some way involved in our immune response. Which makes sense since this is an immune regulated disease. And there is some good evidence that some of these regions overlap with other autoimmune diseases, which isn't that surprising.

[B]

That's very interesting. I didn't know that.

[A]

Yeah. Like type 1 diabetes and lupus and others. There is some, like, mediocre evidence that some environmental risk factors like decreased sun exposure or low vitamin D levels might increase the risk of Ms. Like mediocre. Not super strong evidence. And there's some decent evidence that smoking does increase the risk of Ms.

[B]

Does that also include secondhand smoke?

[A]

I assume I. I believe so. That's what I have read.

[B]

Okay.

[A]

And currently Ms. Is also about three times more common in those assigned female at birth, although that wasn't always the case, which I think is fascinating in and of itself.

[B]

I'll talk about that.

[A]

Great. Can't wait. But none of these genetic or environmental factors tell the whole story. And there is another piece that for a very long time has been thought to. To play a big role in terms of a causal factor of Ms.

[B]

This is such a big lead up.

[A]

I know. I am so excited. Can you tell? So just recently, literally, Erin sent me this paper.

[C]

Weeks.

[A]

Two weeks prior to recording this episode.

[B]

We're recording this in January, by the way.

[A]

We're recording in January. This paper came out literally, like two weeks ago.

[B]

I was excited about it.

[A]

I'm thrilled. Some very strong evidence has been published in support of this particular risk factor. Which is.

Drumroll. Epstein Barr Virus, ebv. Okay. For listeners, EBV or Epstein Barr virus. This is a human herpes virus. We've touched on a lot of different herpes viruses on this podcast. We've covered HSV1 and 2. We've covered varicella, which is human herpesvirus 3. EBV is human herpesvirus 4. There's a lot of other ones. They're DNA viruses that are very highly co evolved with humans and they have these latent analytic phases. So they're really, really good at hiding out in our immune system. Now, EBV is a virus that preferentially infects and replicates within a certain subset of our white blood cells, our B lymphocytes.

[C]

Lymphocytes.

[A]

These are cells that, if we think all the way back to season two, our Vaccines, part one episode, if you remember that far back, barely. B lymphocytes are responsible for producing antibodies. That's their number one drop. So EBV is a virus that preferentially replicates in our antibody producing cells. And it is an incredibly ubiquitous virus. It infects 95% of the human population. By the time we reach adulthood, all of us have it, and most of us will never ever even know that we were infected. Some of us might have been unlucky enough to have gotten mono infectious mononucleosis. That's ebv. That's an acute EBV infection if you get it as like a teenager or young adult, but most of us get it as kids and we never even knew that we had it. EBV has been known for a really long time to be implicated in the development of a whole bunch of different cancers. Hodgkin's lymphomas, B cell lymphomas, nasopharyngeal carcinoma, like the list goes on.

So why am I talking about it about ms? Okay, for a very long time, people thought because of some of the findings, especially on lumbar puncture on CSF fluid, that it is very likely that there is some kind of viral component to ms, some kind of viral precursor, because of the type of immune response that we see in the cerebral spinal fluid. So people thought for a long time, there's something viral going on here. And EBV has long been thought to be one of the main contenders to be the virus potentially associated with Ms. And there have been a lot of papers throughout the years that provide evidence of kind of epidemiological support for this. And a lot of them had pretty solid links showing that infection with EBV puts you at higher risk of ms, especially symptomatic infection. So infection that results in infectious mononucleosis or mono is a substantially greater risk factor than just asymptomatic EBV infection. I think people are two or three times more likely to develop Ms. After infectious mononucleosis compared to asymptomatic ebv. But back to this new paper. This new paper that just came off the press lends even more support to this idea. This paper, which was published in Science on January 13, 2022, showed that infection with EBV increases your risk of Ms. By 32 times. 32 times. Some of the early studies of lung cancer and smoking showed like a 25 times increase in risk of lung cancer from smoking. But the other thing is that. So this paper, and I just encourage everyone to read it because I'm not going into as much detail because I would talk for too long, but they used serum samples from over 10 million active duty military personnel that spanned over a decade. And they looked at 801 people who were diagnosed with Ms. During their time in the military and compared them to like twice as many matched controls. And from this study, they were able to establish a very causal association between first EBV seroconversion that came first, then markers of axonal degradation, so degradation of the axons. They were able to find markers of that in the serum and then later diagnosis of Ms. So a causal relationship. First ebv, then symptoms of neurons starting to degenerate, then a diagnosis of Ms.

[B]

It's a big deal, a very big deal.

