Ep 155 Stiff Person Syndrome: A rare disease in the spotlight

Episode Transcript
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Speaker 1 (00:01):
Hi.

Speaker 2 (00:01):
My name is Alison Lafferty. I'm currently in Nevada and
I suffer from stiff person syndrome. So I was diagnosed
in November eighteenth, twenty twenty one, after almost two years
of searching for a diagnosis. I started out going the
orthopedic route because my symptoms were tightness in my back,

(00:26):
spinal type pain, heaviness in my trunk area, and pain
that went down my legs when I would walk. I
went to the orthopedist and they ran every test under
the sun that they could do, X rays, mricts, and
from their standpoint, I was completely healthy. And I remember

(00:47):
walking out of every single appointment tears streaming down my
face because I knew something was wrong, but I was
being told that I was fine. And a lot of
people will be like, oh, I know, I've been gasolet
like that before, and I will have to say they
were great. They were wonderful. I never felt like they
were telling me I was crazy. They were being honest

(01:10):
and that from an orthopedic standpoint, I was fine. Orthopedics said,
we don't know what else to do. We're going to
refer you to neurology. I was lucky enough to get
a doctor who was European. Why I say that is
because in Europe, stiff person syndrome is studied a little

(01:30):
bit more in medical school than it is here. He said,
you're presenting with some signs of something called stiff person syndrome.
I doubt you have it. It's so rare, but I
want to test you for it. And so I'm going
to run a GAD sixty five test, and I'll always
remember October thirty first, twenty twenty one. I got the

(01:52):
test results back, and the GAD sixty five counting limit
has a cut off at twenty five thousand, was twenty
five thousand. I initially thought this is just my diabetes.
Because GAD sixty five can also test for diabetes. I
called the office, said, hey, do you think I can
get in a little earlier to discuss these results. You

(02:15):
know they've both got red flags next to them. You
know what's going on. She calls me back and says,
your test results are fine. You're totally fine. We'll see
you in two weeks for your EMG because we had
already set that up. I walk in and the doctor goes,
I'm so sorry, and I looked at him and I
was like, what are you talking about, Like, literally, why
are you looking at me with the saddest eyes? He goes,

(02:39):
the nurse didn't tell you like you have stiff persons.
And I remember we had to reschedule the EMG because
I was just racked with sobs and for that you
have to stay pretty still. So first thing I do
at twenty three years old is call my mom and
I go, hey, do you remember that test that We
were like, there's no way I have this. I have it,

(03:02):
and I just remember my mom was silent and she
was like, I'm going to go get your dad. My
dad came on the phone and I remember just crying
like the convert. There were no words, it was just crying,
and I hung up. I went home. My husband worked
on the range, and for people who are not familiar
with the military, this meant like there was no way

(03:22):
I could text or call him. But I waited until
he got home, and I remember I was just like red,
blotchy eyes and I told him and he was like WHOA.
I thought, like the nurse said, you didn't have it.
About a month later, they sent me to MUSC the
Medical University of South Carolina, where I was hospitalized for

(03:43):
a week to try IVIG.

Speaker 3 (03:47):
It worked.

Speaker 2 (03:48):
It is very similar in its side effects to chemo
and radiation. You feel sick, you feel nauseous. The only
difference is there's really no like physical changes.

Speaker 3 (04:00):
I was there for about a week.

Speaker 2 (04:02):
Then I went out patient and they said, well, we
need to make sure that there's nothing in your brain
at all before we continue IVIG. So I had an
angiovinogram where they stick a little too through your thigh
and go all the way up to your brain, and
to this date, it was the most painful experience of
my life. And then after that I went on to

(04:23):
home infusions and I was on home infusions until November
when I found out I was pregnant, and that was
not planned, but pregnancy relieved a lot of the symptoms.
Had my daughter in July of twenty three and was
essentially symptom free for about six more months after that,

(04:44):
before all the symptoms came barreling back. The thing that
I really want to touch upon is the symptoms that
led me to the orthopedic and later the neurologist. In
ju Lie of twenty twenty one, I was in Charleston,

(05:05):
South Carolina, and I had walked half a block, maybe
not even a full block, and my full body went stiff.
My husband ran to go get the car and he
literally had to like bend my knees for me to
get me in the car and like relax because I
couldn't move, and we weren't sure if he did that,

(05:27):
if he would end up like snapping my knee. Trunk pain,
leg pain. It eventually radiated up my back, down my arms,
into my hands, And the best way I can describe
it is it feels like you have weights on your
hands and feet at all time, like you're just carrying
them around. When I have to use pencils or cook

(05:49):
or use anything that uses fine motor skills, my hands
like balloon they swell and like sometimes they'll like kind
of sit in that like claw position, and you could
try your hardest to get them to come out of it,
but you just got to let it happen. Charlie Horses
multiplied by ten is how I would explain the spasms

(06:12):
that a lot of us in the stiff person's community have.
I get them, particularly in my legs and my feet.
All that is to say that I am on the
very low end of the spectrum in terms of severity.
And I feel like that really says something, because any
healthy person or someone who doesn't know a stiff person,

(06:32):
even people with other chronic illnesses who don't know what
stiff person's is, will hear this and go, that's the
low end of the spectrum, Like I can't imagine the
high end of the spectrum. Some doctors will label it terminal,
but most terminal diseases, they'll give you a oh, you
have six months to live, Oh the average time is

(06:53):
so and so. With this, there is none of that.
It's just don't know when it's going to get you,
but you know it's probably going to get you. Right now.
I'm still on ivig. I'm very lucky I haven't had
to move to retuximab, which is a type of chemo drug,
or plasmapheresis, which is a type of very similar to dialysis.

(07:18):
But at some point, I do know ivig will stop working.
My oral medications will stop working. Unless a cure or
an actual treatment for this is found, everything will stop
working at some point, and I will continue to progress.
I was told from the get go expect at some
point to be fully in a wheelchair. I expect to

(07:40):
use a showerchair, expect to you know, need an at
home nurse. And there are people right now living with
this disease that have those things, that are living with
those things. And so that's my story. It is not
the story of stiff person syndrome. It is a spectrum disease.
It is different for every single person who gets diagnosed.

(08:03):
Everybody who is in the community believes that it is
very very much underdiagnosed, and so that's the goal of
this is to get advocacy out there. I think it's
imperative that people do their research. They check out the
National Organization for Rare Diseases to not only learn about

(08:23):
stiff Persons, but other rare diseases that deserve the recognition
and scientific backing that more common, more popular diseases have.
So yeah, that's my story.

Speaker 3 (09:25):
Allison.

Speaker 4 (09:26):
Thank you so much for sharing that story with us.
We appreciate it and for reaching out to us in
the first place, Like we just yeah, thank you.

Speaker 1 (09:35):
Yeah, thank you. It was it was so amazing to
get to have the conversation that we had with you,
and we really really appreciate you sharing your story with
us and with all of our listeners. So thank you
for taking the time.

Speaker 3 (09:46):
Yes, Hi, I'm erin Welsh.

Speaker 1 (09:49):
And I'm erin Alman.

Speaker 3 (09:50):
Updike and this is this podcast will Kill You.

Speaker 1 (09:53):
And today we're talking about stiff person syndrome.

Speaker 4 (09:57):
Which you may have heard more recently because of the
Selene Dion documentary that came out a few months ago.
I am Celine Dion. I am not Seline Dion. That
is the name of the documentary. The documentary and we've
also gotten some requests from listeners to cover this.

Speaker 1 (10:16):
Yeah, I think one of the things so stiff person
syndrome is an incredibly rare disorder. And we've covered some
rare disorders that are like categorized as rare disorders on
the National Organization for Rare Disorders, which we'll talk more
about later on this podcast before. But the thing about
a lot of rare disorders is that no one has

(10:38):
heard of them because they are so rare. And that
is very true, or was very true for stiff person syndrome.
I am a physician in medicine and I had not
heard of stiff person syndrome until I think it was
twenty twenty two or early twenty twenty three when Celine
Dion came out and said that she had been diagnosed
with stiff person syndrome, and I, you know, like most

(10:59):
of us started googling it to try and figure out
what it was. And so I think that one of
the things that we are looking forward to you in
this episode is kind of diving into that idea of
like what does it mean to have a rare disorder
and specifically stiff person syndrome, and what a little bit
more details about what is this syndrome, how does it work,

(11:22):
what kind of symptoms does it cause? And as much
as we can about this truly horrific disease.

