History of Movement Disorders: The story of MPTP and parkinsonism

Prof. William Langston: Well,

It's going to be challenging in a short period of time. It is a true medical detective story.

It's a lot of [00:01:00] fun to read. If you ever wanna read my book, The Case of the Frozen Addicts, but it started with a clinical observation and I like to point out that. Even to this day clinical observations are huge in medical discovery. Never assume that when you see an unusual case that you are not seeing something new.

Follow it through and be curious. In this case, it was a patient who entered Valley Medical Center where I was attending. And there was an argument between the psychiatrist staff and the neurology staff. The neurology staff thought this particular patient was catatonic schizophrenic. The psychiatrist thought he was neurologic, and I got called down to mediate.

It took me about 30 seconds to figure it out on this catatonic schizophrenic quote, had cogwheel rigidity, a classic sign of Parkinson's, and [00:02:00] I'd examined catatonic before you feel an active resistance to them. Not this this cogwheel. So immediately we knew this amazing case was neurologic.

Then the hard part started. Why? Come over a couple of days time it was a bsolutely indistinguishable from typical PD. How this patient was only 43, and as I said, it come on over days. So we found out he had a girlfriend and later it turned out she had the same thing. We thought maybe carbon monoxide in the house, that kind of thing.

That turned out not to be case. And then we found some cases in Santa Cruz, that's a place about 30 miles from us who also had it. The only common link was they were all heroin abusers. So then our chase started in that direction. We went out with police raids, we got different samples trying to analyze this thing.

And it [00:03:00] was quite a harrowing story actually. The break in the case came when we learned of a case at NIH where a young man had been making his own synthetic heroin, and the investigators at NIH had tried to figure the case out. They had samples, they'd done analysis, but they never figured out the answer.

And a crime tech lab technician put me onto this paper, but it was about 15 years old, so I called that lab. This is after a lot of work. I called that lab and said, we had the atomic number from study, but we didn't know the context. But I said, you have several metabolites here.

You have the original compound, did any of them cause this? And they said, no. Everything we tried failed. That's why we gave up. They never figured it out. And using the atomic number, I said this compound on the far right metabolite, which is now called MPTP, [00:04:00] has the exact atomic weight of what we're looking at.

And he said, it's bingo, I've got it. He said, that's the only one we didn't try. Oh my God. We, solved the mystery, funny too, they were very misled because of these other were narcotics. And when you give a rat a narcotic, like heroin, they freeze up and become a catatonic.

So it looked just like what they saw on the patients and they kept chasing it. Turns out it's well known. If you give an opiate to a rat, it develops what's teasingly called ratatonia. That totally misled them. So we rest factored another analysis, and we had it. We finally had what it was and that changed history.

It lived to the first true model of Parkinson's. We didn't, I was always thought we don't have a good model of Parkinson's. In fact, it's a very simple compound, similar to Paraquat in the environment. It could have been an environmental [00:05:00] toxin and it was a a magnificent tool to study nigral cell degeneration.

This compound goes right in blood through the blood barrier, right to the nigra and knocks it out. Amazing compound. It's been used for all types of studies of all aspects of PD. It all started with that one patient who either was gonna have a catatonic schizophrenia. 

Prof. Tiago Outeiro: Yeah, that's really amazing and unbelievable.

So just out of curiosity, were those people that were affected, were they using together or was this just a coincidence as well? 

Prof. William Langston: They were not using together the way we really found a key in the story was. I had a fellow who lived in Santa Cruz. We had two cases. We thought maybe it's just in the environment, I mean in the home, something in the home, because they lived together.

He was having dinner with a neurologist from Watsonville that's further [00:06:00] south. This neurologist totally unattached to any of this said, in these two weird cases, they're two brothers and they just froze up like a pillar of salt. And my fellow who knew our cases said, oh my God, it sounds the same.

We got down there, examined him. It was the only connection was heroin abuse if they had all been together. We would've still been searching for something in the environment, as I said, like carbon monoxide or something like that, or eating something. But the fact those cases were totally unassociated, we had that common link.

And so we had that was one step in this investigation. 

Prof. Tiago Outeiro: Yeah, and like you said, so MPTP causes Parkinsonism, which manifests with similar symptoms to Parkinson's, but it's not of course Parkinson's disease. So this is an important concept to leave here.

'Because people sometimes think that when they use MPTP in mice or in the lab they are [00:07:00] modeling Parkinson's. They are modeling Parkinsonism. So I think this is an important concept. And out of curiosity, did those patients respond to Levodopa and to other typical PD therapies or are there differences?

Did you see any differences at that level as well? 

Prof. William Langston: That's a great question. We had some debate over that. It clinically it looked identical to Parkinson's. The patients were severely disabled, even had trouble eating, and actually, I'm not sure they would survive very long.

So based on that, it looked like Parkinson's patients needed it. We gave 'em levodopa. Three hours later, they were up walking around and normal. I don't know if you've ever seen the movie Awakenings, but I think um, he was the actor that played the patient. They showed it that they gave him levodopa in the Awakenings.