[A]

And they also did further studies on these serum samples that showed a dysregulated antibody response that was specific to ebv, Epstein Barr virus, and no other viruses. And they tested against a whole number of other viruses to look at, like, levels of antibody and dysregulation of antibody response, and found a dysregulated antibody response only to EBV in people who developed Ms. And not for any other virus.

[B]

So why ebv? What's it doing?

[A]

Oh, gosh, Erin.

Great question. We still don't know. But in even further support of this, yet another paper came out. Erin, thank you very much for sending me this one, too. This came out two days before we recorded it found antibodies that were produced in people with Ms. That bind to a specific EBV viral antigen and cross react on a specific human cell surface protein that is associated with autoimmune demyelination. And that's a lot, I know, but basically, this second paper that came out Provided at least one possible mechanistic link that basically says, hey, this antigen that EBV has looks a lot like one of our cell antigens. Right. Like something on our human cells. And in people with Ms. They're making antibodies that are cross reacting. Right.

[B]

It's so interesting and it makes me wonder like EBV has been around for a long time. It infects everyone. Everyone, essentially. So like what's the trigger? What, what is the sequence of events?

[A]

Right. It's, it's so fascinating and it's also, it's why in only some people. Right, right. And that's the question we, we truly really, we don't know.

[B]

But EBV is necessarily a part of Ms.

[A]

It seems based on the most recent papers that EBV is a necessary precursor to the development of Ms. It is not sufficient. EBV infection alone does not cause ms, but EBV is necessary for the eventual development of Ms. Which is an amazing thing to be able to say.

[B]

It really is.

[A]

Maybe someone else like two months from now is going to say no, no. But as of now, I mean, this is pretty amazingly strong evidence.

[B]

Yeah. I mean, and it also has a lot of implications for treatment and prevention.

[A]

And prevention, yes. Speaking of treatments, there are thankfully a lot of different treatments that are now available and that did not used to be the case. And today there is much more of a push towards early detection, like I mentioned, and early initiation of what is called disease modifying therapy or dmt. And these are therapies, many of them target B cells. Since we know that B cells are so involved in this dysregulated immune response or other components of our immune system, inflammatory system, that are directly targeting the mechanisms of damage, trying to prevent this damage, prolong the time between relapses in relapsing, remitting Ms. And prevent the development of disability.

There unfortunately aren't as many therapies for primary progressive Ms. So in both primary progressive and in relapsing remitting ms, there's also a lot of other therapies that are more towards whatever the symptoms are rather than treating the underlying disease. So there's always like a multifaceted approach to treatment.

[B]

Right.

[A]

That was long winded, but that's Ms.

[B]

There's, I mean there's a lot there and it's still like, it's so complicated and I have so many questions about how myelination works and what actually is happening.

[A]

I am sorry, I'm not a neurologist and it's not my strong suit Erin, so tell me. Listen.

You said 160 years.

[C]

Yeah.

[A]

Like it's got to be around for longer than that. So like, what's up with it?

[B]

All right, I will try to get at that just after we take this short break.

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All right, so usually you ask me something like, where did this thing come from? And obviously like, you know, we can't necessarily do that with this disease. Normally I can, right? Like I can at least tell you what's commonly accepted to, you know, for the evolutionary origins, or I can at least, like, take a guess or something, but multiple sclerosis, I can't. I can't do that. I don't. Because we don't know, like you said, what exactly causes it still the mechanism of disease. And I can't even really make a guess because we just lack that knowledge. If it is caused in part by ebv, then, you know, it seems as though ebv, like most herpes viruses, has been co evolving with humans. So it's been infecting humans since before humans were humans. If it's caused by EBV plus genetic predisposition or EBV plus genetic predisposition plus adolescent vitamin D exposure or other environmental exposures, then we still don't know, like I said, how all of those things interact and what that means from an evolutionary perspective. I did read, though, one paper that discussed hypothetically why humans spontaneously get Ms. Whereas other primates don't seem to, although it can be induced experimentally, which I think is really interesting.

[A]

Yeah.

[B]

And in this paper it was suggested that it might have something to do with the fact that humans have big brains with a lot of myelination. So it's just like a lot of myelination, and that's a costly thing. And that the peak onset of Ms. Typically occurs around the same time that myelination kind of like ends or starts to decline or something.

[A]

Yeah. Like, we're not making. More like your brain is still growing until you're like 25.

[B]

Yeah.

[A]

So after that point you're just losing brain. Yeah.

[B]

Yep.

And so. And so that's. Seems like it coincides that transition sort of seems like it coincides with the typical age of onset for Ms. But I think one of the biggest challenges faced in trying to understand the potential evolutionary origins of this or any other disease whose etiology isn't well worked out is trying to sort through which epidemiological data are actually meaningful and which are spurious or just red herrings.

[A]

Yeah.