Speaker 4 (11:28):
Yeah, yeah, and yeah, I think that this has given
us an opportunity to kind of like take a bigger
picture at rare disorders, which are incredibly varied in and
among themselves, Like you know, there are It's not like
all rare disorders are the same thing, but there are
certain experiences that are common among rare disorders, and I
think that's been a given us the sort of opportunity

(11:51):
to explore that.

Speaker 1 (11:53):
Yeah, yeah, before before we get into that all of
those things, it's quarantine.

Speaker 3 (12:00):
It sure is. What are we drinking this week erin
we are drinking a stiff drink.

Speaker 1 (12:06):
We sure are, we should drink nothing else.

Speaker 4 (12:08):
Yeah, and it basically is a paper plane which if
you don't know what that is, because I had heard
of it but had to google it it was. It
is basically contains bourbon, Amorrow and apparel, so it's like
you know, spirit spirit heavy spirit only cocktail.

Speaker 3 (12:30):
And we'll post the.

Speaker 1 (12:30):
Full recipe for that quarantini as well as the non
alcoholic plussy werita. Better bet we could do it on
our website, This podcast Wouldkill You dot Com and all
of our social media channels.

Speaker 4 (12:40):
On our website, you can find all sorts of things,
from transcripts to links to Patreon, links to merch We've
got some great merch coming up, links to bookshop dot org,
affiliate account, goodreads lists, links to music by Bloodmobile you know,
and about us page, a contact us form if you're
interested in having us give a talk or workshop, hit

(13:04):
us reach out to us, hit us up, and there's
also a submit your first hand account form.

Speaker 3 (13:09):
There's a lot of things that you can so many
things so you can seek out and find on our website.

Speaker 1 (13:15):
This podcast will Kill You dot Com Check it out.

Speaker 3 (13:17):
Check it out. Also double check while.

Speaker 1 (13:20):
You're I don't know on your internet service provider that
you are subscribed to your podcast catcher app, whichever one
that you like to use, and if you haven't, take
a minute to smash that subscribe button and maybe even
give us a rating or a review, because it really
helps us out. So thank you so much for doing that.

Speaker 3 (13:39):
It does. I can't believe you said smash that subscribe button.

Speaker 1 (13:42):
Isn't that what they say on YouTube?

Speaker 3 (13:44):
I think it is.

Speaker 1 (13:45):
I just can't watch us like these really ridiculous YouTube
and they're always like subscribe and I'm like, you watch this, but.

Speaker 3 (13:55):
Oh, that's amazing.

Speaker 4 (13:56):
I don't think there's any other business. So let's take
a break and then get started.

Speaker 1 (14:14):
As an incredibly rare disease, unsurprisingly, we do not fully
understand the biology of stiff person syndrome. But I'm going
to tell you everything that I learned in all of
the papers that I read, and what it seems like
we know in medicine thus far. Based on what we
know about stiff person syndrome, it's a very likely that

(14:36):
this is an autoimmune disorder, meaning that it's something where
your body is making antibodies that attack your own cells.
And we've covered quite a few autoimmune disorders on this
podcast before, We've covered lupus and MS Celiac disease. There's
probably more than I'm forgetting, but for this episode, what
I want to start with is actually what stiff person

(14:59):
syndrome looks like, what the symptoms are, and what happens
to people who have stiff person syndrome, and then after
that get a little bit more into the nitty gritty
of how we think this happens.

Speaker 3 (15:10):
So let's get started.

Speaker 1 (15:12):
The name stiff person syndrome, and Aaron, I'm sure that
you're going to talk a little bit more about how
this name came to be. Yeah, yeah, but in some
ways it's an accurate description of what is happening in
this disorder. The stiffness in the name comes from rigidity
of the muscles, and this is most often muscles in

(15:32):
the trunk, so you're like your torso and your upper legs,
but sometimes also the arms, and really it can be
any muscle, muscles in your face, muscles and your hands,
muscles and your feet in the trunk meaning like again.

Speaker 3 (15:45):
The core of your body.

Speaker 1 (15:47):
You get this stiffness both in the abdominal muscles on
the front side, and the parispinal muscles, so the muscles
on either side of the spine, and especially in the
lower back, and sometimes extending down in to the upper
legs as well. And what's happening in this stiffness is
that the muscles are firing, so the muscle fibers are

(16:08):
continuously contracting without you trying to contract them. These are
voluntary muscles, right, meaning that you have to move them voluntarily,
but in stiff person syndrome, they are contracting without voluntary movement,
even when you're trying to be at rest or trying

(16:28):
to relax, and they can become so contracted that it
becomes over time difficult, if not impossible, to do things
like bend over. And this process is often described in
stiff person syndrome as insidious, meaning it's not that somebody
wakes up one day with muscles that are so tense
they can't reach down and touch their toes. But it's

(16:51):
a gradual stiffening process, and early on it's often kind
of waxing and waning in severity, so some days might
be more stiff, some day might be less, but progressively,
over time these muscles contract more and more and become
more and more stiff. But on top of that kind
of progressive stiffness, what we also see are these episodic

(17:15):
spasms where muscles contract all at once. So the way
that I think of this is to make everyone kind
of understand what that means. Is like, picture a Charlie horse,
because I think we've all had Charlie horses at some
point in our lives.

Speaker 3 (17:30):
Right. Usually when we get.

Speaker 1 (17:32):
A Charlie horse, it's like you're laying in bed, You're
probably dehydrated. You stretch out your leg and all of
a sudden, your calf muscle.

Speaker 3 (17:39):
Just seizes up. Right. Yeah, it's horrible.

Speaker 1 (17:42):
You yelp out in pain, and there's not really much
that you can do, right. You have to either just
kind of wade it out. You can try and stretch
it out, though sometimes it makes it more painful or
just sees up even more, so you just have to
kind of wait it out and eventually that muscle will relax.
In stiff person syndrome, those kind of muscle spasms can happen,

(18:02):
but it's not just in say your calf. These can
happen in any and all muscle groups, and especially they
happen in the legs, but in multiple muscle groups at
the same time. And they're not just happening because somebody
is like dehydrated and resting in bed and move their
leg But they can happen at any given moment, but

(18:24):
seem to happen especially in relation to things like unexpected noises,
unexpected touch like say you bump into a coffee table
that you didn't mean to. Also emotional upset, so major
stressors or rapid movement, so imagine like getting out of
a car and a bike swerves up so you have

(18:46):
to jump back. Something like that could trigger one of
these spasms.

Speaker 4 (18:50):
And so the spasm is like the intensity of that,
like the strength of that contraction and the not irreversibility
of it, but like how long it is contracted or
is it in the ready Is it that plus the
readiness to contract.

Speaker 1 (19:06):
It's both, and so it's that they contract very forcefully.

Speaker 3 (19:11):
But the other thing.

Speaker 1 (19:12):
That's notable about these spasms, and like you said, they
happen very readily, just kind of out of the blue.
But the other thing that's happening is that so all
of our muscles, like all of our limbs and things
you have like two sets of muscles for most movements.
They call them agonist and antagonist. So if you think
of like bending your knee right, to bend your knee,

(19:33):
you have one set of muscles that helps you to
bend it, and you have another set of muscles that
helps you to flex it or to extend it right.
So one for reflection, one for extension. So in the
Charlie Horse example, there's just one set of muscles, like
just your calf muscle is contracting. But what's happening in
stiff person syndrome is that both sets of muscles, if

(19:55):
you're talking about maybe spasms happening in your legs around
your knee, for example, the muscles to flex your knee
and the muscles to extend your knee, they all contract
at once. You have agonist and antagonist spasm, and that
is what creates that rigidity, that super super stiffness. Okay,

(20:15):
and it's not like this happens in just say one
knee at a time. What can often happen is that
these spasms might start with one muscle group, but then
they kind of progress to encompass multiple muscle groups, even
potentially somebody's whole body. And I think if anyone did
watch the Celine Dion documentary, there was a really really

(20:36):
horrific moment in that where you see her go into
one of these muscle spasms, and you can really visualize
just how rigid and stiff all of her muscles become
during this.

