Ep 30 Encephalitis Lethargica: Sleep Perchance to Dream (& Dream & Dream)

00:00:00
Speaker 1: I first saw Leonard L in the spring of nineteen sixty six. At this time, mister L was in his forty six year completely speechless and completely without voluntary motion except for minute movements of the right hand. With these he could spell out messages on a small letter board. This had been his only mode of communication for fifteen years and continued to be his only mode of communication until he was given el Dopa in the spring of nineteen sixty nine. It was obvious to me from my first meeting with mister L that this was a man of most unusual intelligence, cultivation, and sophistication. In the six and a half years I have known him, he has taught me more about parkinsonism, post encephalitic illness, suffering, and human nature than all of the rest of my patients combined. The picture which mister L presented in nineteen sixty six had not changed since his admission to the hospital. He showed extreme rigidity of his neck, trunk, and limbs, and marked dystrophic changes in his hands which were no larger than those of child. His face was profoundly masked, but when it broke into a smile, the smile remained for minutes or hours, like the smile of the cheshire cat. At the end of my first meeting with Leonard L, I said to him, what's it like being the way you are? What would you compare it to He spelt out the following answer, caged deprived like Rilke's panther, and then he swept his eyes around the ward and spelt out, this is a human zoo. El Dopa was started in March nineteen sixty nine. Little effect was seen for two weeks, and then a sudden conversion took place. The rigidity vanished from all his limbs, and he felt filled with an excess of energy and power. He became able to write and type once again, to rise from his chair, to walk with some assistance, and to speak in a loud and clear voice, none of which had been possible since his twenty fifth year. I feel saved, he would say, resurrected, reborn. I feel a sense of health amounting to grace. I feel like a man in love. I have broken through the barriers which cut me off from love. For this, it was worth it my life of disease. In April, intimations of trouble appeared. Mister L's abundance of health and energy became too abundant and started to assume an extravagant, maniacal and grandiose form. His sense of harmony and ease and effortless control was replaced by a sense of too muchness of force and pressure and a pulling apart, a pathological driving and fragmentation, which increased, obviously invisibly with each passing day. We stopped his el dopa towards the end of July. His psychoses and tics continued for another three days of their own momentum, and then suddenly came to a stop. Mister L reverted during August to his original motionless state. In September, he opened up again to me, tapping his thoughts on his original letter board. The summer was great and extraordinary, he said, But whatever happened then will not happen again. I thought I could make a life in a place for myself. I failed, and now I am content to be as I am. A little better perhaps, but no more of all that.

00:03:53
Speaker 2: WHOA, yeah, I totally understand why you are so excited about this episode.

00:04:01
Speaker 1: Yes, I just got chills. Yeah just now when you said that, yeah, I'm thinking about this. That was from Awakenings by Oliver Sacks, and this episode of this podcast will kill you. It's about encephalitis lethargica.

00:04:18
Speaker 2: Yeah it is. Hi.

00:04:19
Speaker 1: I'm Aaron Welsh.

00:04:20
Speaker 2: And I'm Aaron Alman Updyke.

00:04:22
Speaker 1: Welcome.

00:04:23
Speaker 2: We're really excited about this, yes, Aaron, just like can't. Also, we're in the same room for the first time in many, many months recording this, which is thrilling.

00:04:35
Speaker 1: It's really thrilling.

00:04:37
Speaker 2: So I can see the goosebumps that she has.

00:04:43
Speaker 1: Oh yeah, I'm really excited about this episode for so many reasons, and we'll get into those later. But I do want to point out very quickly, yes, that there's a movie called Awakenings, which I have told you to watch about one hundred thousand times Aaron. And in the movie, Leonard is a featured character played by Robert de Niro, who was nominated for and possibly won the Best Actor Oscar for Awakenings when it came out.

00:05:12
Speaker 2: Do you want me to fact check that?

00:05:13
Speaker 1: Please? Also, Robin Williams plays Oliver Sacks, but not by the same name.

00:05:19
Speaker 2: They changed the name.

00:05:20
Speaker 1: Yeah, well, it's a fictionalized version of events.

00:05:24
Speaker 2: Yeah. No. Robert de Niro won for Best Actor great.

00:05:27
Speaker 1: Job, Aaron. Thanks. So what are we drinking?

00:05:34
Speaker 2: Our quarantine this week is called the Lullaby. Yes, as it lulls you off to sleep.

00:05:43
Speaker 1: By the way, we should state that alcohol is not a sleep aid, No, and it actually makes your sleep much worse. Yes, absolutely, But there is the traditional nightcap nightcap, and so this is a form of nightcap.

00:05:58
Speaker 2: Sure it.

00:05:58
Speaker 1: The ingredients include.

00:06:00
Speaker 2: Food, vanilla, vodka, lavender, simple syrup with honey, and some lemon ye soothing. Soothing, but yeah, it does contain alcohol. We'll post the recipe for that along with our plassy burrita, which is our non alcoholic version. Maybe better for getting you to sleep?

00:06:17
Speaker 1: Yeah, I don't know.

00:06:18
Speaker 2: Probably.

00:06:18
Speaker 1: Wow, turning off your cellphone and not looking at the screen is really good too.

00:06:24
Speaker 2: We'll post the recipes for both of those on our website along with all of our social media. Okay, do we just get started?

00:06:32
Speaker 1: Get started?

00:06:32
Speaker 2: Okay, tell me what is this medical mystery? Let's get just let's tell me all about it, Aaron. But first we'll take a quick break.

00:07:04
Speaker 1: The year is nineteen eighteen. Walking the nearly empty New York streets on this freezing gray January morning, you feel like you're the only person in the world. Crumpled newspapers blow by their headlines shouting of the endless death and horror experience by those young men fighting overseas in the Great War. By the end of the year, the war will be over, but that would hardly come as a consolation to you and many others. Between the brutal violence that laid wreckage to an entire generation and the influenza pandemic that killed between fifty to one hundred million people worldwide, nearly everyone had lost someone or several someones in the most horrible ways imaginable. In those months following the armistice. As the pandemic began to wane, people mainly concerned themselves with moving on, because steing in your own tragedy was too painful, and over time, the stating effects that the Great War and the influenza pandemic had on the world began to fade from memory or at least open acknowledgment. Among those forgotten was a small group of people who, from around nineteen seventeen to nineteen twenty four fell asleep one day and by doing so lost themselves some forever and others for a few decades, but all this lay in your future. Today, you are just a physician specializing in a now extinct field of neuropsychiatry, and on this particular morning, you're following up on some house calls. Your first patient of the day is a sixteen year old girl named Ruth. Ruth's parents had called for your expertise because Ruth was asleep. And yeah, teenagers sleep a lot, so there's nothing wrong with that, right, Okay, Well, Ruth had been asleep for over a month.

00:08:57
Speaker 2: A month straight, a month?

00:09:00
Speaker 1: What uh huh?

00:09:01
Speaker 2: And her pints wait in a full months, They're like, just give it a couple more days. She had a rough she had a rough time, ended a semester.

00:09:09
Speaker 1: Maybe they saw other doctors before you came aroung I mean, I would guess. But before she fell asleep, she noticed a severe pain in her right index finger, and the pain spread up her arm, eventually resulting in paralysis. Then her personality changed. She flew into a rage at any provocation and violently lashed out. During one of these outbursts, she had to be restrained, and it was then she fell into this deep sleep.

00:09:38
Speaker 2: Wow.

00:09:40
Speaker 1: While sleeping, her temperature rose to one hundred and two degrees fahrenheit thirty eight point nine degrees celsius.

00:09:46
Speaker 2: Whooh, that's hot, that's very hot.

00:09:48
Speaker 1: She slept through Christmas through New Year's and had to be put on a feeding tube and hydration drip.

00:09:54
Speaker 2: So they definitely saw other doctors.

00:09:56
Speaker 1: Yeah, yeah, yeah, but she wasn't sleeping the sleep relaxed person. All of her muscles were taught, never losing their rigidity, She could be molded into different positions. Her pupils were dilated, her eye muscles didn't twitch, and she appeared not to smell or hear anything. But underneath that illusion of sleep, she did hear her parents grief stricken voices. She smelled the flowers in her room and felt the restraints on her wrists, but she had no way of telling anyone this, and a few days later, as her fever climbed ever higher, she died. Ruth would not be the only patient you saw with the strange disease progression, and New York would not be the only location where the outbreak occurred. After the war ended and information was more freely passed across political borders, it became apparent that an epidemic was brewing and had been for some time a few years before you saw Ruth, a couple of physicians at neuropsychiatric hospitals in Germany and France noticed that their clinics were filling up with soldiers with very unusual symptoms, which varied substantially from person to person. Sometimes they had fevers, headache, nausea, but not necessarily, some had bizarre tics, some looked to be in a catatonic state, and some could not stop hiccupping. One actually hiccupped so much that he died as a result of that. There seemed to be no common exposure and no family links among these people. The only thing that they seemed to share was their unbearable sleepiness. After seeing several of these patients, neurologists Constantine von Economo.