He'd been in like [00:08:00] catatonic basically for 30 years and when they came back, the bed was empty and he was out walking around and the movie critic said, oh, that's ridiculous. That's just Hollywood. Nope, absolutely. 

Prof. Tiago Outeiro: That was reality. Yeah, 

Prof. William Langston: It worked. It worked. 

Prof. Tiago Outeiro: And this Parkinsonian state, so it responded to levodopa, but did it improve with time or did it stay, was it a permanent damage that the patients had?

Prof. William Langston: That's a really good question. They had a lot of side effects, including hallucinations and. Not all of them. And I really wanted a brain that's been getting a lot of major league drugs just like Parkinson's Levodopa can induce hallucinations. And they were young and several of them developed very severe dyskinesia.

And that's, in my opinion, typical young. They get it much quicker [00:09:00] earlier. One, one patient got dyskinesia within three weeks which you don't usually think of with typical PD. Actually that was depicted in the Awakenings too. So there are lots of complications. And the last thing is, I have to tell this tongue in cheek.

The goal in medicine is usually to get a person back where they can resume their normal life. That first patient was a drug dealer and junkie, and we actually returned him to that selling drugs. Yeah. I don't think he used him again. And boy, he got in all kinds of trouble. And I think at one point some gang picked him out, so he was back to his normal life.

But that wasn't necessarily a good thing. Others lived longer, but again, had problems with side effects, not using their drugs correctly, et cetera. One patient was in a New England Journal, [00:10:00] sent one patient to Sweden for a embryonic cell transplant. That did help her a while, but eventually it didn't.

She wound up terribly disabled and eventually died years later. It's really, I'm writing this up right now. On the other hand, one patient who we had to get him outta jail had two state troopers in his hospital room with him. We did deep brain stimulation. He did great. He just died of liver cancer about six months ago.

So it's a single nigral lesion and that's what DBS does. Yeah. And it's a real interesting comparison between cell transplantation, which they're trying again right now. We've tried 30 years ago and failed and DBS, it's a one in one, but one failed. That didn't work. And the DBS and the other, had DBS pretty much he had assisted living, but he lived a pretty good life.

[00:11:00] So I think it's a very interesting comparison. We're gonna write the two cases up. 

Prof. Tiago Outeiro: Absolutely. And did any of those people come to autopsy and do you know if their brains showed Lewy body pathology? 

Prof. William Langston: That is the million dollar question, and the answer is no. 

Prof. Tiago Outeiro: So no pathology. 

Prof. William Langston: No pathology. In monkeys, we saw something that looked a little like Lewy bodies, and we saw it in the para amygdala n ucleus and turns out very often you'll see concurrent Alzheimer's and Parkinson's. And in those cases lots of Lewy bodies in that area. But we were never able to convincingly prove we had Lewy bodies. I think the we had a few cases where it was close but never could, it's it's more like parkin , PARK2 which is pretty much in some, most cases, just the nigral.

Prof. Tiago Outeiro: Yeah. [00:12:00] So it's suggests that maybe when it's such an aggressive damage maybe there's not enough time to form the mature Lewy bodies that would normally take decades to, to form. 

Prof. William Langston: Yeah. Except for the one who had DBS lived long enough. That's a very good point. Unfortunately he died.

I was out of town and we were not able to get the brain, but that would've been an incredible case to examine. 

Prof. Tiago Outeiro: Wow. So this is very interesting. I think of course people have to go and read your book to, to understand all the little details that I'm sure would make it even more interesting.

In the interest of time for our listeners. Are there any other. Interesting facts anecdote that you could share related to this historical finding. 

Prof. William Langston: There are just so many. I guess here's an anecdote. One of our patients had severe tremor and went to a major university hospital, [00:13:00] and they filmed him as a case of phenol toxicity. A bad tremor , and I actually got the video. It was in the teaching library. They said this is a case of phenol toxicity.

You can see it causes full blown Parkinson's, severe tremor as a teaching case. The only problem was he'd never been exposed to phenol. Minor glitch. And I guess there's this tendency this day, you think everything that's ever out there has been seen. So we always wanna ratcheted into the wrong size hole in this case.

New phenocising toxicity, not unlikely. He might've gotten it and they pushed it in. And that, that was before any of my cases. And he got discharged. Yeah. And it in the teaching library to this day. 

Prof. Tiago Outeiro: Yeah. Very 

Prof. William Langston: Interesting. I think there's a lot of lessons at that level to be learned. 

Prof. Tiago Outeiro: Yeah. Bill, [00:14:00] thank you so much.

It has been very nice listening to this brief and short version of the full story. But I hope this is enough to entice our listeners to go and read your book about the this finding. So thank you so much for participating in the podcast. 

Prof. William Langston: My pleasure.

Prof. Tiago Outeiro: So we've interviewed Professor William Langston on the historical discovery of MPTP as a toxin causing Parkinsonism back in the early eighties. We thank you all for listening, and I invite you to join us in our upcoming podcasts. [00:15:00]