Speaker 4 (20:49):
I feel like I'm really trying to not ask the
why yet, I know, I know, are there other situations
in which both sets of muscles or both both muscles
are spasm in that way? So like the Charlie Horse,
you know, as an example, it's just one.

Speaker 3 (21:07):
Of those muscles.

Speaker 4 (21:08):
But yeah, when else do both sets of muscles contract?

Speaker 1 (21:12):
YEA, they shouldn't be. Yeah, they shouldn't be. It's a
it's not a it's not a type of contraction pattern
that happens in typical voluntary muscle movement. It is abnormal.

Speaker 4 (21:27):
Yeah, and this is voluntary muscles only where this happens.

Speaker 1 (21:32):
So no, not necessarily this can happen in any of
your muscle. So we'll get a little bit more into
this when I talk about the kind of what we
know of the pathophysiology. But this is a neurologic disorder,
and so this has the potential to affect more than
just your skeletal muscles. But it does primarily affect your
skeletal muscles, which means the muscles that control your limbs,

(21:55):
that control your trunk, that control your breathing and things
like that.

Speaker 3 (22:00):
Wow, okay, yeah.

Speaker 1 (22:03):
But so that is why you end up with such
profound stiffness is because of how quickly this is happening,
how strongly these contractions are happening, and that they're happening
in like multiple sets of muscle groups all at the
same time.

Speaker 3 (22:20):
And what this leads to is.

Speaker 1 (22:21):
People not being able to move, which also means that
they can't react. So this can lead to things like
falls because people stiffen up and then are unable to
right themselves or catch themselves, which is potentially very dangerous,
especially if you think of the scenario that I mentioned,
like trying to get out of a car or something

(22:42):
like that, and if you have a spasm in a
moment like that or trying to walk down the stairs,
and these spasms are quite painful. I mean, think of
how painful a Charlie horse is. These spasms can be
similarly painful, where it is it is painful to have
a muscle spasm and you're having spasms in multiple muscle
grips at the same time. Stiff person syndrome is a

(23:04):
progressive disorder, so if untreated, it does tend to get worse,
both in terms of that progressive overall stiffness, which we
see again mostly in the trunk muscles and a little
bit in the legs as well, but also in these spasms,
whether they're becoming more frequent or just more powerful, more unpredictable,
whatever it might be in terms of most severe outcomes.

(23:28):
Of course, people can have very severe outcomes if they
have falls during these muscle spasms, but you also can
have spasms in muscles, including the muscles used for things
like breathing. So while it is rare to have spasms
severe enough to cause respiratory distress or death, it can
happen and it has happened. So stiff person syndrome is

(23:49):
a very rare and potentially very life threatening disorder depending
on the scenario. So when it comes to Aaron, I
know the questions that you have that are burning of
like why and how on earth something like this happens?

Speaker 3 (24:01):
Right, I'm like, is this like tetanus? Little like is
it the same? Sort of like what is that, Yeah,
what are the are there?

Speaker 1 (24:06):
Yeah, I'm glad that you mentioned tennis, because there are
some similarities with tetanus, especially in terms of what these
symptoms can look like. So these spasms can look a
lot like tennis.

Speaker 3 (24:16):
Okay, But what I first.

Speaker 1 (24:17):
Want to say before I get into the path of physiology,
and I swear I am getting there, is that all
of this description of stiff person syndrome is what is
often called kind of classic or typical stiff person syndrome.
There are also other types of stiff person syndrome that
have been described, and sometimes SPS I'm gonna call it
SPS a little bit is considered a spectrum disorder. So

(24:39):
some of the other types include something called stiff limb syndrome, which,
as the name suggests, is very similar but tends to
begin or be mostly focal to one limb, like an
arm or a leg or something like that, which may
or may not become more widespread. There's also something called
it the long name per aggressive encephalitis with rigidity and

(25:02):
mile clonus. It has an acronym it's PERM, and this
is a similar disorder, but that is often a lot
more rapid in onset rather than this very insidious slow onset,
and it tends to have more brainstem involvement most of
what I talked about with classic SPS, it's really like muscles.
It's really like your peripheral muscles that are being most affected.

(25:27):
But with some other types of SPS, including like a
non classic SPS and PERM, you can see more of
brainstem involvements. You might see more things that look a
little bit more like Parkinson's than classic SPS. And then finally,
there are also types of SPS disorders that are associated
with certain cancers. But what I'm going to focus on

(25:49):
because what we know the most about in terms of
the pathophysiology is the more classic stiff person syndrome. Okay,
but know that this doesn't necessarily encompass everyone who has
a stiff person spectrum disorder. So I mentioned already that
this is most likely, and I say most likely because
we don't fully know an autoimmune disease, so we are

(26:11):
making antibodies against our own cells instead of antibodies against
a virus or a bacteria or whatever, or in addition
to those, in most cases like sixty to eighty percent
depending on the paper that you read, the auto antibody
that's involved here is against something called GAD, specifically GAD

(26:32):
sixty five. So we're going to get deep into what
the heck these things mean. GAD or glutamic acid decarboxylase,
is an enzyme. This enzyme is present in our nervous
system and our pancreas, but we're gonna ignore that for
now and we'll get there, and in our central nervous

(26:54):
system and our peripheral nervous system. Gad's job is to
make something called GABA, like yo, gaba, gabba. I feel
like we've talked about GABBA before, Yeah, on our alcohol episode.
Probably yes. GABBA, which is short for gamma amino butteric acid,
is a neurotransmitter, which means it's a chemical messenger that

(27:15):
our brain and our nervous system is using to send
signals so that our nerves can do their job, for example,
so that our nerves can talk to our muscles to
tell them to contract or relax. That's what neurotransmitters do.
As one example, GABBA is an inhibitory neurotransmitter, which is
a fancy way of saying that GABA tells our body

(27:37):
to chill. In our brains and in our nervous system,
GABA goes uh, oh, you need to calm down. You're
being too loud. You need to just stop, like can
you just not? That's a quote from Taylor Swift.

Speaker 3 (27:53):
Oh my god.

Speaker 1 (27:57):
Anyways, so that is what GABBA is doing.

Speaker 3 (28:01):
GAD.

Speaker 1 (28:02):
This enzyme is what makes GABA, and GABBA is what
tells us to chill out. So in stiff person syndrome,
you're making antibodies that are targeting GAD, so you're screwing
up this enzyme. So then you cannot make GABA, so
you can't calm down. Your nervous system can't just stop.

(28:25):
So what's happening is that your muscles are getting uninhibited
excitatory signals with no ability to inhibit them. So that
results in spasm, continuous contraction, and stiffness. Now, I know
one of the things you're gonna ask because you probably
have a lot of questions, But one of the big
questions then is why then is this a waxing and

(28:48):
waning phenomenon? And why do we see the stiffness in
these spasms in relation to certain triggers and not just
all the time, especially like at first, Well, let me
tell you it's at least in part because in our
nervous system, we have two different kinds of this enzyme GAD.
We have one called GAD sixty seven, which makes like

(29:10):
basal levels, which means a little bit all the time
of GABA, So we have some GABA floating around, and
then we have one called GAD sixty five, And GAD
sixty five makes GABA just as needed whenever we have
some kind of excess excitement, like times of stress, where
our nervous system gets over excited and is sending too

(29:31):
many signals, then GAD sixty five makes GABA just to
be like, well, calm it down, bring it back down.
So in stiff person syndrome, we make antibodies just against
this GAD sixty five, not sixty seven. So you have
production of this all the time gabba, but you don't
have or you have very limited production of this as

(29:53):
needed gabba, which is perhaps why we see these spasms
in relation to those triggers like times of stress, et cetera.