[B]

For instance, you mentioned that over the past 100 years, there's been a shift in the ratio of who is most often diagnosed with Ms.

[A]

Yes.

[B]

At the beginning of the 20th century, the disease was diagnosed either fairly evenly in people assigned male at birth and people assigned female at birth, or it was diagnosed slightly more often in people assigned male at birth. But since the middle of the 20th century or so, people assigned female at birth began to be more commonly diagnosed. And the ratio today, like you said, is around 3 to 1. So is this an indication that people assigned female at birth are developing Ms. At higher rates today than they have historically? Or could it be partially an artifact from how difficult to diagnose diseases were viewed differently between men and women, especially in the days when hysteria was considered a valid diagnosis? Like, this is all pre mri, right? Like, this is before. Before you could see a physical sign of Ms. As a physician.

[A]

Oh, that's such an important point, Aaron.

[B]

Yeah, so that I think is really important to consider, and it sort of is commonly talked about in the narrative of Ms. Like, this is an increasing disease, it's increasing more in people assigned female at birth. Is that actually the case? Has there been something that changed over the past 100 years or so? And if there has, like, we should obviously look for it. We should absolutely try to find out what that is, but we should also examine other reasons that might have led to that shift.

[A]

Right, okay.

[B]

So that's all like a very long winded way of saying, I don't know the evolutionary origins of this disease because we don't know enough about it.

[A]

Yeah. Okay, fair enough.

[B]

Okay, so what do we know? Let's go back to what are commonly reported as the earliest recorded cases of Ms. The first is Saint Ludwina of Schiedam in Holland, who was born in 1380. Around the time she was 15, Ludwina went out to do some ice skating. And while she was skating, she lost her balance, she fell down, and she broke a ribbon. She never fully recovered from this. And for the rest of her life, she experienced difficulty moving around, paralysis, pain, and visual deficits, all of which would come and go, but over time got progressively worse until she died at the age of 52.

Throughout her life, Ludwina felt that she was sent to accept the suffering for the sins of others. And this was taken to be a sign of a miracle. And so after she died, she was canonized and is the patron saint of ice skaters and the chronically ill. Wow. Yeah. She does it all.

It's still kind of debated whether or not it actually was Ms. That Ludwina was experiencing. And how much is truth versus how much is myth or exaggerated over time or, you know, certain bits are picked out to support, you know, this was Ms. But it does seem a lot more like Ms. Than another early story that's commonly mentioned, which is that of Hala, a woman who was written about in the Icelandic saga of St. Thorlax. So sometime between 1293 and 1323 CE, Hala suddenly lost her Sight and speech. She prayed for them to recover, and they did. Ms. Could be something else, could be that.

[A]

Yeah, but that was it. It was just that.

[B]

Just that one thing, essentially. I mean, I think there was, like, a little bit more to it, but that was the gist.

[A]

Okay, yeah.

[B]

So, you know, the first case of what definitely seems like Ms. Takes place much more recently. Augustus Dest was a grandson of King George III, who began experiencing symptoms of Ms. In his 20s. In a diary entry from 1822, when he was 28 years old, he described being at the funeral of a close friend.

I attended the funeral. There being many persons present, I struggled violently not to weep. I was, however, unable to prevent myself from so doing. Shortly after the funeral, I was obliged to have my letters read to me and their answers written for me, as my eyes were so attacked that when fixed upon minute objects, indistinctness of vision was the consequence. Soon after, I went to Ireland, and without anything having been done to my eyes, they completely recovered their strength and distinctness of vision. For most of his life, Dest kept a journal describing his symptoms, the way he felt about them, and his experiences with the doctors he saw. And it's a really valuable and interesting insight into this disease and how it was perceived. And it kind of shows in some ways how far we've come, but also in other ways how some things haven't really changed very much at all. So I want to read another quote from Dest from 1843. About 21 years after that other entry, I read quote, what I complain of now is that sitting produces a numbness all down the back part of my thighs and legs and gives me a curious numb sensation in the lower region of the belly. When standing or walking, I cannot keep my balance without a stick. I sleep well when I am not annoyed with little nervous twitching in my legs and feet. For the first time in my life, I was attacked by giddiness in the head, vertigo, sickness, and total abruption of strength in my limbs. I was able to drive to my own house, but totally incapable of getting out of the phaeton. I was carried up to my bedroom where I was sick as a dog and broke out in the most profuse perspiration. And so some of these descriptions, you know, even though they were from the early 1800s, they may sound completely familiar to people living with Ms. Today. But hopefully what will not sound familiar are the treatments that doctors prescribed for dust. Here's the.