00:11:41
Speaker 2: Let's hope that's how you say it, yeah, living in.

00:11:44
Speaker 1: Vienna, declared this a sleeping sickness in around nineteen seventeen, and he published a description of it, and he called this disease encephalitis lethargica. Forty to fifty percent of people who came down with this particular encephalitis lethargica died, usually due to failure of the respiratory system and autopsies show that there was something going on in the brain, the mid section of the brain, the part that controls sleep. It was swollen and looked to be damaged. Although von Economo didn't know what had caused the disease, he did think it was some sort of infectious pathogen, because if you injected a bit of the brain tissue of an encephalitis patient into a monkey, you would get similar symptoms.

00:12:29
Speaker 2: Oh, I saw that too, and I think that's so interesting.

00:12:32
Speaker 1: Interesting. And then there was an event that van Economo vaguely remembered from his childhood, another wave of sleeping sickness that came on the heels of a big influenza epidemic in Western Europe in the eighteen nineties. Because of how it knocked the life out of those affected, the disease was known as the living dead or no, na.

00:12:55
Speaker 2: It's not another zombie episode. Guys, it's not sorry, sorry, not sorry. Don't worry either way.

00:13:01
Speaker 1: Yeah. At that time, doctors linked the sleeping disorder to the recent flu epidemic, wondering if it was caused by the lingering effects of the flu infection or whether this foreshadowed an upcoming severe epidemic. Vana Konomo wasn't the only one to begin investigating this mysterious epidemic, which by nineteen eighteen had popped up all over the world in England, Sweden, India, Egypt, China, Australia, Uruguay, and of course the US. When looking back in medical textbooks and papers, British doctors did find some evidence that this sleeping sickness wasn't entirely new. There had been epidemics of unexplained sleep problems going back to the sixteen hundreds in Denmark and England, and these epidemics may have been used as inspiration for Sleeping Beauty. I mean Who Knows, which was written in sixteen ninety seven, and Rip van Winkle in eighteen nineteen, Okay, and a couple of Edgar Allan Poe's stories, like the Fall of the House of Usher and the Premature Burial. I mean, right, we're rewriting history here, We're doing a little bit of a just so story. But this is just what I read, so who knows. But beyond these tenuous links there was nothing else to give doctors any sense of what was really happening and why, And it was getting worse within a year of its first appearance in England in nineteen eighteen, there were over a thousand cases of the mysterious illness, and as this disease spread, doctors learned that there seemed to be no end to the ways that it manifested. So most patients might be sleepy, but others grew hyperactive and they would jump and run around with terror in their eyes as they realized they could not control their own movements.

00:14:49
Speaker 2: It's so fascinating to me that doctors even connected those cases. They were like, these are the same things, even though they're so different from each other, right.

00:15:01
Speaker 1: And that kind of comes into play a little bit later on, But in general, doctors were at a loss to explain what was happening. The leading hypothesis was that it had something to do with influenza. So the epidemic of encephalitis lethargica started in Earnest, about a year before the nineteen eighteen influenza pandemic. Interesting, which is interesting. And then the incidents of cases remained fairly high until declining through the mid nineteen twenties, and then slowed to a trickle over the next two decades. Most people who had developed symptoms of encephalitis lethargica had either had the flu recently or got flu after, and the appearance of the Italian known as sickness in after the eighteen ninety flu pandemic was also suggestive of a connection. But this was mostly situational evidence, and adding to the mystery was the manifestation of the disease itself, which seemed deeply personal. Eve Though this disease caused physical damage to the brain, the personality or experiences of the patients seemed to play a role in what symptoms they would have.

00:16:10
Speaker 2: Like hyper people would be more hyper, or like hyper people would be the sleepy ones.

00:16:15
Speaker 1: Well, let me give you an example. Craze. So there was a child named Adam who had developed and scephalitis lethargica, and he had respiratory attacks that were triggered by authoritative personalities. And that's because he apparently, growing up, had sort of had problems with authoritative personalities. And here's another example. This sounds like a fairy tale, so you know, take over the grain of salt maybe, But in New York, one twenty nine year old woman who loved music had been asleep for one hundred days. This is a fairy it's a fairy tale. Her husband supposedly hired a violinist to play for her, and she woke made a full recovery one hundred days. One hundred days. I mean, it could have been Is this a movie? Has someone made a movie of this? Yeah? Well awakenings?

00:17:09
Speaker 2: I mean I meant of her.

00:17:12
Speaker 1: Not yet but okay. But yeah, So this was a deeply it seemed to be a very deeply personal disease, which is just it blurs the line between the mind and the brain.

00:17:21
Speaker 2: Absolutely, yeah.

00:17:23
Speaker 1: And the fact that it sort of blurred this line may not have been a coincidence because doctors at that time, so the doctors that were treating these people were neuropsychiatrists, as I mentioned, which is is sort of this not it's not really a field that is in existence today inso much, I guess, because these people were treating both nerves and nervous disorders as they were called. They were treating both the mind and the brain at the same time, and they sort of assumed that they were part of the same thing. And as we've seen that sometimes it is and sometimes it isn't. But this in particular was one of the first times that it was so amorphous that distinction between the two. In the early twentieth century, New York City was brimming with neuropsychiatrists who worked closely with public health officials, and they worked together to identify and track cases of this strange epidemic, which made New York a pretty good place to sort of study how this epidemic played out. By the time it came to an end, the encephalitis lethargica outbreak would infect over five thousand New Yorkers. Wow a lot.

00:18:34
Speaker 2: Yeah, And is this still true that you said forty to fifty percent would die.

00:18:40
Speaker 1: That's what the estimates were.

00:18:41
Speaker 2: Yeah, Okay, dang, that's a lot of people.

00:18:44
Speaker 1: Yeah. And even though doctors were no closer to understanding the cause of the disease, they were beginning to realize the horrifying extent of the epidemic. When epidemic encephalitis was first observed, it was viewed as the strange and phenomenon that affected an unfortunate few. But as the years went on, the duration of this supposedly acute illness stretched from weeks into months and months into years, and the disease itself was constantly changing. Post encephalitics as they would come to be called exhibited an array of neurological symptoms that had never been seen before, much less in epidemic form. Most adults would develop a small tremor that would turn into an extreme form of Parkinson's disease, where tremors would increase to the point of absolute stillness. The average age of onset for Parkinson's disease during the decades after the encephalitis lethargica epidemic was thirty six.

00:19:42
Speaker 2: Ooh, that's not normal. No, no, Parkinson's is a disease.

00:19:46
Speaker 1: Of held really yes, in general. In children with epidemic encephalitis, which there were a lot, there were more often than not psychological changes, including extreme beheld behavioral changes. Doctors weren't sure why exactly it affected children differently than it did adults, But in children, the disease caused brain swelling that damaged the frontal lobe, often which is where decision making, personality, addiction, impulse control, all those things happen, and almost all of the changes seem to be negative. Homicidal or suicidal tendencies emerged complete lack of morality, anger, rage, etc. And these children who changed because of epidemic encephalitis could be distinguished from those with schizophrenia or psychosis because the encephalitic children had awareness of their actions and thoughts and that they were wrong. They would ask to be restrained.

00:20:43
Speaker 2: Wow.

00:20:44
Speaker 1: One child said, quote, it's so sad to be like me. This is only the beginning. It's going to get worse. You don't understand how it is not to be yourself. I feel so vicious at times. I was always good and kind to people. There are other people in the world like me. I feel sorry for them. I know a little girl like me, and I only pray that something will happen to her before she grows up. I want to tell you about this because the time is coming when I won't be able to. But you're well, you can't understand now I have child.

00:21:19
Speaker 2: I know why what?

00:21:22
Speaker 1: Yeah?

00:21:24
Speaker 2: This is so weird, Aaron.

00:21:25
Speaker 1: Can you, I mean, can you imagine how that would feel to know that it's you have no control and it's slowly ebbing away more and more and more.