Speaker 4 (30:00):
Yeah, why but why, like what do we know anything
about the initial trigger that causes these first antibodies to
be produced?

Speaker 3 (30:11):
Like it just setends, Like.

Speaker 1 (30:12):
Why Aaron, that is the actual million dollar question, right
it is?

Speaker 2 (30:18):
What?

Speaker 1 (30:19):
So we believe that nearly all autoimmune diseases are both genetic.
There's a genetic predisposition, and then there's some kind of
environmental trigger, be that an infection, be that an exposure.
We don't know what either are in this case. We
don't necessarily know or have it pinpointed what specific genes

(30:40):
might be most strongly associated with stiff person syndrome. And
we also have no idea what the trigger could be.
Could it be infectious maybe, could it be some type
of exposure? Who knows. We do not know what is
the first trigger? Why do some people start making these antibodies?
We have absolutely no idea in the case of stiff

(31:00):
person syndrome.

Speaker 4 (31:17):
Okay, so I have a question about GAD sixty five.
I know you said it's like as needed when times
are stressful, but like, can you tell me more about
what those times look like? Like, what does that actually mean?
How long are those times? Short periods of time? Is
it on the order of seconds to like days?

Speaker 1 (31:36):
I don't have absolutely no idea that answer to that question.

Speaker 4 (31:39):
Okay, So, like on a day to day basis, are
you producing GAD sixty five.

Speaker 1 (31:45):
Yeah, so GAD sixty five is there all the time,
Like you if you and I, we've got GAD sixty
five all the time. We've got it in our pancreas,
we've got it in our nervous system, and we're using
it all the time. Any given moment, you're probably using it.
You are getting like, I don't know, you get stressed
about a work deadline, you're definitely using it. You're going
out for a run and you see something that is novel,

(32:06):
you're probably using it. It's there all the time. You've
got GABBA and other excitatory Listen, GABBA is inhibitory. You've
got both excitatory and inhibitory neurotransmitters floating around like all
the time, all the time. Yeah, so what's happening here
is that you just have an overall reduction in GABBA
and you're not able to then produce it in this

(32:28):
as needed basis. And again we don't fully understand because
there's a lot more that's complicated about this. Here are
some of the things that make it more complicated. Number One,
GAD sixty five is not the only auto antibody that
we see in stiff person syndrome. There are actually six

(32:49):
different auto antibodies so far that have been characterized that
are present in people with stiff person syndrome or stiff
person spectrum disorders. Like those ones that I mentioned earlier.
The other ones are also against either related neurotransmitters or
related receptors like even the GABBA receptor itself or other

(33:10):
related receptors that are present at this synapse where your
nerves are talking to your muscles and sending these signals.
But on top of that, some people with stiff person
syndrome are antibody negative entirely, which means we either haven't
identified the auto antibody that they have that's causing damage,

(33:31):
or they're having these exact same symptoms by some different,
as yet to be described mechanism. So then that begs
the question, are we have this possible explanation right. We
know what GAD sixty five is doing, we know what
happens in mice models, et cetera.

Speaker 3 (33:49):
When we have.

Speaker 1 (33:51):
Auto antibodies against GAD sixty five, we have a lot
of data to support what we think is going on
in the case of GAD sixty five associated stiff persons.
But this disorder is bigger than that. And so we
really don't fully understand it, and like you mentioned, we
do not know what the triggers are for why somebody
makes these antibodies.

Speaker 4 (34:09):
Okay, but it's the end result is more or less
for classic SPS is more or less the same with
these muscle spasms and rigidity, and so it's like something
likely along that pathway to exactly that blocks the production
of GAD sixty five or something like that.

Speaker 1 (34:28):
Although that blocks the production of gabbad of GAD sixty five, Okay, there's.

Speaker 4 (34:32):
So many I know, I can't keep up with it.
Has stiff person syndrome been observed in other species?

Speaker 3 (34:42):
You know?

Speaker 1 (34:43):
I read one thing that said it has been seen
in a horse, okay, And I know that we have
like induced it in mouse models in a lot of studies,
but I don't know in terms of like naturally occurring
in other animals. I didn't look deep into it, so
the only one that I saw was that it seems
like maybe there's something similar that has happened in a horse.

Speaker 4 (35:02):
Okay, Aarin, I have. I have two other questions. One
you mentioned pankris and the other I know that you
mentioned cancer, and you're like, we're not going to talk
about cancer associated with stiff person syndrome, but I kind
of would like to know just a little bit more.

Speaker 1 (35:17):
Yea about that, So okay, so I'll address the cancer
question first. Some cancers, and this is true, this is
like not stiff person syndrome specific, but some cancers can
cause there's a fancy name for this. They're called para
neoplastic syndromes. So it basically means your cancer starts doing
weird things, and your body, in trying to attack it,

(35:41):
starts making things that then end up hurting your body
further in a way that's not the cancer directly, that's right.

Speaker 4 (35:48):
It's like throwing the kitchen sink or like exactly. But
also you're throwing the baby out with the bathwater.

Speaker 3 (35:56):
Yeah, something like that.

Speaker 1 (35:58):
Yeah, So what we see sometimes in some types of
it seems like breast cancer is one of the strongest
associations and some types of lymphoma I saw as well.
There are some people who have developed very similar symptoms
to stiff person syndrome, and it's found that they have
these auto antibodies, usually against something called amphifizon. In any case,

(36:22):
it's auto antibodies against a neurotransmitter that cause symptoms very
similar to stiff person syndrome, but as a result of
the cancer itself, if that makes sense. It's very very rare,
even among cancers. It is incredibly rare. I don't even
have statistics on it. It's like it has happened, but
it is not something that is common with cancers, okay,

(36:45):
including breast cancer, which is very common. And then you
asked about the pancreas. So yes, this is another way
that the story of stiff person syndrome is more complicated.
And it's because of God so Goad and specifically that
GOAD sixty five is not only present in our nervous system,
it's also present in our pancreas, specifically in the cells

(37:06):
that make insulin. So we actually see the same type
of auto antibodies, that is, antibodies against GAD sixty five
in type one diabetes. That is one of the ways
that we diagnose type one diabetes. And we can also
see very similar auto antibodies in some other neurologic disorders
as well. And this is where that ultra super hyper

(37:32):
specificity of antibodies comes into play in a way that
we've only kind of briefly mentioned in the past. So
if you think of this enzyme GAD GAD sixty five
as like a chunk of lego, I imagine it as
like one of those like six or eight lego blocks,
you know, the like long ones.

Speaker 3 (37:51):
Uh huh.

Speaker 1 (37:51):
The auto antibodies that you're making are like a little
square lego, and they're only attaching to one section of
that enzyme. Okay, So the ones that you make in
type one diabetes attach on one side of the GAD
sixty five lego, and the ones that you make in
stiff person syndrome attach on the other side of that lego,

(38:12):
even though they're attacking the same enzyme.

Speaker 3 (38:14):
So there's room for both exactly.

Speaker 1 (38:16):
Yeah, And so we do see because there is crossover,
we do see an association between stiff person syndrome and
type one diabetes. About thirty thirty five percent of people
with stiff person syndrome also have type one diabetes, though
only about one in ten thousand people with type one
diabetes have stiff person syndrome.

Speaker 4 (38:36):
But everyone who has type one diabetes produces antibodies against
GAD sixty five.

Speaker 1 (38:42):
GAD sixty five is one of the major antibodies in
type one diabetes.

Speaker 3 (38:46):
Interesting, Yeah, but.

Speaker 4 (38:47):
All of this, like all of the complicated and the
fact that we don't still know like the root cause
or there might be multiple root causes, Like how does
that affect then treatment prospects?