Leeches, beefsteaks with wine twice a day, back rubs with alcohol, opium and oils being slapped. Extremely hot baths. Strychnine, quinine, nitric acid, ammonium carbonate, mercury, cinnamon, rhubarb, horseback riding, and a little bit of light electrotherapy. So it's getting shocked.

Yeah. Extremely hot baths. Like, we didn't talk about this in the bio, but that's. That would have exacerbated the symptoms so much, it would have felt horrible. So it does.

[A]

Yeah.

[B]

Yeah. And there's a huge variety in those treatments that he was prescribed, which I think speaks to the fact that doctors could clearly had no idea what was causing the disease, and that no one single therapy seemed truly helpful for symptom control, let alone as a cure.

And this didn't change once Ms. Was formally described as a disease. Throughout the first half of the 1800s, several different anatomists described lesions in the brain or along the spinal cord while doing an autopsy, which, if you remember, from our puparal fever episode, had become quite popular. Around this time, pathology had grown greatly as a field, and many people wanted to make a name for themselves by identifying a new disease. One of these was Jean Martin Charcot, whose name may be familiar from our endometriosis episode, or because of a genetic disorder that bears his name. Charcot, Marie Tooth disorder. Or just because he's kind of a big figure in the early history of neurology, he played a role in the identification of many neurological disorders.

[A]

Yeah, he's a big deal.

[B]

Big deal. Charcot was a French neurologist and pathologist who worked at a huge teaching hospital that was built to treat the poor women of Paris. His approach was to follow his patients for a long period of time and when they died, perform autopsies on their body. Bodies to see if he could identify any pathological basis for the signs or symptoms that they reported. The story of Charcot and Ms. Begins when he hired a woman who had some motor problems to be his housemaid. He thought she had neurosyphilis. He kept her on until her disease progressed to the point where he was like, you can't really clean anymore, so you're going to this hospital for poor Parisian women. And he shipped her off there.

[A]

Oh, gosh.

[B]

And that's where she lived until she died, at which point he performed an autopsy. And he noticed some plaques scattered throughout her nervous system. And within a few years, he had seen several more of these plaques in several more of the autopsies. And so he was thinking, hmm, okay, I think I might have a new condition here. Because a lot of the people that had these plaques had reported Reported things like numbness, vision problems, movement difficulties, speech problems, etc. And he noticed, too, that these signs and symptoms tended to relapse and remit. And so, yeah, he was like, this has got to be a new disorder, and I'm gonna go describe it. So in 1868, Charcot gave a series of lectures that named the disease, although they didn't. He didn't use the name multiple sclerosis. That would really only be settled upon in, like, by the 1950s or so, like, there was disseminated sclerosis. There were a ton of different names for this. But he also drew, like, boundaries around it, right? He described the pathological anatomy, the symptomatology, pathophysiology, etiology, which he described as being anything from unknown infections, moist, cold or trauma. And treatment, which he said there wasn't any. He hadn't come across anything that seemed to work. And he also noted that the disease seemed to be more common in women than in men. Does this mean that Charcot was ahead of his time? Because like I said, that's something that really only in the. Since the mid-1900s or so people recognized and kind of yes and no. If he was ahead of his time, it wasn't for the right reasons, because let's hear why he thought people, especially women, developed Ms. Oh, yeah. Quote. Okay. Long continued grief or vexation, such, for instance, as might arise from illicit pregnancy or the disagreeable annoyances and carking cares which a more or less false social position entails. This is often the case as regards certain female teachers. Having said so much with respect to women, the question of the male sufferer arises. These are, for the most part, persons who have lost caste and who, thrown out of the general current and too impressionable, are ill, provided with the means of maintaining what in Darwin's theory is called the struggle for life.

[A]

Oh, dear.

[B]

End quote.

[A]

Yeah.

Okay. I feel like these early descriptions.

Have probably.

Progressed into some of the thinking that has taken a long time to overturn because there was a lot of, like, earlier studies that were like, is it stress that causes ms?

[B]

Right? And, like, it couldn't possibly be that someone's disease caused them stress, right? Couldn't possibly be that, no. And obviously, if you listen to the endometriosis episode, Charcot was involved in hysteria. Like, he, you know, was a huge influence of Freud. And there was so much in this time that built this foundation for the disease becoming a part of someone's identity. Right. Or someone's identity influencing what disease they were thought to have. And it's still a big problem today, and it's taken decades to even try to undo.

[A]

Right.