00:21:34
Speaker 2: Your fears are all very similar and intertwined, Aarin, because this is not so different from Lockedin's. And yes, I know, I know, Yeah, it's there's so many similarities in terms of just this. Your your brain and your mind. Your mind is intact right, but your brain isn't and your body isn't, and it's not under your control.

00:21:58
Speaker 1: Yep, oh creey, it's really horrible. Yeah, so impost control and self harm was another common manifestation in children. One girl diagnosed with posts and stephalitis pulled out her teeth in her family's bathroom when she was fourteen years old. A few years later, she plucked out her right eyeball during the night. The next day, mid morning, after they found her eyeball on the floor and her eye socket empty, they baited her eye socket. They cleaned it out and then left her for a few hours, and a few hours later gone her left eye was gone. She plucked it out as well, and she didn't seem bothered by the pain or the act itself. And when they asked her, why did you do this, she kind of shrugged and said something made me do this. It was a you see the apathy there, and a complete sort of disassociative like, I'm this is not some that I care about what I'm doing.

00:23:02
Speaker 2: I can't I can't even close my mouth.

00:23:06
Speaker 1: I know. Yeah. Ah, the hallmark of the disease. If there was any was that the deterioration happened slowly over years. Most of those who survived the acute phase encephalitis eventually lost the ability to care for themselves, and tens of thousands, maybe more, around the world were placed in institutions where they would live out the rest of their days. In the couple of years following the epidemic, interest in the disease was still high enough to get organized to try to find some answers. The Mathison Commission was put together by William John Matheson in nineteen twenty seven. So Mathieson was a wealthy, relatively young guy who was post encephalitic, and he was frustrated with the inability of doctors to do anything for him. He appointed Josephine Neil, neurologist, bacteriologist an encephalitis expert, as its leader. A lot of her male colleagues that she was the boss of really did not like her, and they continually tried to vote her out, but Matheson was like, no, she's the expert at all of this.

00:24:13
Speaker 2: She stays shocking to hear, right.

00:24:18
Speaker 1: So the first order of business though, in this Mathison Commission, was to get an idea of the extent of people affected by the disease, which was easier said than done. Both the acute stage and chronic symptoms of epidemic encephalitis could be easily confused with other illnesses, so the number of diagnoses probably wasn't super reliable. To get an idea of the number of people with post encephalitis, as well as any clue as to a pattern behind the cases, they had to look wider than New York City. It was time for international collaboration, which previously when the epidemic started it was during wartime, and so then even though these cases were climbing, it's not like French doctors and German doctors were talking to each other saying, hey, we've got some soldiers.

00:25:01
Speaker 2: No, definitely not.

00:25:04
Speaker 1: And so the Commission ended up compiling reports from all over the world to get a clearer idea of the history of this disease, and then they set their sights on understanding the disease itself, with the ultimate goal of developing a vaccine. But they didn't even know what the causative agent was. Where do you even start. Was it the influenza virus, was it bacterial? Was it viral. Was it something else that no one had ever known before. The leading hypotheses were that it was some sort of Streptococus bacterium, or that it was a type of herpes virus, or that it was another virus yet unidentified. Three different groups began working on vaccines to test, but just when small scale vaccine trials began and started showing promising results, Matheson died of a heart attack and the funding for the commission was cut short. Though Josephine Neil tried to keep the commission together by securing funding and then donating her own salary, any hope that the mystery would be sold basically died with Matheson. Because as the number of acute epidemic encephalitis cases declined over the nineteen thirties, forties, and fifties, the disease began to fade from memory. You didn't see people on the streets with this. They were all in long term care facilities, and doctors who had not lived through the height of the epidemic started to wonder if the whole thing had just been a complete misunderstanding. Wow, maybe there were no link between these cases and it was just sort of an umbrella term for unexplained behavior or some sort of psychosis or catatonic states, whatever it was. Yeah, and so encephalitis, lethargica, and post encephalitis started to be viewed as this one hit wonder, never to be seen again. It stopped being taught in med schools by the nineteen sixties.

00:26:52
Speaker 2: Oh, we don't talk about it, right at all. Right, we haven't talked about it at all.

00:26:57
Speaker 1: Yeah.

00:26:57
Speaker 2: Yeah.

00:26:58
Speaker 1: In this first part, I focus a bit more on the individual side of the disease rather than a big picture of view. But I do want to give that to you, so I'll end this part with this great quote from the book Asleep by Molly Caldwell Crosby. Epidemic encephalitis was considered one of the most important diseases in the development of twentieth century American neurology. In all, it afflicted and estimated five million people worldwide, wow, killing one third of them and leaving one third to die inch by inch, minute by minute in asylums. One neurologist wrote that no other infectious disease affected so large a portion of its victims or for so long a period of time. Aaron, Uh, oh, so tell me what was actually going on with these people?

00:27:52
Speaker 2: This is such a good question. Let's talk about it right after this break. So before we talk about encephalitis lethargica specifically, Okay, let's take a step back for a minute, let's just define encephalitis, right, That seems like a good place to start, fantastic. So, encephalitis just means inflammation. That's itis, Okay, inflammation of your actual brain n the en as an inside and seth comes from head brain. Okay, So we have actual inflammation inside of your brain, which you know is going to be something that's not good and.

00:29:04
Speaker 1: Very horrible, bad badness.

00:29:06
Speaker 2: There are tons of different things that can cause encephalitis, and different forms of encephalitis are going to have slightly different manifestations. So you can get encephalitis from viruses, you can get it from bacteria, parasites, fungus, you can get encephalitis from autoimmune diseases, you can get it from medications that you take. And there's a number of different symptoms, kind of overarching that we tend to see in all encephalitis cases. These include things like headache, shocking, right, your brain is inflamed.

00:29:39
Speaker 1: Just pressing against your skull, like me out right. Okay, So you get.

00:29:43
Speaker 2: A headache, a fever, which is common with a lot of infections, very general confusion, which makes sense because your brain, if your brain is being inflamed and scrambled, you might feel confused, vomiting, and then you can get different symptoms based on where the inflammation is most prominent. So if you maybe have inflammation of the speech centers of your brain, then you might have trouble speaking. If you have inflammation of the memory centers of your brain, then memory maybe you'll have memory problems, and you can have hearing problems. Yeah, natcha. So different types of encephalitis are going to manifest slightly differently. So if encephalitis is just brain inflammation, then encephalitis lethargica is lazy brain inflammation, apathetic brain inflammation. I didn't know that the word lethargic comes from forgetful.

00:30:40
Speaker 1: Oh I didn't either.

00:30:41
Speaker 2: I it never happened, This is fun.

00:30:46
Speaker 1: I just assumed it was like tiredness, me too, that's great.

00:30:50
Speaker 2: Yeah or or yeah, but it's not. It means forgetful. So that's weird.

00:30:54
Speaker 1: The more you know.

00:30:55
Speaker 2: But but you know lethargic magic, Yeah, you're feeling lethargic. So it seems, especially based on some of your descriptions, like that's a good term for the type of encephalitis that we see. But so back in the early nineteen hundreds, von economa.

00:31:14
Speaker 1: I mean, if that's how you say it, I kept.

00:31:15
Speaker 2: Saying it echomomo, which is clearly wrong.

00:31:17
Speaker 1: I think that might be wrong.

00:31:18
Speaker 2: Yeah, definitely wrong. He described three main clinical varieties of encephalitis lethargica. At least I think that it was him. These are sort of the three main varieties that were used for diagnosis for a number of years, all the way through the forties. So these three forms are the somnolent ophthalmoplegic form okay, the amiostatic a kinetic form aren't these fun words? And the hyperkinetic form. So let's go through what these all mean. Yes, so the somnolent form had the somnolent form I think is the one that you talked about the most. It's the most it's the sleepy one, right right, So it's kind of the most lethargic of encephalitis lethargica's And so this was characterized pretty specifically by a prodrum period. And we've talked about the word prodrum before, but it basically is like a prequel to the real disease, and it's usually very non specific symptoms that happened before the real kicker of the disease comes through. So the somnolent form had this type of prodrum which had symptoms like general malaise, feeling cruddy, headache, en cephalits, and a mild fever but not a crazy high fever.

00:32:36
Speaker 1: Okay.

00:32:37
Speaker 2: But then the patient would become increasingly increasingly tired and they would fall into a very deep sleep, and if you tried to wake them up, you could, they'd wake up super easily. You could shake Little Ruth and she'd wake up, but then immediately she'd fall back into a really really deep sleep, which is so bizarre to think about.