Speaker 1 (39:01):
Such a good question, Aaron. So in terms of treatment,
we don't have a lot. But it does get even
more complicated if you have someone who say, you can't
identify any auto antibodies, because then you're wondering is this
truly autoimmune or not? Are there symptoms going to respond

(39:21):
to immune modulators the same way that we might use
for somebody who has these identifiable auto antibodies. But so
that is one of the big things that we can
use in treatment. It's something called ivig, which is probably
interesting enough to do a whole episode on Erin. All right,
let's do it. It is really really interesting. It's basically

(39:43):
really really high doses in this case of pooled antibodies
from literally thousands of people, and you're giving people antibodies,
and in the case of an autoimmune disorder, it ends
up paradoxically kind of reducing that person's own a typical
autoimmune response. Like the problem is antibodies you're giving them

(40:04):
antibodies to help deal with their antibodies. It's so interesting
and weird.

Speaker 4 (40:09):
Is there a way to produce ivig like in a
lab setting or do we still need to get it
from people?

Speaker 1 (40:17):
Yeah, as far as I know, it's still collected from
people and pooled like from thousands of donors, so that
you have like a really huge variety of it. It's
not like a monoclonal antibody which we can make in
a lab that is like one specific kind of antibody.
And there are some one specific type of monoclonal antibody
called retuximab that some people sometimes use for stiff person

(40:38):
syndrome because that targets the cells that make antibodies in
your body. It targets some of your B cells. Interesting, yep.
But those treatments aren't necessarily the first line that's offered
to everyone with stiff person's inndrome. Often the first line
of treatments are medicines called benzodiazepines, which is things like

(40:59):
advan valium, xanax. If you've heard of those, those are
like the common names. I feel like everyone's heard of. Xanax.
Valium is the one that's most commonly used because it
has a bit of a longer mechanism blah blah blah.
And I want to talk a little bit more later
about benzodiazepines in relation to stiff person syndrome, because I
think that they have created this really interesting, kind of

(41:21):
problematic paradox, but they are very effective in a lot
of cases at treating the symptoms of stiff person because
the mechanism of benzodiazepines.

Speaker 3 (41:33):
Is they act like GABA.

Speaker 1 (41:35):
That is what they do in our brains, So they
aren't GABA, but they act at the same receptors, and
so if you're not making enough GABA, we're basically giving
you replacement GABA. So those and then other types of
muscle relaxers that are used to treat those spasms that
we also use for spasms in other conditions as well.

Speaker 3 (41:56):
Those are kind of.

Speaker 1 (41:57):
The main types of treatment that we have. Are none
of them fundamentally change the course of the disease. None
of them come close to approximating a cure.

Speaker 4 (42:08):
Because there isn't like a you know one autoantibody that
you're looking for. Is diagnosis primarily based on symptoms.

Speaker 1 (42:18):
Yeah, it's what we call a clinical diagnosis. So there's
not like one single test that you can do to
kind of clinch the diagnosis. It's a combination of those symptoms.
The stiffness, especially in the abdomen and the spine and
the trunk, the spasms that we see, especially having them
be triggered by specific things like noises or stress or

(42:40):
a touch or something like that. You can do the
antibody testing and if that's positive, that's really helpful. If
it's negative, it might not be that helpful. But then
there also are tests that you can do called EMG,
which is electromiography, and that's actually testing your muscles, and
what we see is continuous activity of those muscles again

(43:03):
in both those agonists and the antagonist muscles, so you're
looking at multiple muscle groups and you're seeing continuous activity
even when the person is at rest. And then some
people say that if there is a good response to benzodiazepines,
that's also helpful, though it isn't technically part of the
diagnostic criteria. And then also just like ruling out other

(43:26):
things that might be more common neurologic disorders, that you
might have other additional symptoms, like for example, Parkinson's causes
a lot of stiffness and can cause spasms sometimes, But
then you also expect to see other things. You expect
to see tremor, you expect to see MRI findings maybe,
et cetera. So there might be a whole battery of

(43:47):
tests that someone has to undergo, and there is often
really significant delays in diagnosis. Very often this can be
misdiagnosed as a primary psychiatric just order something like anxiety, depression,
phobias about it. Yeah, and we'll talk more about that later.

(44:08):
But it's a huge problem.

Speaker 3 (44:10):
It is.

Speaker 1 (44:11):
But that is stiff person syndrome, and what we know
about the biology.

Speaker 3 (44:16):
Of it, it's a lot.

Speaker 1 (44:18):
It's a lot, and it's a really I think that
in the next I hope, I guess that in the
next ten fifteen years. I'm jumping ahead, but I really
hope that we learn so much more about the different
types and about like what the underlying mechanisms are and
what the triggers really are for these auto into body
productions in the first place.

Speaker 4 (44:37):
Yeah, I mean, I feel like it seems like we
know a lot, but there's still a lot that we
will need to get figured out.

Speaker 3 (44:43):
But hopefully that will happen.

Speaker 1 (44:47):
Yeah, and I always wonder how much are we going
to be wrong about? Like this is what we think
we know and might be true for a good proportion
of people, but it's such a big umbrella. It seems like,
so what are we missing and what are we wrong about?

Speaker 4 (45:00):
Are what's underneath the stiff person syndrome umbrella that will
not be in fifty exactly?

Speaker 1 (45:07):
Yeah? Yeah, well Aaron along that line, how did we
get to where we are today? When did we first
find out about this? Tell me everything?

Speaker 5 (45:17):
You know, I will do that right after this break.

Speaker 4 (45:56):
We've said this a thousand times. Stiff person syndrome is
a disease. To be classified as a rare disease, the
condition has to affect no more than one in two
thousand individuals.

Speaker 3 (46:10):
That's in the EU or one in one two hundred
and fifty in the US.

Speaker 4 (46:14):
And maybe those numbers have changed slightly. I'm not sure.
This is from like paper from maybe nine years ago,
and I know that you're going to talk a lot
more about numbers later in the episode. But from some perspective,
stiff person syndrome affects one to three individuals per million,
just very very very much a rare disease. Yep, but

(46:38):
numbers are only one small part of the rare disease experience.
Rare diseases as a group are, in fact not that rare,
and estimated twenty five million people in the US are
living with a rare disease. And while the symptoms or
pathophysiology or treatments might be very different among rare diseases,

(46:59):
there are some elements that they're likely to share. Diagnostic delays,
inappropriate treatments or medical interventions, a disconnect between a patient's
needs and a provider's ability to provide them not being believed.

Speaker 3 (47:14):
Just to name a few.

Speaker 4 (47:16):
Many of these challenges for the management of rare diseases
exist because of what is simply a lack of information
about them. Research is less likely to be funded, studies
face issues of sample size, and awareness is just of course,
much lower than for other more common diseases. Over the
past few decades, a huge effort has been made across

(47:38):
the globe to address some of the challenges facing rare diseases,
and I'll talk a bit more at the end of
this history section about some of these organizations or legislations
and the work that they have done or are doing.
But first I want to go through the story of
the rare disease that is the focus of today's episode
of course, stiff person Syndrome. In nineteen fifty six, a

(48:02):
report was published in the proceedings of the staff meetings
of the Mayo Clinic by two neurologists, Frederick Morsch and
Henry Woltman and shout out to the Mayo Clinic librarian
like I emailed the librarians to be like, I can't
find a copy of this online anywhere? Can you please
send me a copy?

Speaker 3 (48:20):
And they did. It was really.

Speaker 4 (48:24):
This report was titled Progressive Fluctuating Muscular Rigidity and Spasm
in quote stiff Man Syndrome. Report of a case and
some observations in thirteen other cases, and it described a
series of patients who experienced muscle cramps, attacks of muscle tightening,
muscle rigidity, and spasms, often preceded by a sudden voluntary movement.

(48:49):
The first of the individuals described was a forty nine
year old farmer from Iowa who came to the Mayo
Clinic in nineteen twenty four for quote muscle stiffness and
difficulty in walking nineteen twenty four Wow. This report was
published in nineteen fifty six. Wow, if you're feeling bad
that you're sitting on data that you swore you would

(49:09):
publish a couple of years ago, like from your PhD dissertation,
At least you didn't wait thirty two whole years.

Speaker 1 (49:16):
Oh, Aaron, you're talking to me specifically.

Speaker 3 (49:19):
I'm talking about myself. Yeah.