[B]

But anyway, for decades, Charcot's description of Ms. From these lectures basically remained unchanged, with just a little refinement here and there. Not because no one was studying the disease. Charcot's lectures kicked off a huge amount of interest in Ms. But just because the general outline of the disease remained the same, that doesn't mean that the way it was perceived also was unchanged. So going back to Dest and his journals, I think reading through them, as well as other people's accounts of their experiences with Ms. In the late 1800s and early 1900s, it helps us to better consider this disease through the lens of history. Pick any point in the history of Ms. From the mid-1800s and ask what else was going on in biomedical science at the time, what new discoveries have been made or technologies developed, and you'll see how that historical context affected not only the diagnosis of this disease, but also how it was true treated and what was thought to be the cause. So improvements in microscopes and the autopsy trend that led to this disease being defined because it allowed people to see the connection between these lesions and the symptoms of Ms. And since germ theory was in full swing around the time Ms. Was first fully characterized, researchers proposed microbe after microbe responsible for the disease, and even produced some Ms. Vaccines, none of which was able to be repeated or panned out, really.

And this focus on a microbiological cause of ms, so early on, it was surprising to me initially, but it also makes sense in light of the ability of syphilis to cause neurological disease. So a lot of people were like, oh, if syphilis can do this, then, you know, we see neurological disease. This could be caused by another pathogen.

[A]

Yeah.

[B]

And more recently, you know, one of the current trends is the gut microbiome in general, and what are microbiota, how that influences our health and other diseases. And so there has been attention more recently regarding what role that has to play in Ms. So we don't, you know, we don't know, maybe we'll learn more. And I think, you know, we've now, with this EBV super robust study, we've kind of come full circle and maybe some EBV vaccines in the works. Yeah. A quote from the early 1900s by Pierre Marie, a student of Charcot, may soon seem very prophetic. Quote I have little doubt, in fact, gentlemen, that in the employment of such a substance as the vaccine of pasture or the lymph of color, the evolution of insular sclerosis will someday be rendered absolutely impossible.

[A]

Wow.

[B]

And hopefully that's true.

[A]

Fingers crossed. Yeah.

[B]

And the prevailing medical thought at various times also affected treatment. So, like with the development of Salvarsan for syphilis and penicillin, people attempted to treat Ms. With antibiotics. And the same happened when, like, anticoagulant factors were developed or other types of treatments. Right. That were effective for other diseases.

[A]

Right. Any new treatment doesn't work for Ms. Right.

[B]

And that's a completely reasonable approach. I think it also just speaks to, like, people were like, we don't know what is causing this.

And I also think it's important to talk about how diagnosis was impacted by common biases or trends in medicine. And I've talked before about the difference between signs and symptoms and how advancements in medical technology and measuring devices led to this shift in physicians relying more on signs than symptoms for many diseases. So, like, signs are things that are observable, detectable by someone who's not the person experiencing them, and symptoms are only able to be described by the person experiencing them.

[A]

Right.

[B]

And so this switch from focusing more on signs rather than symptoms that also applied for Ms. So in the days before MRIs, diagnosis was often described as being difficult. Or maybe it was that a proper diagnosis required that a physician had to listen to and believe their patient.

[A]

Difficult.

[B]

Difficult, yeah. And people with Ms. Were often diagnosed with a variety of other conditions. So in the 1700s and 1800s, that was often paraplegia. This is what Dest was diagnosed with. And paraplegia was this umbrella term under which a lot of diseases that included partial paralysis or movement disorders were thrown. And then when the spirochete that causes syphilis was identified in the late 1800s, it was common for a person living with Ms. To get a diagnosis of neurosyphilis, which is what another couple of people in the 1800s or early 1900s were diagnosed with formally or just suggested to have. The German poet Heinrich Heine and W.N.P. barbellion, pen name of Bruce Frederick Cummings, who wrote a book describing his life with Ms. Titled the Journal of a Disappointed Man. So they were both thought to have neurosyphilis, but more likely Ms.

But doctors also suggested to Barbellion that it was all in his head. And in that same vein, Margaret Gatti, who was a Victorian novelist and naturalist who also had ms, was told by her physician that her illness was, quote, caused by her tendency to use excessive physical effort in gardening, using heavy tools in the manner of a man.

[A]

Oh, how dare you.

[B]

I want to see her garden, like, but it was incredible.

But all of that sounds familiar, right? Because the history of Ms. Shares a lot of parallels with that of endometriosis and other, quote, invisible diseases, which is a term often used to describe diseases where doctors or other people may look at someone and go, oh, you don't look sick to me, because there are no outward signs of the disease.

[A]

Right.

[B]

And I don't love this term because I think it can be misused to undermine or discredit the very real things that people with one of these diseases are experiencing. If I can't say, you're sick, then you must not be sick, or those things you say you're feeling are just not real. Like you're exaggerating them.

[A]

Right.

[B]

And this is the kind of logic that led to hysteria being diagnosed for all manner of diseases, including Ms. As Maya Dusenberry puts it in her book Doing Harm, quote, perhaps one of the clearest examples of an autoimmune disease carved out of the wastebasket of hysteria is multiple sclerosis. That phrase is so excellent, the wastebasket of hysteria.