00:33:03
Speaker 1: It's yeah, it's fascinating.

00:33:05
Speaker 2: Yeah. And then this would just get worse and worse, and the patient would either die about fifty percent of patients would die, or they would wake up. That's it. They would die or they would wake up. And you might get muscle involvement, you might get weakness of like muscles being very weak or what we call hypotonic, which means that they have like they're flaccid, like there's no rigidity to them, or you might get the opposite, you might have really rigid muscles where they're all they're all clenched all the time. And yeah, the mortality rate for this type of encephalitis lethargical was about fifty percent, right, Okay. The other form that was kind of second most common was the hyperkinetic form, which you also described, And this is the restless form. So instead of just sleepiness, you get more twitching and muscle jerking. You might get anxiety, like a feeling of anxiety, and often you'd have severe pain in your muscles, so pain in your back or your neck, your muscles would feel weak. And instead of having sleepiness, you might actually get insomnia, so you're not sleeping at all. So in both of these you have major sleep disturbances, but they're in opposite directions.

00:34:25
Speaker 1: Okay, why, great question, Like, so this is the same part of your brain is affected, presumably in terms of the actual physical damage being done, but in one time, one type it makes you extremely sleepy. Hether it makes you super awake.

00:34:40
Speaker 2: Well, it gets weirder because the hyperkinetic form would often then progress to the somnolent form. So you start out having insomnia, and then later in the course of the disease progression, you end up really really sleepy, and then you maybe fall into this deep, deep somnolent sleep. Aaron, this is such a weird disease.

00:35:02
Speaker 1: One thing, it's bizarre, and one thing I didn't mention, but I thought it would be. It's a really interesting little tidbit is that this disease actually was one of the things that made scientists realize how important sleep is and how crucial it is for function.

00:35:15
Speaker 2: Oh that makes so much sense. Yeah, because it totally messes with your sleep. Yeah, yeah, I don't understand this disease.

00:35:22
Speaker 1: I don't either.

00:35:23
Speaker 2: Still, it's going to be spoiler alerts you guys. We don't have answers for you. So, in the early phase of this hyperkinetic form of encephalitis lethargica, mortality was actually even higher than fifty percent. But if a patient progressed then to the somnolent form, mortality was a little bit lower than if you just started with somnolent straight out of the gate, which it doesn't even make any sense to me whatsoever. It's like very bizarre. Another thing that you would get more in the hyperkinetic form than in other forms of the disease is problems with your eye muscles, so whether they are paralyzed or whether your eyes would kind of get stuck in different positions because of paralysis of only some of your eye muscle. Your eye muscles are actually very cool. You have there's like six different muscles that move your eyes in different directions, and they're controlled by three different nerves, oh.

00:36:18
Speaker 1: Mud, And so you can get it's very fun.

00:36:21
Speaker 2: So you can get paralysis of just certain muscles and then your eyes will be stuck in certain positions because of that.

00:36:28
Speaker 1: Yeah, one more thing to fear. Cool.

00:36:30
Speaker 2: Yeah, it's it's fine. And finally, the last form is called the amiostatic kinetic form of encephalitis. This was the least common but seems to have had the most chronic issues associated with it. Interesting, Yes, I agree. So this form of the disease, you'd get more of that weakness, muscle weakness and rigidity that you see in the somnolent form, but you also then progress and early in the disease would have symptoms that resembled what we know today as Parkinson disease. Okay, the thing that you wouldn't see that's very very common in Parkinson disease is a tremor. So the the tremor that you get in parkinson is very specific. It's called they call it a pill rolling tremor. It's a resting tremor, and it's it's if you are trying to make active motion, like conscious motion, like can you lift up this glass, you you wouldn't see the tremor. But when you're just sitting still at rest, that's when you would see this tremor.

00:37:36
Speaker 1: I always think about that. So my grandpa had Parkinson's and I always think about that one because I get very shaky hands when I drink coffee, and I always go and like, I'm like, okay, do I have a tremor when I pick up the coffee or is it because of.

00:37:49
Speaker 2: The coffee or a resting tremor.

00:37:52
Speaker 1: That's exactly what I think to I saw very frequently.

00:37:54
Speaker 2: Yeah, okay, yeah, So that type of resting tremor would not be seen in patients with encephalitis lethargica type parkinson symptoms, which I find very interesting. But what you would see that was very similar is that you see in Parkinson disease is a very rigid muscle, so you're especially on your extremities would be very rigid. You could move them and then they would stay where you placed them.

00:38:19
Speaker 1: Mold.

00:38:20
Speaker 2: Yeah, yeah, it's very interesting. And then you'd also see the same kind in this type of encephalitis lethargica. You'd also see the same type of problems with sleep, either excessive sleepiness or insomnia. And you'd get a lot of that ocular involvement especially, you'd get things like double vision or diplopia. And tosis, which is one of my favorite medical words of all times.

00:38:46
Speaker 1: Is there a hidden peak?

00:38:47
Speaker 2: There's a piece.

00:38:49
Speaker 1: It's a pt sis tosis.

00:38:53
Speaker 2: It means a droopy eyelid.

00:38:56
Speaker 1: I'm so thrilled that I guess that there was a P in this?

00:38:58
Speaker 2: Is it the way I moved my mouth.

00:38:59
Speaker 1: I think it was thinking about was it? What's the one in tuberculosis? Tyss, I don't know. Do you remember this? No, No, you don't remember that.

00:39:10
Speaker 2: I don't remember this. I'm the worst, Aaron. Sorry, tyss.

00:39:16
Speaker 1: P t H I s I S this is p t H would.

00:39:21
Speaker 2: Be this is pulmonary tuberculosis. Is that's another word for pulmonary tuberculosis.

00:39:25
Speaker 1: Yeah, we can't. We call it tysis the whole the whole episode. Who knows if that's wrong.

00:39:30
Speaker 2: You know, we do a lot of things whatever.

00:39:33
Speaker 1: Okay, So, but droopy island, droopy elid. Okay, Why are the ocular nerves so involved?

00:39:40
Speaker 2: That's a really good question. I don't I don't know if they It's possible that they're in the same because they probably come out in the same regions where the parts of your brain that are being inflamed. That's where it's just a lot of your fee ye, just geography essentially. Yeah, because also a lot of your your other muscle nerves, they come out lower, like a lot of the nerves that are controlling other muscles in the rest of your body come out lower in your brain stem.

00:40:05
Speaker 1: Oh but it makes sense, so like all of your facial nerves would be.

00:40:10
Speaker 2: I'm so anatomy of the brain is not my strong suiting. So you're asking me really hard questions. I'm having to dig deep in my knowledge bank here for these. I'm sorry, but yeah, you're the your ocular motor nerves come out a little higher up in your brainstem than other even than other facial nerves. Okay, okay, so it's probably probably has to do with that, just the geography of it, okay. And also I think because because it's three different nerves, if you affect any one of those, then you're going to see ocular impairment in some way, if that makes sense right, there's yeah, So you've got a lot of chances, Like you have three techniques. You have four whole nerves that just do your eyes because you also have your like your vision eye. No, it seems like not very many nerve. Four nerves just for your eye. That's it. You have one that does all of sensation.

00:41:04
Speaker 1: Oh okay, to your face and like, can I get some more nerves on my eyes anyways?

00:41:13
Speaker 2: Okay. So those are the three main forms of encephalitis lethargica, and what often happened, like you mentioned, in many cases, not all cases, no matter what form is, the patient would later go on to develop post encephalitic parkinsonism. So what does that look like? It looks like you actually described it really well. You get this rigidity in your muscles, very delayed movement. So another feature of parkinson disease is something called cog wheel rigidity. So it's like if you imagine trying to move a hand of a clock along a cog, that's how they move. It's like a movement that jumps exactly right. Yeah, And I found another quote from Awakenings that I think actually describes post encephaltic parkinson as't very well, so I'm going to read it wonderful m hmm. He says they would be conscious and aware, yet not fully awake. They would sit motionless and speechless all day in their chairs, totally lacking energy, impetuous initiative, motive, appetite, affect, or desire. They registered what went on about them without active attention and with profound indifference. They neither conveyed nor felt the feeling of life. They were as insubstantial as ghosts and as passive as zombies.

00:42:42
Speaker 1: Chills.