Speaker 4 (49:21):
But also you know, I'm also kidding because a single
case report probably wouldn't have been published or gotten as
much traction as one that described a new syndrome and
had like multiple cases, so you know, and actually there
was to further underline this in retrospect, people picked apart
another case report of what was later agreed upon as

(49:44):
probably being stiff person syndrome. It was described by this
guy Ornstein in nineteen thirty five, but no one really.

Speaker 3 (49:51):
Talked about it, likehit of it.

Speaker 4 (49:53):
Yeah, exactly, And probably it was in part because Ornstein
concluded that it was myocyte.

Speaker 3 (50:00):
Fibrosa at the end of it.

Speaker 4 (50:02):
But anyway back to this farmer, So for the previous
four years before nineteen twenty four, he had experienced increasing
muscle stiffening that got even worse after a fall in
nineteen twenty three, after which he could not work.

Speaker 3 (50:16):
Quote.

Speaker 4 (50:17):
His muscular condition had worsened, His neck muscles had remained
rigid most of the time, and his head could be
brought forward only with great effort. Also, the abdominal muscles,
and to a lesser degree, those of the lower part
of the back, and those of the thighs had partaken
of the same stiffness or tightness. Moreover, the rigidity had
been punctuated by intermittent and moderately painful spasms.

Speaker 1 (50:40):
End quote.

Speaker 4 (50:42):
So Morsh and Wooltman, after examining this person, performed all
of the neurological examinations that they could think of, but
they couldn't come up with the diagnosis. They prescribed warm baths, massages,
physical therapy, things that would increase this person's comfort, and
that did seem to help, but without knowing what was

(51:03):
causing his symptoms, they were powerless to actually treat the
root cause. And over the next few years they kept
in touch, and the last they heard from him was
in nineteen thirty two.

Speaker 1 (51:13):
Quote.

Speaker 4 (51:14):
The stiffness lessened and muscular spasms were fewer than they
had been. He could be on his feet, but he
was weak and could take only a few steps unassisted
end quote. But this case, even though the last they
heard was like, you know, had decades previously, it's stuck
in their minds. And as neurologists at the Mayo Clinic,

(51:34):
which is one of the world's largest and most famous
hospitals for treating difficult cases, Morsh and Woltman were in
a unique position to observe not just one instance of
this unexplained neurological disease, but thirteen more. Because oftentimes, if
you're like, something is wrong with me, I don't know,
you go to the doctor and they're like, we don't know,
go to the specialist, they don't know, go to the specialist,

(51:55):
and then eventually you end upt the Mayo.

Speaker 1 (51:57):
Class, you end up at Mayo.

Speaker 3 (51:58):
Yeah.

Speaker 4 (51:58):
Absolutely, and so this thirteen more fourteen in total was
enough for them to say, Okay, there might actually be
a pattern here, like these seem to have symptoms in line,
there's like a trajectory of the disease that seems like
they have in common, and we're going to call this
stiff Man syndrome, a name which, in their own words
quote could not be taken by anyone to be final

(52:21):
end quote, but which nevertheless stuck around for thirty five
years until it would changed to stiff person syndrome in
nineteen ninety one. We've talked about the importance of names
on this podcast before many many times, and this is
no exception. But it does make me wonder whether it
was the man in stiff Man syndrome that delayed diagnosis

(52:45):
for women or if it was just the way that
medicines saw and treated women at the time. And I
feel pretty strongly that it was the latter. Like I
don't think I'm not in Morsh and Woltman's heads, but
I don't think that they called it stiff Man syndrome
to say only men, right, this disease.

Speaker 3 (53:00):
I think it was just I think the nineteen fifties.

Speaker 1 (53:03):
Yeah, nineteen fifties, I feel like they just used the
word man all the time.

Speaker 4 (53:07):
Right, It was like, instead of humanity, it was just man, sanity,
person yeah, just manity.

Speaker 3 (53:15):
Yeah.

Speaker 4 (53:16):
And to illustrate my point further, I'm just going to
read you some snippets from a nineteen fifty eight article
by Richard Asher, a physician in London. The title of
the article, a woman with the stiff Man Syndrome has
at the end of it a lovely little asterisk that reads, quote,
I cannot avoid the paradoxical title stiff person syndrome might

(53:38):
be a better name.

Speaker 3 (53:39):
End quote. It was nineteen fifty eight.

Speaker 1 (53:42):
Well, and wasn't It was still like so many years later,
but actually changed the name.

Speaker 4 (53:47):
Yeah, yeah, but I think that just goes to show
like how slowly things can move sometimes in medicine, Like
everyone knew that it wasn't just man affected, and it
was just like, come on, let's make this official.

Speaker 1 (53:59):
Yeah.

Speaker 4 (54:00):
So, Asher's case report is unlike any other case report
or article that I've come across before.

Speaker 3 (54:07):
It reads like a story. There's a narrative.

Speaker 4 (54:10):
Asher uses first person pronouns, there's self reflection, there's humanity,
not just manity. Asher starts off the article by describing
how he was reading Morsh and Woltman's report when he
realized that it sounded pretty familiar. Quote they were a
clear description of the case of a woman whose extraordinary
spasms had puzzled me ten years previously.

Speaker 1 (54:33):
End quote.

Speaker 4 (54:34):
So he tracked her case down. He was like, Okay,
I remember this person. This sounds like she had stiff
Man syndrome or stiff person syndrome, and so he was like,
let me see if now like what she's doing these days.
It was ten years ago, and then he retells the
story of this woman who had essentially not been believed
by anyone and was cast aside as a problem patient

(54:56):
for years until her death. And Asher himself was complicit
in her mistreatment and he acknowledges this. So after checking
into the hospital in nineteen forty six with extremely painful spasms,
she was diagnosed by Asher with quote spasms secondary to
spinal arthritis with hysterical overlay. The hysterical part as in,

(55:19):
it's all in her head and she's doing this for attention.
That part would stick with her over the years. That
would be on her case forever, all her cases wow.
Two years later she was supposed to be. In nineteen
forty eight, she was admitted to a quote mental hospital
with depression and troublesomeness. The latter was shown by attacks
of spasm and screaming. A month after admission, she felt

(55:43):
her femur snap during a spasm. A later spasm then
broke the screw and plate that had been put into
her leg. She became a chronic case and stayed for
five years in the wards end quote, all just still
thought to be hysterical. In nineteen fifty five, nine years

(56:04):
after her first admission, she checked back into the hospital.
The note read quote condition worsening, hysterical outbursts on little
or no provocation, becoming worse if soothed, gradually quiteening if
ignored end quote. And so Asher, after learning of this readmission,

(56:26):
was like, oh wow, I remember this patient and her
condition seems the same. I think that there might be
something actually like organic going on, like something actually physical
going on. Yeah, But the psychiatrist who saw her was like,
no way.

Speaker 3 (56:42):
Man quote.

Speaker 4 (56:44):
Whatever her difficulties are, she appears to be completely lacking
in insight and therefore psychologically inaccessible. It is obvious that
her rehabilitation is a formidable proposition. She appears to have
satisfied some emotional need in her illness end quote, and
later adding to this quote, very difficult and uncooperative prefers

(57:08):
to stay in bed. As the patient obviously does not
want to get better. It is time we realized we
have lost this battle end quote.

Speaker 1 (57:16):
Ah.