[A]

Mm.

[B]

Because it's like, how many things were misdiagnosed as hysteria? And this was even commented on in the early 20th century. Doctors were like, Ms. Is not that difficult to diagnose. But there are a lot of misdiagnoses, with doctors most commonly confusing it with hysteria. And people living with Ms. Were diagnosed with hysteria well into the 1950s. It happened at such a high rate, in fact, that it drove the definition of hysteria to change in the early 20th century to distinguish it from Ms. Wow.

[A]

I did not know that.

[B]

Yeah. But although Ms. Remained underdiagnosed for many people, especially women, in the first half of the 20th century, rates of diagnosis did in general go way up. And a big part of that was due to the fact that there were simply more neurologists. By the 1910s, the 1920s or so, there had been a substantial rise in trained neurologists in the US and not just restricted to cities, but also to smaller towns and rural areas. And by the 1950s, what had once been thought to be a rare disease was now considered one of the most common illnesses of the central nervous system. And with this rise in neurologists, there also grew to be more focused attention, specifically on Ms. Wider scale studies, such as, you know, the one that was able to be done with soldiers from World War I and World War II, where we had a lot more medical information about thousands and thousands of people readily available, which is kind of funny that this 2022 paper is mirroring the same thing.

[A]

Yeah.

[B]

But from the data from World War I and World War II, that's where it sort of paved the way for these large scale epidemiological studies looking at geographical trends where it seemed to be occurring at higher rates or more often diagnosed in people from more northern areas. Northern regions that I want. Like, I'm, I'm very excited to hear you talk more about that because I know it's like a more complicated story than that, but this pattern where Ms. Seems to be more frequent in not. Not as you go farther away from the equator, but just more northern climates, the Northern hemisphere has led some people to suggest that this disease has Viking roots, as in the frequent travels of Vikings in history essentially disseminated that, like Ms. Predisposition around certain places. Yeah. I don't know how much evidence there is to support this, but my guess is that as better and better genetic tools are being developed all the time, maybe we will be able to tease out some sort of historical story for why we see what we see. By the mid-1950s, there was much more awareness about multiple sclerosis among the medical community. And scientific advancements had helped to understand more about what was going on inside someone living with ms, which helped in the development of some treatments to manage the signs and symptoms of the disease. But this growth in awareness was not just limited to healthcare workers working directly on Ms. One of the biggest turning points in the history of Ms. Happened on May 1, 1945, when a woman named Sylvia Lowry, whose brother Bernard had Ms. And Sylvia had gotten so frustrated by the lack of clear information and adequate treatment from her brother's physicians. And so she posted an ad in the New York Times with the following request, quote, multiple sclerosis, will anyone recovered from it, please communicate with patient. And she got dozens of replies, like, way more than she expected, expected. And so she thought, okay, I can't be the only person who could use this information. I'm going to bring all of these people together. And in 1947, she brought over 20 leaders in the field of neurology together to try to set objectives for an organization that was dedicated to understanding the disease and finding a cure. Wow. And Sylvia, like I said, didn't stop at founding the Multiple Sclerosis association, which was later changed to the National Multiple Sclerosis Society. She also helped found the Multiple Sclerosis International Federation. And for the rest of her life, she campaigned incredibly hard to raise awareness of this disease and bring in more funds for Research, as well as supporting people living with the disease. And her efforts were hugely successful. Her work and the work of these and other Ms. Organizations show once again how incredibly important it is for people to share their story and how much of a positive impact patient advocacy groups can have on bringing awareness to a disease and providing support and resources to those who need it. Within 10 years of the National Ms. Society being founded, there were 120,000 members. She brought in celebrities and politicians, including Shirley Temple, which I'm now realizing would have been a great quarantini, but that's okay.

[A]

Would have been. Love a Shirley Temple.

[B]

Me too, me too. And Shirley Temple and other celebrities, they use their incredibly powerful platform for good. And they turned, like, talk into action, right? Like, instead of just being like, hey, we should, you know, raise awareness for ms, it was like, no, we are raising awareness for. We are getting funds. We are, you know, providing resources. And this is also still a common theme today, which I think is wonderful with celebrities like Jamie Lynn Siegler, who plays Meadow on the Sopranos, which I'm finally watching right now, and former U.S. representative Donna Edwards and many others raising funds and awareness for the disease. I would also just like to encourage anyone who is interested in learning more to check out the national, National Ms. Society website because it's an amazing resource for seeing the latest news, finding support, understanding the signs and symptoms of the disease, and so much more.