00:42:43
Speaker 2: Yeah, so that's what these people would look like if they were suffering from post encephaltic parkinson, which is a bit different. It's kind of like a very extreme Parkinson disease almost because in Parkinson, we see a lot of very similar symptoms. You see a flying what we call flattening of the affect, which means your face is kind of expressionless. Even if you feel emotions, your face doesn't reflect those emotions that you feel. And so I think that's one of those things that's very I don't even know the word for it. It feels bad. Like if you think of seeing a person who's clearly has emotion and their brain is still intact in there, but their face can't express any of that.

00:43:29
Speaker 1: Well, it's just like what Leonard's first hand account was was feeling like you are a panther in a cage.

00:43:36
Speaker 2: Yeah, yeah, and the cage is your own body that's depressing. So then the question is what's actually happening in the brains of these people? And it's okay. So in the acute form of encephalitis lethargica, so before people progress to post encephalitic Parkinson's, especially obviously if they die, because we're looking at brain specimens here and this is the early nineteen hundred, so we don't have MRIs, there's a lot of very non specific stuff that happens. So you get congestion of blood vessels, meaning like the blood vessels in your brain get filled up with like blood and lymphocytes, your white blood cells.

00:44:21
Speaker 1: But not like a clot, but just like a reduction in the amount of blood that can go through.

00:44:25
Speaker 2: Well, yet not a clot like you just have one stroke or anything like that, but you would just get a bunch of stuff sort of filling up small vessels, which would then lead to you're not getting blood flow. Okay, right, okay. You also could see small hemorrhages in different areas of the brain, and all of this is indicative of some kind of inflammation going on, which makes sense, right, We're talking about it encephalitis, which is inflammation, and you tend to get more involvement of the brain stem, which is oh gosh, I should have written like how to explain the brain stem, which is the part of your brain that comes out at the base and then goes down into your spinal cord like connects up with your spinal cord. And this part of your brain stem is involved a lot in movement. So it makes sense that we see all of these different movement related things. But what's different is that while we see these similar changes in patients with Parkinson disease, like what we define as Parkinson disease today, the changes aren't the same changes. So in Parkinson disease, we see accumulation of something called this is getting very specific. We see accumulation of certain types of proteins. We don't see that in patients with encephalitis lethargica. We see different proteins accumulating that actually look more like Alzheimer's, but it's in the wrong part of the brain. What what Yeah, you get something called neurofibrillary tangles in a lot of patients with encephalitis lethargica.

00:46:04
Speaker 1: Okay, so in both in both Alzheimer's and parkinson you get accumulation of certain proteins, right, But in cephalis lethargica you get accumulation of protein, but it's Alzheimer's, not the Parkinsonian form. But yet the disease is more manifested in a Parkinsonian way.

00:46:25
Speaker 2: Yeah. Why different because it's in different parts of your brain. So it's essentially what part of your brain is being messed up? What part of your brain is stuff accumulating that it shouldn't be. What part of your brain are white blood cells coming and invading and taking up a whole bunch of space that they shouldn't be.

00:46:43
Speaker 1: So it's not so much about the proteins themselves or the identity of the proteins. It's more about the location in which they are accumulating.

00:46:48
Speaker 2: Yeah, and it's also I mean, we define parkinson disease today as accumulation of these certain proteins, right, So that's how we've defined this set of disease. This is something different, So it's not parkinson disease, it's something different. Yeah, So parkinsonism is kind of like a broader umbrella term for things that have similar manifestations that we see in parkinson disease. Okay, but this what we were seeing after these this epidemic encephalitis is not the same thing as parkinson disease essentially, right, that makes sense, yes, so, but as it turns out, it can be treated similarly in some cases. So I'm going to stop there, Aaron, and ask you about how we figured out how we could treat this and whether it was still going on or what happened to all those patients with post encephalitic parkinsonism.

00:47:49
Speaker 1: All right, this is a fun little format.

00:47:52
Speaker 2: I like this is it's really fun.

00:47:53
Speaker 1: I hope that everyone's listening likes it too.

00:47:57
Speaker 2: I have to p do you have to be I do so?

00:48:22
Speaker 1: Yeah, like you said, there were still thousands of people affected by this disease that were spending their lives in an institution. But at the same time, interest in post encephalitis had basically stopped, so what was happening, what was going on? Supportive care was about the only thing that doctors at these places could do, or tried to do, and they did see that a stable and nurturing environment greatly helped with the quality of life, as you might expect. Mount Carmel was an institution in New York that was opened after World War One for returning soldiers who had nervous injuries and for those with post encephalitis symptoms. When it was first opened, it was small and cozy, with just forty beds tucked away in the countryside. When Oliver Sacks arrived in Mount Carmel in nineteen sixty six, about fifty years after it opened, much had changed. The quiet village nearby had grown into a huge suburb of New York City, and the forty beds had grown into a thousand. Whoa yeah. And it was at Mount Carmel that Sachs met eighty post encephalitic patients still alive almost fifty years after first being diagnosed.

00:49:36
Speaker 2: Some of them Wow m.

00:49:40
Speaker 1: Oliver Sacks, upon interacting with these patients, said, quote, we're going to quote him a lot. I'm sorry.

00:49:46
Speaker 2: Why would we be sorry, I.

00:49:47
Speaker 1: Don't know, because he's Yeah, we shouldn't be he's the He's I think he's called the poet Laureate of medicine. Yeah, yeah, amazing. I would not have imagined it possible for such patients too exist, or if they existed, to remain undescribed more chills. They had been forgotten, and at Mount Carmel was one of the largest groups of people with posts encephalitis left. Some had been living in a hospital, never stepping foot outside for decades. Wow. And they all looked so young. Their faces were unlined since their facial muscles hadn't been used in expression for decades.

00:50:31
Speaker 2: Oh my gosh.

00:50:33
Speaker 1: So even Leonard, who was we heard about in their first hand account. Oliver Sack said about him that he looked like he was in his twenties even though he was forty six, because he was just had never used his facial muscles in like twenty years or more.

00:50:47
Speaker 2: Wow, yeah, I should use my facial muscles, lest I know.

00:50:52
Speaker 1: It's what I keep thinking, like, Oh man, okay, that's the true, no more laughter, just kidding it. But so many doctors at Mount Carmel and other institutions regarded these patients as past the point of hope. Many appeared to be catatonic, completely unresponsive, or dealing with irreversible brain damage in some way, if something could be done, Was there anyone even left inside to save? Was their thought? Sax thought there was. He noticed that with many of these patients who appeared frozen mid movement, you could get them to react as if they just needed prompting. So if you threw a ball to them, which he did try, they could catch it.

00:51:36
Speaker 2: What uh huh like a reflex.

00:51:38
Speaker 1: Yeah, it just they could initiate that movement. That was all that it was. If you held their hand, they could walk along with you. Yeah, if you started the if you started to walk, they could walk with you.

00:51:55
Speaker 2: Weird.

00:51:56
Speaker 1: Yeah, And so Sax linked this inner shall like state to a Parkinsonian tremor taken to the extreme, which then led to his moment of inspiration and the awakenings of patients who had long been given up as lost. In nineteen sixty seven, the year after Sacks started working at Mount Carmel, Levedopa, which is a synthetic form of dopamine was discovered to be effective for people with Parkinson's to treat some symptoms. Sax could think of no reason why it might not also have an effect on these post encephaltic patients that he saw, so he decided to conduct a double blind ninety day trial of el dopa. Several of those who received the drug regain the ability to move, to talk, to dance, to write, and it wasn't a gradual improvement for many of these it was like flipping a switch. One day a person was completely frozen, and the next day they were laughing along with you at a joke.

00:52:57
Speaker 2: It's just that's so, that's so amazing to imagine, because it's so not anything that we normally see in medicine at all.

00:53:06
Speaker 1: No, no, yeah, it's it was, And it must have been so such an emotional experience too, because you had parents who could talk with their children who were now grown up, but the last time that they actually engaged with them was when they were kids decades ago.

00:53:26
Speaker 2: Jesus.

00:53:29
Speaker 1: And it became horrifyingly clear as el dopa started to be administered to these people that many of these people had been aware of their situations and were trapped but unable to say anything and had no control over their body or sometimes their mind for so many years. Usually the one thing that seemed to be spared with all of these patients was their mind, was their ability to think, to wonder, to be the human that they had always been, to be the person that they always had been, and think about their experiences and the whole time they were just watching they just that was their fate, that was their their doom, their fate, their destiny, whatever, was just to watch the world around them pass them by. I can't imagine.