Speaker 4 (57:21):
Four months later, after Asher had come across Morsh and
Waltman's paper, he finally succeeded in seeing her and diagnosing
her with stiff Man syndrome. Six months after that, at
the age of fifty, she died unexpectedly after a severe spasm,
described in the notes as a quote hysterical turn. Asher

(57:41):
notes quote her hysteria had at least been awarded the
posthumous dignity of inverted commas end quote. So like at
the end, at least hysterical was in quotes. He's saying, wow,
and not just as a as a diagnosis. And I
I wanted to I spend so much time on this

(58:02):
article because I think it is a such a perfect
and heartbreaking example of how people with rare diseases, both
historically but also today are often not believed, and how
you have to wait years for a diagnosis if it
ever comes. But I think the other thing that stuck
out to me is the remarkable fact of the author

(58:27):
recognizing his role in this and changing his perspective. In
the intro, he writes that one of his reasons for
reporting on this case was quote because it shows that
syndromes are sometimes labeled hysterical for no better reason than
that they are not yet officially described. Even in this case,

(58:47):
where the patient's hysterical spasms were so titanic that with
their power she bent a Smith Peterson pin and fractured
a steel plate and screws end quote. So I just
I really like we talk a lot about this period
of medicine, and that still has its effects today. The
echoes are very present, as probably everyone who's listening can

(59:10):
attest and not being believed by their doctor, not being
listened to. But I think things have gotten better, and
I really appreciated reading about like part of the transition
of that, right, this awareness, this self awareness of like,
oh that I was wrong and I was wrong, writing

(59:33):
a case report about it, and being like, I want
people to know that this is what happened, and that
there might be other things out there, other cases labeled
as hysterical that might actually be not hysterical, not just
be because the illness satisfies some need in the patient.

Speaker 3 (59:50):
No, I agree entirely.

Speaker 1 (59:51):
It's so rare, I think to see that much self
awareness and willingness to admit your own fault, how complicit
you were in the suffering of another person. I don't
think that that publicly happens in publications very often at all, and.

Speaker 4 (01:00:10):
That was from nineteen fifty eight, which is I think
just a really interesting Yeah. I just think it's fascinating.
And this article seemed to strike a chord with other
people too. I found correspondents addressed to the British Medical Journal,
which is where that one was published, about this case study,
and people were like, I loved this article.

Speaker 3 (01:00:29):
It was so readable.

Speaker 4 (01:00:30):
I read it before the newspaper at breakfast, and people
were like, Oh, I wonder how many other cases, like
you know, Charcot in his hospital. There was a woman
who maybe was just who had that, but she was
of course in this you know, quote unquote insane asylum.

Speaker 3 (01:00:47):
So it's you know, so many.

Speaker 1 (01:00:50):
Oh, eron, we'll talk more about it too, because we
absolutely still do it today.

Speaker 3 (01:00:54):
Oh yeah, yeah, I'm curious to hear some of that. Yeah.

Speaker 4 (01:01:00):
And after Asher's article, after Morshen Woaltman's article, other case
reports of quote unquote stiff Man syndrome quickly followed throughout
the rest of the nineteen fifties and into the nineteen sixties,
with most authors acknowledging how long symptoms were present before diagnosis,
often years, sometimes decades, and how for most people, hysteria

(01:01:21):
was the first diagnosis made or I saw one patient
who was labeled as drug seeking initially because of pain yep.
One paper from nineteen sixty suggested that quote it is
possible that the disorder may not be as rare as
it seems. Since emotional disturbance is one of several factors
which may lead to exacerbation of symptoms, these may be

(01:01:43):
mistakenly regarded as of psychogenic origin end quote, And from
nineteen sixty six, quote Frequently in medicine, when we are
confronted with a new set of symptoms that we cannot explain,
we readily label these as hysterical or functional end quote.
I just it feels weirdly reassuring to read that from

(01:02:06):
papers back then, decades and decades ago. And even though
it took a long time for change that changed to
be for the tides to turn, it seems like this
is beginning that a bit.

Speaker 3 (01:02:18):
The increase in.

Speaker 4 (01:02:19):
Awareness about stiff Man syndrome stiff person syndrome was not
immediately followed by a better understanding of the underlying pathology
of the disease and how to treat it, though in fact,
the first effective treatment in symptom management was reported seven
years after that Morsh and Woltman paper in nineteen sixty
three with diazepam aka vallium. I don't know the full

(01:02:41):
history of the development of diazepam slash valium, but I
know it first came on the market in nineteen sixty
three and was primarily then used to treat anxiety, but
was soon prescribed by neurologists to manage muscle spasms and stiffness.
And so given the high rate of hysteria diagnoses, I'm
not sure if patients were given diazepam initially for anxiety

(01:03:04):
or for muscle spasms which were about to be voluntary
like this person is, you know what I mean.

Speaker 3 (01:03:11):
So I don't know.

Speaker 4 (01:03:12):
I didn't pick that up in any of the case
reports I saw, but in any case, this drug remains
a frontline treatment. As you mentioned, Aaron and its success
in alleviating spasms gave researchers some potential clues as to
the underlying disease processes in stiff person syndrome, especially the
potential role of GABBA or anti GAD antibodies. The nineteen seventies,

(01:03:34):
nineteen eighties, and nineteen nineties saw a steady rise and
awareness of stiff person syndrome, improved diagnostic criteria, a slightly
better understanding of the path of physiology, and some hopeful
avenues for treatment, including diazepam, immunoglobulin therapy, steroids. But despite this,
many challenges remained.

Speaker 3 (01:03:54):
For this rare disease.

Speaker 4 (01:03:56):
And to give you some idea of what I mean,
I'll just read you the title of a nineteen seventy
seven paper, quote the stiff Man syndrome a psychiatric disease
end quote.

Speaker 3 (01:04:08):
And I'll also.

Speaker 4 (01:04:09):
Share a statistic from a two thousand and two paper
which surveyed sixty eight individuals with stiff Person syndrome diagnosed
in Germany and found that two thirds of these sixty
eight individuals were initially diagnosed with hysteria. So yeah, wow, okay, yep,
that papers from two thousand and two.

Speaker 1 (01:04:28):
Two thousand and two hysteria his diagnosis in two thousand
and two.

Speaker 4 (01:04:32):
And I will say that I didn't see in the
article where like when people were diagnosed.

Speaker 1 (01:04:37):
But still, you know, it doesn't matter. Yeah, I mean, you.

Speaker 3 (01:04:40):
Can give some benefit of the doubt, but they're still
you know.

Speaker 1 (01:04:44):
Very small one.

Speaker 4 (01:04:45):
Yeah, yep, These misdiagnoses with hysteria or a functional neurological disorder,
which you're more likely to see today in notes, Aren't
that surprising given that stiff person syndrome is so often
accompanied by things phobia, anxiety, depression, and just by the
fact that it's a rare disorder, because as they teach

(01:05:06):
you in med school, when you hear hoof beats, you're
supposed to think horses rather than zebras.

Speaker 1 (01:05:11):
Oh. That is the quote, over and over and over
again in med school.

Speaker 3 (01:05:15):
Errant right, right, and me yeah.

Speaker 4 (01:05:18):
And this delay in correct diagnosis is a characteristic shared
among basically all rare disorders, most of them, and it's
not the only thing they have in common. As I
mentioned earlier, limited treatment availability, challenges conducting clinical trials, inappropriate
medical interventions, small research programs. And that's not even mentioning

(01:05:38):
the personal and quality of life challenges that someone might
experience living with a rare disorder. So, even though the
diseases themselves may be very different, the designation as a
quote unquote rare disease is a useful one from an
advocacy standpoint. And I want to close out this section
by chatting about a couple of really impactful developments over

(01:06:01):
the past few decades that have helped to put rare diseases.

Speaker 3 (01:06:04):
In the spotlight.

Speaker 4 (01:06:06):
The first is the Orphan Drug Act. So approving a
medication is not a simple thing, nor should it be.
It requires pharmaceutical interest aka dollars, and multiple stages of
trials before its efficacy and safety can be confirmed. For
rare diseases, this poses a huge challenge because you need

(01:06:26):
people with the disease at each of those trial phases
and new individuals at each phase, and even then to
show statistical significance, you often need more people than are
available to participate.

Speaker 1 (01:06:38):
Right Think about how many thousands of people were enrolled
in something like the COVID vaccine trial. We need lots
of people for medication research. Yep.

Speaker 3 (01:06:48):
Yeah.

Speaker 4 (01:06:49):
It's logistically and financially challenging to say the least, and
this problem drew the attention of the FDA in the
late nineteen seventies, who along with leaders of advocacy groups,
groups like Marjorie Guthrie who I mentioned in the Huntington
Disease episode Witty Guthrie had Huntington's disease, and also Maurice Klugman,
star of the show Quincy Mmey, whose brother had a

(01:07:12):
rare form of cancer. All of these individuals drafted up
legislation to provide financial incentives for the pharmaceutical industry to
develop drugs for rare disorders. And this legislation was called
the Orphan Drug Act, and it was passed in nineteen
eighty three, and it completely revolutionized the development of therapeutics
for rare disorders. For some perspective, before this act, only

(01:07:35):
ten drugs for rare disorders had been approved. By two
thousand and eight, that number went up to three hundred,
translating into treatment for over eleven million people.