[A]

I was also going to shout them out because I found their descriptions of symptoms and everything to be, honestly so much better than most of the papers that I read.

[B]

Yeah, it's. It was. It's a great website.

[A]

Yeah.

[B]

The second half of the 20th century saw a few more big advancements in multiple school sclerosis. Outside of this huge growth in awareness, the development of clinical trials, combined with better guidelines for staging the disease really helped to evaluate whether certain medications were helpful, harmful, or did nothing. Something which previously had been really difficult to assess because of the relapsing, remitting nature of this disease. And finally, the development of the MRI in the late 1970s meant that you could find, finally visualize this disease, which helped not only with understanding more about it, but it also lent credence to the people who had had their symptoms repeatedly dismissed. Kind of reminiscent of the way that laparoscopic surgery was used to legitimize endometriosis. Just parallels, but it's true that the MRI revolutionized diagnosis, especially early diagnosis for people with ms, which, like you said, has been tremendously helpful for coming up with a treatment and management plan for people living with the disease, as well as being able to evaluate which medications might have an impact. There is so much more that I could have included in this history in terms of like the specific medical developments and who discovered what and who wrote this paper and who found this sign or whatever over the past 160 years. And that information is out there. If you're interested in learning more, I recommend the book Multiple the History of a Disease. But I'm going to leave off with the history here where since the MRI we have many medications that seem to be very helpful in managing symptoms. And we are now so much better than we used to be in our knowledge about multiple sclerosis. But at the same time, there are still so many unanswered questions. Why? First and foremost, because without a why, it's going to be nearly impossible to find a cure. Right. Or it's going to be very difficult. And I also think that we still have a long way to go in terms of understanding how much of the criteria that we use to define multiple sclerosis actually captures the experience of someone living with it.

[C]

Right.

[B]

So Erin, can you tell me more about where we stand today with ms?

[A]

I will try my best right after this break.

So Ms. Is the most common demyelinating disease.

It is the most common inflammatory neurodegenerative disease in young adults. It's the most common non traumatic cause of neurologic disability in young adults. It has a lot of most common designations.

In terms of the overall prevalence which has been increasing. And there's kind of a lot of factors that might be going into that.

In the Global Burden of Disease study which looked at data from 1990 to 2016, it was estimated that in 2016 there were over 2,200,000 prevalent cases of multiple sclerosis globally.

[B]

Okay, how was that distributed?

[A]

Great question. Very unevenly across the globe. So the highest prevalence by far is in North America with 164 cases per 100,000 people, closely followed by Western Europe at an estimate of 127 cases per 100,000 people. Australasia, only 90 per 100,000. In Sub Saharan Africa, between 2 and 3 cases per 100,000. Oceania, 2 cases per 100,000. So it really does vary across the globe. And like you mentioned, Erin, there is some kind of question where sometimes people say it's, it's closer to the equator, is less or northern latitudes is, is greater. And there's even been some studies that have tried to look at, even within countries whether there are like north to south gradients in cases. And part of that is why the idea of sun exposure and vitamin D has some support, as in more northern areas, where you have less sun exposure is where you have higher rates of Ms. But it also doesn't hold true like 100%, because there are specific indigenous populations in areas that actually have very low rates of ms, even though they live in very northern areas. So it's not the whole story. Like a north to south gradient isn't the whole story, but there does seem to be at least some associations.

[B]

So what if somebody moves like for instance, from an area of high risk to low risk or low risk to high risk? What does their risk profile look like?

[A]

Yeah, it's a good question. I read in at least one paper that, for example, migrants from low risk areas, let's say Africa, to a high risk area, let's say North America, those migrants still have low risk of development of Ms. They came from a low risk area. When they move to a high risk area, they still have a low risk of development of Ms. But children of those migrants tend to have higher risk of development of ms, which is really interesting.

[B]

That's very interesting.

[A]

Yeah. Now, in terms of prevalence, it is interesting to look at the prevalence being increased, which it has in 2016. That prevalence rate is 10% higher than the estimated prevalence in 1990, for example.

But we are diagnosing Ms. Earlier, which could contribute. We also have such better treatments that people are living longer with Ms. So globally, the age standardized death rates decreased significantly in that time period by about 11%.

So those things combined might explain some of this increase. So there's still a question as to whether an increase in prevalence means also that there is a true increase in ms, or if we're just diagnosing it better and people are living longer with it, which is always going to increase.

[B]

The prevalence of disease and has like the age specific rate or like incidence changed.

[A]

It's hard to get a handle on incidence. And so most all of the studies just really look at prevalence.

[B]

Okay.

[A]

Yeah, but it's a good question.