00:54:20
Speaker 2: This is so depressing.

00:54:22
Speaker 1: It is it is. It's such a fascinating story of humanity and living versus surviving versus yeah. Yeah. After being given el dopa, there were such spectacular improvements in the treatment group that all of our sex could not continue to give placebo, and so he started giving el dopa to all patients, and nor could he stop the experiment. At ninety days, when it was clear that this drug was having miraculous effects. This was looking like a before and after story, a new life for people who had so unfairly lost theirs years ago. Unfortunately, for many, the miracle would not last things had started out well enough with these incredible awakenings, but the patients grew sensitive to el dopa and stopped responding, or they begin responding in bizarre and unpredictable ways. He learned that with many of these patients you had to walk a razor's edge with the drug too much and they could be awake for days on end, or suffer an oculogyric crisis lasting for days too little, and they would remain unresponsive. Even though Sacks throughout the treatment control setup of his experiment, which is common when a drug or treatment is shown to be highly effective, he still had to present and compile the data in some way. So he chose to write extended case histories for those who had awakened, a thing which really isn't done that much anymore because numbers and statistics do take precedence and they are really important. I mean, numbers and statistics are essential in order to make decisions, in order to see, okay, what is the overall effect. But there is something really interesting that in his book Awakenings that Sax pointed out is that there is something lost when you reduce people down to numbers and figures, because sometimes humanity or empathy may cloud your judgment and make it more difficult to suss out what is actually going on. But other times it can really help us make that leap to understanding or make those connections, and maybe it can tell us why this person responds to the drug in a different way compared to someone else, and why they might be slower to recover than others. And so these case histories are what make up the majority of the book Awakenings. Eventually he grouped together sixty of these case studies and he published a letter in the Journal of the American Medical Association in which he laid out some of the patterns that had emerged throughout his treatment of these patients. And his letter brought a lot of open, often angry, disagree or opinions. Somehow, many doctors viewed his letter as anti el dopa and urged being quiet so it as not to hamper the wonder drug's growth in other realms of therapeutics.

00:57:12
Speaker 3: That's very interesting, very interesting, And what Sachs has suggested, what he had observed with his study of Mount Carmel post encephaltic patients, was that it's difficult to know the full ramifications of a new drug.

00:57:25
Speaker 1: And thus particularly one that affects your brain, right, and.

00:57:29
Speaker 2: I know so little about the brain still, yeah, yeah, and so.

00:57:34
Speaker 1: Then it's impossible to have control over these drugs and say, well, this dose works and this dose doesn't and so on. It is a trial and error type thing. But it's a risky game to play, particularly when it's being touted as a wonder drug.

00:57:48
Speaker 2: Well, and it's interesting too because these patients are not Parkinson disease patients, right, so it's not shocking that they respond differently. They have you know, similar similar brain area is being affected, but being affected in different ways. So yeah, and.

00:58:05
Speaker 1: The thing is too like what he started to observe though in his patients. This sort of come down from the awakenings started to be observed in patients of different sorts of brain disorders all over. Yes, and so one of the things that came about is that when there already is brain damage, such as in the case of people with POSTS and ccephalitic syndrome or Parkinson's, there is a risk of overstimulation. Oh absolutely, and you just don't you can't control that.

00:58:35
Speaker 2: But a lot of the symptoms that you might think of as Parkinson's actually have to do with the treatment, which is el dopa. Still it's el dopa and another drug, carbon dopa, right, but yeah, and so it is very interesting, like a lot of the things if you think of if you think of Parkinson's and think the big jerky movements, that's actually often from al dopa. It's not from uh huh, it's not from Parkinson's disease itself. So interesting. We'll do a whole episode on Parkinson some day, yeah.

00:59:02
Speaker 1: We really will.

00:59:03
Speaker 2: Yeah.

00:59:05
Speaker 1: And so some of the people that Sex treated did with al dopo were able to find a happy medium where they could initiate movement and respond and begin to take care of themselves a bit, but many others could not tolerate it and return to their pre al dope estate, as you heard in the first hand account. And it's just it's so heartbreaking. Yeah, it to have that taste of like that freedom, that hope that that the world is open to me once again, and then to have it be ripped away. It's really hard to.

00:59:39
Speaker 2: Imagine what a deep philosophical which is worse right to have a little taste of something sweet or never know, never know, never get it again. Yeah, that's too heavy for me.

00:59:52
Speaker 1: We'll come back to that, or tell us how you feel. That's how you feel.

00:59:56
Speaker 2: Actually, I don't want to think about it. Yeah.

01:00:00
Speaker 1: The people with post encephalitis from the early twentieth century epidemic of encephalitis lithargica are all gone now. Several of the patients that Sachs treated at Mount Carmel died as a result of a hospital strike, and the last known survivor of encephalitis lithargica epidemic, named Philip, died in two thousand and two after seventy years in a long term care facility. Wow. Encephalitis, lithargica and post encephalitis serve as a reminder that disease is a deeply personal thing. Yes, we can make these generalizations about the course of a disease and reduce it down to numbers, and those generalizations are necessary to prevent and treat the disease, but it is essential to remember that every person is different and that the response to disease may be different, and it may be informed by their history, or their personality, or their upbringing, their experiences, everything that makes them a unique individual. No matter the language the words that we use to describe illnesses or disorders such as post encephalitis are inadequate. There's no checklist of symptoms, there's no way to describe in medical terms when something feels like it's going wrong. We've come a long way in our understanding of disease, but it's also clear we have a long way to go. So I want to end with one final quote from Oliver Sacks about these awakenings. In the years I have known them, and most of all, in their years on el dopa, those patients have been through a range and depth of experience that is not granted to or desired by the majority of people. Many of them, by superficial criteria, appear now to have come full circle and to be back where they were in their starting position. But this in actuality, is by no means the case. They may still or again be deeply parkinsonian instances, but they are no longer the people they were. They have acquired a depth of fullness, a richness and awareness of themselves and the nature of things, of a sort which is rare and only to be achieved through experience and suffering. I have tried, insofar as it is possible for another person, a physician, to enter into or share their experiences and feelings, and alongside with them to be deepened by these. And if they are no longer the people they were, I am no longer the person I was. We are older and more battered, but calmer and deeper. The flashlike drug awakening of summer nineteen sixty nine came and went, its like was not to be seen again. But something else has followed in the wake of that flash, A slower, deeper, imaginative awakening which has gradually developed and lapped around them in a feeling, a light, a sense a strength which is not pharmacological, chimerical, false, or fantastic. They have, to paraphrase Brown, come to rest once again in the bosom of their causes. Aaron. Yeah, Encephalitis lethargica doesn't start and end with these patients. So what do we think we know about this disease? Could another flu pandemic, for instance, lead to another outbreak of encephalited lethargica? Are there other posts encephalitic patients somewhere out there?

01:03:21
Speaker 2: Great question questions, let's try and answer them after this quick break. The trouble is, I could end this very quickly by telling you the real answer which is we don't know. We don't know what caused encephalitis lethargica outbreak back in the early nineteen hundreds or in the eighteen nineties. We don't know what has caused sporadic cases since then. We don't know what actually causes it, and we have no idea what the relationship is between encephalitis lethargica and post encephalitic parkinsonism. That is entirely unclear.

01:04:30
Speaker 1: But there is a connection.

01:04:31
Speaker 2: There probably is. There probably is. But what's very interesting is that I did find a paper that it wasn't trying to discount. It was a series of two papers. Actually I only read one of them, the second one Full Disclosure here transparency, right, full transparency. It wasn't trying to discount that either of these two things are real. They are real things that really happened. These are real diseases that people suffered from. But it seems like a lot of cases of post encephalite parkinsonism that had been diagnosed were diagnosed maybe without a really good connection to a previous case of encephalitis lethargica. So if you look back at a lot of the evidence, there actually wasn't always a case of encephalitis lethargica that the patient could even remember, or that had ever been documented. There maybe wasn't an infection before that either. So it's very messy the whole connection between it. It doesn't mean that these things aren't real, of course, it just means we don't really understand how they might be related or what that relationship might look like.

01:05:42
Speaker 1: There's definitely a correlation, but it might not be a causative link exactly. And so that's something where I remember, for instance, in all of our Sacks awakenings, he had seen influenza in the case histories of all of these people that he had treated, But that was the only thing I think that he mentioned there being a link.

01:05:58
Speaker 2: Right, Yeah, exactly a lot of cases, In a lot of cases there would maybe be influenza, but it might be a very long time ago, or sometimes you'd have cases of encephalitis lethargica that had been diagnosed and then very shortly thereafter post encephalitic parkinsonism, or in some cases it would be years later, which like that's pretty bizarre, right, right, how can you say? So? Yeah, it doesn't mean that there's not a connection necessarily. It just means that we don't understand what that might look like or or what is causing it.

01:06:29
Speaker 1: It's worth exploring, but it's not by any means definitive.

01:06:33
Speaker 2: Exactly, definitely not. Nothing about this episode is definitive, except it's definitively horrible. But this exists. Yeah, But let's talk about what we think about encephalitis lethargica today, and I'll focus mostly on encephalitis lethargica because there's quite frankly more information on that than there is post encephaltic parkinsonism. Interesting, okay, at least what I was maybe because I was googling encephalitis lethargica.

01:07:00
Speaker 1: And so just to just to reiterate, cephalitis lethargica is that acute stage right following whatever follow infection, but it is, it's a cute, whereas post incephaltic parkinsonism is a chronic.

01:07:18
Speaker 2: Yes exactly, okay, right, And it's that rigidity that all of our sachs awakenings, that's pep right, okay, and quite possibly connected to in cephalites lethargica. We just don't know how. Yeah, Okay, So what's causing in cephalites lethargica or does it even exist today? It does, but we've never seen an epidemic like we've seen like we had seen in the nineteen early nineteen hundreds. So since the nineteen forties there have only been I saw something that said eighty case reports. But this is that accounts for at least over two hundred cases okay since the nineteen forties.

01:07:58
Speaker 1: Since the nineteen Yeah, whereas between nineteen more sixteen and nineteen twenty five there's like.

01:08:06
Speaker 2: Five million worldwide. Yeah, so it that right, there is bizarre as heck, right that we've seen a handful of cases in decades since then. Okay, so what could be causing it? There's three main thoughts as to what might actually cause encephalitis lethargica. One is very easily ruled out, or was very easily ruled out, and that was the idea that it was toxins or some kind of environmental association. This one pretty much hasn't been explored since it was an original idea back in the nineteen eighteen era because of how widespread that outbreak was. It didn't seem to make sense that you could have a worldwide epidemic of an environmental related something or other. Right, Okay, so it's not that so that leaves two possibilities, One that it's an infectious disease like a virus or a bacteria, or two that it's an autoimmune disease of some kind in epidemic form, in epidemic form. So let's examine the evidence for those so. Originally influenza that was the most kind of obvious connection because we had seen a connection with previous influenza epidemics and this epidemic of encephalitis lethargica, pandemics, pandemics. This has been looked at quite a lot, and there does seem to still be a few people out there who really want to believe that it is influenza.

01:09:47
Speaker 1: Like the influenza virus itself.

01:09:49
Speaker 2: The influenza virus itself. Yes, yeah, there's people that are saying it's a slightly different strain. The thing is, they have gone back to look at the brain of people who died of encephalitis lethargica. They haven't found any evidence of influenza infection, no evidence of influenza RNA in these people's brains. And the thing about influenza is that it's not really a virus that tends to enter your brain. It doesn't replicate in your neurons, and so it doesn't really make sense for it to be something that's caused by influenza. I did find one paper where someone was saying, it's a slightly different strain that can enter, but it was just one dude.

01:10:33
Speaker 1: Who was but it was a slightly different strain from was it the H one N one that was the pandemic strain?

01:10:40
Speaker 2: It was circulating at the same time, So it was a slightly different strain that was circulating at the same time as the nineteen eighteen pandemic.

01:10:47
Speaker 1: Okay, yeah, interesting, but you didn't buy the paper.

01:10:50
Speaker 2: It wasn't and it was the only one like it.

01:10:54
Speaker 1: Right, which, as we learned at the amazing Amplify the Signal Yes workshop, you need to have replicated studies.

01:11:02
Speaker 2: Yes, definitely, Well we know that from life as well. And the other thing is that we have seen a lot of outbreaks of influenza since then, and we have never seen any outbreaks of encephalitis lethargica. And even when there was the outbreak of encephalitis lethargica, it didn't necessarily match temporally with the outbreak of influenza, right.

01:11:23
Speaker 1: It either preceded it or it lasted longer than exactly.

01:11:28
Speaker 2: Do you want to have a gup.

01:11:30
Speaker 1: But we didn't have antibiotics for secondary infections following influenza.

01:11:34
Speaker 2: Right, yes, so yeah, it could theoretically be possible that if influenza leaves you susceptible to a secondary bacterial infection, that this could be a bacterial invasion that's causing this specific type of encephalitis. We haven't found a specific bacteria that would indicate that has caused this type of disease so far. Okay, now there's another viruses that are interestingly possible. This is very recent compared to nineteen eighteen.

01:12:09
Speaker 1: How recent the.

01:12:11
Speaker 2: Twenty twelve, I think is when this paper came out. So there was a group who looked at brain tissue from patients from the nineteen eighteen epidemic and they found evidence of viral inclusions, small viral inclusions that were suggestive of enteroviruses. So enteroviruses are a group of viruses that include poliovirus and cocksacki virus, both of which do replicate in nervous tissue and do cause things like encephalitis and meningitis and nervous issues. So this paper suggested that they found evidence for enterovirus infection in the brains of these patients. The problem is that these tissues are very old and degraded. There hasn't been a lot done since then to try and sort of bolster this, but it is still it's a theory that is possible. It's out there that maybe it wasn't an influenza virus. Maybe it was an enterovirus of some kind that caused this outbreak and that can still cause cases today. So I don't know. I would assume that that group is still working on it, but I don't know how many other groups are looking into it to try and figure out is it an enterovirus of some kind?

01:13:29
Speaker 1: I mean, I would imagine there's not a whole lot of research funding for medical mysteries that are no longer super relevant or appear not to be super relevant.

01:13:38
Speaker 2: The NIH page four encephalitis lethargica is embarrassingly sparse, like this is a thing that exists, period, that's it. There's no I mean, yeah, okay, so it's still possible that it's viral, even if it's not from influenza directly. But there's a third possibility, and that is that it's odd immune, and this is a very interesting one to me. I think it's super interesting. A paper came out in two thousand and four that suggested and they did a lot of different work on modern cases. So this was not looking at cases of epidemic encephalitis from the nineteen hundreds. This is from modern cases twenty children, mostly children, actually there was a few adults, and they suggested, based on their study that this was caused by antibodies post infection with a Streptococcus bacteria a group a.

01:14:41
Speaker 1: Strep Okay, so autoimmune induced by this exactly.

01:14:45
Speaker 2: So it's not the bacteria itself, is what they were suggesting, but what happens, and this does happen with strep infections in general. So if you've ever heard of rheumatic fever or rheumatic heart disease, that is something that happened after you get infected with strap pyogenies, which causes strep throat, and then your body makes antibodies against that bacteria that happen to cross react with stuff on the surface of your own cells. They look similar enough. The proteins on the surface of that bacteria look similar enough to some proteins in your body that your antibodies that you make start to attack your own self, and so that's why it's called an autoimmune disease. So it was suggested because they found in some of these patients, about sixty five percent of these patients, they found elevated tighters, which means really high numbers of antibodies against what's called anti strepto licein O, which is a surface marker of streptocaucus.

01:15:53
Speaker 1: So basically saying you've had STRAP.

01:15:56
Speaker 2: You've had STRAP, right, and your tighters are higher than they should essentially.

01:16:01
Speaker 1: Huh uh what should be eh.

01:16:07
Speaker 2: It would indicate a recent infection, but they're higher than they are in most of the rest of the population, even if those people had been infected. So it's like extra extra, like it's like you just made a crap ton of antibodies essentially.

01:16:22
Speaker 1: So it's not just showing that you've had a recent infection, it's showing that it's.

01:16:27
Speaker 2: In these patients they found an elevated number. So they measured it against other patients who had had recent STREP infections, and in sixty five percent of people that they had diagnosed with encephalitis lethargica, they found a higher amount of antibodies against this protein. Does that make sense? It's a little bit wishy washy, and it is a little wishy washy.

01:16:49
Speaker 1: What's our sample size if you have?

01:16:51
Speaker 2: If you have, it's sixty five percent of twenty. Okay, Well come on, okay, okay, So that was their suggestion.

01:17:00
Speaker 1: And I know that it's hard to come across and sevilize lethargical patients, but that's.