In 2016, in this same study, it was also estimated that there were over 18,000 deaths due to Ms. In that one year alone, as well as over 1,100,000 disability adjusted life years. And we've talked about how that's not a perfect measure of the impact of a disease, but. But it is at least a measure that we have, that this is something that is significantly impacting people's lives. Right, right.

[B]

For a long part of their lives.

[A]

Right, exactly. Like diagnosis at between 20 and 40. And, you know, this is something that's lifelong and. And progressive. Yeah.

So the good news, and I do feel like we get to end with pretty good news in terms of ms, is that there is an incredible amount of research being done. Like, yeah, two papers that came out in the last week that are a big deal.

[B]

Yeah.

[A]

And, like, we kind of really highlighted a lot in this biology section. There is just so much that we don't know. And I think that what's especially exciting about research on Ms. Is that the kinds of studies that are being done are incredibly important, not just for ms, but also for our understanding of neurodegeneration and cell regeneration. Right. And this can help in the treatment of so many different diseases and neurodegenerative disorders. This is also what has led to so many new treatments for Ms. And related disorders as we better understand these kind of mechanistic underpinnings of this damage. Right. This kind of basic science is phenomenally important.

And then there's also so many questions as to, you know, the genetics of. Why does one person develop Ms. After an infection with EBV and another person doesn't, like, what is it about those immune responses? And that is important not just for ms, but also for so many other immune disorders. Right. Understanding what these triggers are, what these predispositions are, and, like, what we can actually do about them.

[B]

Yeah.

[A]

And these new studies really showing that EBV is likely, in fact, a necessary precursor to the development of Ms. Meaning that Ms. Is like viral sequelae of infection with this virus. That means that we could prevent ms, Right? Yeah, if we could prevent infection with ebv. And it also means we could prevent so many other things that EBV also causes. Right. Burkitt's lymphoma, mono. Like, so. So many other things. Right. And moderna of COVID vaccine fame just started, like, literally. This press release also came out within the last couple of weeks. They just started phase one trials of an MRNA vaccine targeting ebv.

[B]

Oh, my gosh. It's so thrilling. It is.

[A]

And this technology has been able to happen so quickly because of the research that was done on Covid. So, like, it's just. It's one of these things that the interplay between the basic science research on one aspect of a disease can have implications for so many others. I just think it's really fascinating.

[B]

Yeah. So totally.

[A]

I think there are really exciting and promising things to come when it comes to Ms. Treatment and possibly prevention.

[B]

Yeah. It really does feel like we're on the edge of having like a firm, complete picture for what causes some people to develop Ms. And hopefully that'll lead to better treatments or cures or tools for prevention.

[A]

Yeah.

[B]

And if it turns out that the Epstein Barr virus is a good way to focus those tools, even better. And if you want to know more about EBV and all the tricky ways that it acts to cause disease or predispose to disease, make sure you tune in for next week's bonus episode. I am so thrilled to get to chat with Dr. Mika Luftig, Associate professor and Vice Chair in the Department of Molecular Genetics and Microbiology at Duke University.

[A]

It's going to be so good.

[B]

I am so excited. Dr. Luftig has worked on the Epstein Barr virus for nearly his whole career and he is going to be subjected to my many, many questions on the how, the what and the why of EBV infections. And I also want to get into some bigger picture questions about like, grad school and academia. Good stuff, bad stuff, all the stuff in between. I think it's. I think it's going to be a good one. So make sure you mark your calendars.

[A]

Okay. Tune in. Don't miss it.

[B]

Sources, Sources. Okay, so I have several, but I'm just going to shout out one in particular, and that is a book by Jock Murray called Multiple the History of a Disease. And then I have more about like evolutionary history and so on that I'll post.

[A]

I had a number of papers on the kind of general biology and a lot more on the specifics and mechanisms of the damage in Ms. Specifically, I want to shout out the Science paper and the Nature paper that we're really looking at.ebv and Ms. Those were both very exciting. Published January 2022. And like I also said, I do want to give a special shout out to the National Ms. Society website because I think that it is just such a helpful breakdown of so many different aspects of ms, but especially like different symptoms of ms, because I think that's something that most of the papers just don't do a good job of explaining. Yeah. Yeah.

[B]

Thanks again so much, Nikki, for taking the time to chat and sharing your story. It honestly means so much to us.

[A]

So much. Thank you. Thank you also to Bloodmobile, who provides the music for this episode and all of our episodes.

[B]

And thank you to you listeners. We hope you like this episode. We hope that you found something new that you didn't know about and that you take a little tidbit and share it with somebody else.

[A]

Yeah. Yeah. Tell your friends.

[B]

Yeah.

[A]

And a special shout out to our patrons.

[B]

Yes.

[A]

Thank you. Your support means the world to us.

[B]

It does. Okay, well, until next time.

[A]

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