01:17:04
Speaker 2: A six twenty.

01:17:05
Speaker 1: Is there a fact size?

01:17:06
Speaker 2: Okay? So prevalue they didn't have any in this Oh yikes, Actually they might have, so don't quote me on them.

01:17:14
Speaker 1: Okay.

01:17:15
Speaker 2: They also tried to find some other they found other evidence of inflammation. They did a lot in this paper to try and suggest that this was some type of autoimmune thing. A few years later, they kind of backed off.

01:17:29
Speaker 1: Of that, okay, because the thing is they.

01:17:33
Speaker 2: They didn't find this elevated tiders of this specific antibody in all of their patients. They found it in a subset of patients.

01:17:43
Speaker 1: Were these patients from the same long term care facility?

01:17:48
Speaker 2: These are not in a long term care facility. This is an acute infection. Oh oh okay, yeah, so this is encephalitis lethargica okay.

01:17:54
Speaker 1: I thought maybe they had all been infected by something at the first time in the first study, and I was like, would have been okay.

01:18:02
Speaker 2: But so the most recent I think that the idea that it's that it's a strep infection autoimmune has pretty much been pushed to the side. That's no longer something that is really there's not strong support for it.

01:18:17
Speaker 1: Essentially cool.

01:18:19
Speaker 2: There is another autoimmune potential that you can find more studies about now, and that is there's a type of encephalitis that's called nm DA r encephalitis.

01:18:32
Speaker 1: What does that stand for.

01:18:33
Speaker 2: It stands for n methyl d aspartaate receptor.

01:18:38
Speaker 1: I regret that I asked.

01:18:40
Speaker 2: So NMDA is a neurotransmitter right that your brain makes. It's an excitatory neurotransmitter, so when it is released, it increases neuron activity. Essentially okay. But a number of drugs that treat disorders like Parkinson's all time and Huntington's are actually anti NMDA receptors. So this is very interesting because this receptor, this neurotransmitter is very intricately involved in a lot of neurodegenerative brain diseases. So there is a type of encephalitis that has been found recently where people have antibodies against the NMDA receptor, so they are they're making antibodies that are targeting this specific receptor. Most of those cases there is a tumor somewhere else, so it's probably this tumor that's making these antibodies. But they've also found in patients diagnosed with encephalitis lethargica, which I put in air quotes here, they have also found anti NMDA receptor antibodies. So is it this antibody maybe that's causing these symptoms that we associate with encephalitis lethargica. Hmm, what we don't know because again it's not in all the patients. Basically, basically the answer to all of this at the end is we do not know. We do not know what causes this. And the other problem is that we don't even have a good definition anymore for what encephalitis lethargica is. So we have those three acute phases or those three acute syndromes that were described in the early nineteen hundreds, but since then, in nineteen eighty seven, two people came up with some new criteria for diagnosing encephalitis lethargica. Again, I put that in air quotes because at this point it's like, what is even the definition of this disease. They included new symptoms, including oculogyric crises, which you mentioned before is often associated with post encephalitic parkinsonism. And this is specifically I kind of getting stuck in one position for a really long time. That wasn't necessarily part of the original description of encephalitis lethargica, okay, but this was included in the eighties as this is how we should decide if we're calling a case encephalitis lethargica. Also, things like obsessive compulsive behavior were added that didn't used to be part of it, and so and some of these things were more associated with post encephaltic parkinsonism and now are being grouped in as part of encephalitis lethargica. So it makes the distinction between these two syndromes that are maybe related, but it makes their distinctions very blurry, and it makes it difficult to even diagnose somebody with encephalitis lethargica.

01:21:47
Speaker 1: Because just a subset of those with encephalitis lethargica will go on to develop post encephalitic parkinsonism exactly, And so what do we have any demographics for those who have developed either of those things?

01:22:02
Speaker 2: No, especially because there's been so few cases since then. And what's very interesting is that a lot of the case reports that you find today are in children. And while children could be affected and were affected, in the early nineteen hundreds, it was mostly adults. And so it's very weird that now most of the cases we tend to see are in children. Oh gosh, erin what is happening? So someone in twenty eleven proposed new criteria to diagnose encephalitis lethargica, and their criteria say, you have to have number one some kind of prodromal signs influenza like is what they said, influenza like prodromal signs, So that would mean fever, body aches, malaise, things like that. Two and this one seems to me to be very important. Hypersomnolence so you're very sleepy. Three wake ability so you can wake that person up very easily, okay, or ophthalmoplesia so that means problems with your eyes okay. And five psychiatric changes, which is very general, right right, that could be And then they also said that maybe finding later that this person developed PEP could be considered to be a criterion to fit into encephalitoesotharchica as well.

01:23:22
Speaker 1: Okay, so like a retrospective diagoms a little circular.

01:23:25
Speaker 2: Okay, Yeah, if you use those criteria, then out of those two hundred cases that we've seen since nineteen forty, only about fourteen actually fit.

01:23:36
Speaker 1: What happened in the early nineteen hundreds, erin.

01:23:41
Speaker 2: What happened in the early nineteen hundreds, erin what happened? We don't know, that's the answer. We don't know, will we ever know?

01:23:52
Speaker 1: Will we see it again?

01:23:53
Speaker 2: Will we see it again? That's a very good question. We don't know.

01:24:00
Speaker 1: We could though in theory, I suppose, I suppose, I mean, what on earth?

01:24:08
Speaker 2: It's very very very interesting though.

01:24:11
Speaker 1: I mean it's interesting because this episode we're both walking away with a lot more knowledge. But also I feel very unsatisfied.

01:24:19
Speaker 2: I feel very sorry. Guys, were you hoping for a satisfying ending. We're not going to have one for you. No, really, truly, there is no good answer to this well.

01:24:30
Speaker 1: And the thing is too, is that it has been so forgotten, and if it were not for the works of particularly Oliver Sacks and then also Molly Caldwell Crosby. This would have been forgotten andsoletely. How many other epidemics have there been where people just didn't write about them or they didn't notice them.

01:24:50
Speaker 2: We know of some right, people have asked us to do.

01:24:52
Speaker 1: Some of the other ones, the dancing dancing for yeah.

01:24:56
Speaker 2: So we'll have more of these medical mysteries to go on in the future, which is exciting but also very unsatisfying.

01:25:05
Speaker 1: I know, don't hate the messenger, but.

01:25:15
Speaker 2: It's very I mean, it's it's very fascinating to think about and that and the I it does seem that we've learned a lot about the brain in general from looking at these you know, looking at these cases and thinking about these cases, what kinds of things could cause these types of symptoms, and the similarities between this and between Parkinson's.

01:25:35
Speaker 1: And it's well on the whole the mind and the brain.

01:25:37
Speaker 2: Right.

01:25:39
Speaker 1: I love this. I love this.

01:25:42
Speaker 2: I have fun.

01:25:43
Speaker 1: I had a great time. Also, it's so nice to be in the same place. I know, I'm miss I have to go catch my flight in a few hours.

01:25:50
Speaker 2: A bummer. We hope that you guys enjoyed this. Let us know. If you hated it, let us know, because then we'll like not do medical mysteries again. But hopefully you loved it.

01:26:00
Speaker 1: Yeah, I don't know, Okay, sources, sources, Let me guess.

01:26:04
Speaker 2: You read Awakenings by Oliver Sacks, Oh my god, how did you guess? And was it Asleep by Molly Caldwell Crosby.

01:26:15
Speaker 1: And then you read No, I can't predict this.

01:26:17
Speaker 2: I read a bunch of papers, all of which will be cited on our website this podcast will kill you dot com under the episode's tab.

01:26:27
Speaker 1: And we I want to shout out the movie Awakenings. Oh for sure, go go watch it. It's emotional. It does simplify the story a whole lot.

01:26:37
Speaker 2: Should we watch it before you leave? Oh my god, we should.

01:26:40
Speaker 1: Good, Yeah, so it is. It's a it's really wonderful. And all of our Sacks, upon watching Robert de Niro's performance as Leonard, who was a posting sephalletic patient, said he was amazed at his performance and how much he incorporated the movements and the in all these different aspects of posting cephletic parkinsonism. All right, yeah, with that, With that, thank you so much to everyone who listens.

01:27:08
Speaker 2: We love it, We love you. This is so much fun. We love making the podcast. Thank you to blood Mobile for the music in this episode and all of our episodes.

01:27:19
Speaker 1: And until next time, wash your hands, you filthy animals.

01:27:29
Speaker 2: A