Speaker 3 (01:07:45):
Wow, it's huge.

Speaker 4 (01:07:47):
And it also kind of helped to deal with some
of the logistical challenges too by simultaneous phases. And yeah,
that part I don't I'm not as familiar with, but
there's lots of papers that I'll link to about that
and advancements when it comes to rare disorders, they're not
just limited to drug development. The same year that the
Orphan Drug Act was passed nineteen eighty three, the National

(01:08:11):
Organization for Rare Disorders was established NORD, bringing together advocates
under one umbrella, with the recognition that quote alone we
are rare, Together, we are strong that's the NORD slogan.
NORD represents more than two hundred individual disease organizations and
has done tremendous work in promoting and funding basic research

(01:08:33):
into rare disorders, providing support and education for individuals impacted
by these disorders as well as their families, and overall
just raising awareness because that's one of the biggest challenges
in this is just awareness. Because if you hear hoofbeats,
you think horses? Are you ever going to think zebras?

Speaker 1 (01:08:54):
And at what you have to know that the zebras
exist to even think of them in the back of
your mind, right right?

Speaker 4 (01:09:01):
And I would say zebras are also like a little
bit more common. What about some rarer equis right? You know,
I can't think.

Speaker 1 (01:09:08):
Yeah, it's not the best analogy, right right.

Speaker 4 (01:09:12):
But yeah, I mean it's that sort of thing like
you think horses, Okay, you think what else?

Speaker 3 (01:09:16):
What else could it be?

Speaker 4 (01:09:17):
Zebras, donkeys, giraffes, those yeah? Sure, yeah, okay, and we're
talking ungulates like that's a.

Speaker 3 (01:09:24):
Whole thing, koodoo.

Speaker 4 (01:09:27):
Okay, I don't know lots of things, but yes, I
mean yeah, with the Orphan Drug Act with NORD, there's
been a lot of progress made, and things aren't perfect right.
There's often medications for very disorders are prohibitively expensive, making
them inaccessible to those who need them, And some of
these disorders are themselves varied, so a drug that might

(01:09:50):
be effective for one person might not be for another,
just like we discussed in stiff person syndrome. But ultimately
I wanted to highlight these efforts as well. Is sort
of like that those shifts from those case reports in
the nineteen fifties where we could actually see this dawning awareness,
self awareness of like, oh maybe it's not hysteria, just

(01:10:13):
to appreciate how far we've come over the last seventy years,
not just in terms of stiff person syndrome and our
understanding of that, but awareness of all rare disorders and
the challenges that they face.

Speaker 3 (01:10:27):
So with that, Aaron, can you.

Speaker 4 (01:10:31):
Tell me where we are with stiff person syndrome today?

Speaker 1 (01:10:35):
I would love to try right after this break. As

(01:11:03):
with so many rare disorders and not rare disorders that
we cover on this podcast, we don't have great data
on the incidents and prevalence of stiff person syndrome, but
there are numbers that are cited pretty frequently, and that
is that you mentioned already. Erin the estimate is that
the prevalence the number of people living with stiff person

(01:11:24):
syndrome is I saw mostly one to two cases per million. OK.
Some might say one to three. I will say that
the Stiff Person Research Foundation website says four to five
cases per million. I didn't see that number other places,
so I'm not sure where that estimate came from. But
in any case, it is an estimate because we really

(01:11:45):
don't know, especially when you consider stiff person syndrome versus
stiff person syndrome spectrum disorders.

Speaker 3 (01:11:52):
Right.

Speaker 1 (01:11:54):
But if we take that number of one to two
cases per million and do some air in math, because
it's been a while since we've done that in a while,
I know that would be so that people can get
a sense of this. Somewhere in the range of three
hundred to six hundred people in the United States living
with stiff person syndrome.

Speaker 3 (01:12:11):
That is very rare.

Speaker 1 (01:12:12):
It's very rare, and between eight thousand and sixteen thousand
people worldwide. This is a super rare disorder. The incidence, though,
is also estimated to be about one per million new
cases every year. So we're talking about another eight thousand
cases worldwide every year, okay, And some studies suggest that

(01:12:33):
up to sixty five percent of people living with stiff
person syndrome can no longer function independently in their activities
of daily living because of a combination of their symptoms
of stiffness, rigidity, pain, frequent falls, and also phobias that
are related to the falls or to doing specific tasks.

(01:12:55):
And I want to kind of spend a minute to
talk about that this anxieties and phobias that can result
or that can be kind of what we call comorbid
with stiff person syndrome. You mentioned it, aaron I mentioned
it earlier as well. One study tried to kind of
put a number on this, like how much more common
are things like anxiety, depression, or phobias in people with

(01:13:17):
stiff person syndrome compared to people without stiff person syndrome,
And they're significantly more common than in the kind of
what we call general population. But overall, this one paper
found that the rates were pretty similar to people living
with something like MS, which is another chronic neurologic condition.
But there's a couple things that I want to mention

(01:13:39):
about the anxieties especially that can present with stiff person syndrome. First,
because stiff person syndrome is so rare that many practitioners,
including experienced neurologists, might have never seen a case of
it before. Even if they've heard of it, they might
have never seen it, so it's not necessarily going to

(01:14:00):
be the first thing that they think of. And because
most people present to a primary care physician who's even
less likely to have ever seen it before, it is
very common for stiff person syndrome to be initially misdiagnosed,
just like it was called hysteria as a primary psychiatric disorder,

(01:14:20):
like you have anxiety with these symptoms, rather than you
have a neurologic disease and you have anxiety as a
result of it. But that isn't true in the case
of stiff person syndrome. First, the anxieties and phobias tend
to be very directly related to their symptoms and very

(01:14:43):
realistic and appropriate given the degree of stiffness, spasms, injuries, pain,
things that can result because of the symptoms that they're having. Right,
And it kind of goes even beyond that this is
a neurologic disorder that's affecting GABBA, which is a neurotransmitter
that is involved in decreasing our excitatory like decreasing that

(01:15:08):
anxiety response and reducing that can further drive anxiety. And
on top of that, benzodiazepines, valium, the valumes of the world. Yeah,
these are medicines that function, like I mentioned at that
GABA receptor. They act like GABBA. They are considered a

(01:15:29):
first line treatment for stiff person syndrome because they act
on that mechanism, but they're also used in the treatment
of anxiety disorders and they're very effective in the treatment
of anxiety disorders. Especially in the past they were used
kind of like a free for all for anxiety. Today,
I hope most people are using them less for primary

(01:15:52):
anxiety disorders. But what that means is that somebody who
has stiff person syndrome but hasn't been diagnosed with that,
who gets given a benzodiazepine and has improvement of their symptoms,
that might further misrepresent them as having a primary anxiety
or psychiatric disorder rather than having this neurologic disorder that

(01:16:13):
is stiff person syndrome. So all of this can really
really contribute to the major delays in diagnosis that we see.
One paper that I read cited an average of six
years from onset of symptoms to diagnosis, but that range
was up to eighteen years, which is just yeah, yeah.

Speaker 4 (01:16:31):
Not having the big picture, like the full picture of things,
but being like, oh, this answers this. So then the
other things that you're that you may be experiencing that
are not just anxiety related symptoms, you're like, well, those,
oh no, well those aren't related because this is clearly
treating your anxiety. So those things you're not really experiencing,

(01:16:53):
it's just your ahead or they're not related to this,
And so you're left still with these questions of but
right there something more.

Speaker 1 (01:17:01):
Yeah, And I also don't want to like make this
seem as though anxiety is also not real.

Speaker 3 (01:17:06):
It is.

Speaker 1 (01:17:07):
That's like a whole different situation, and there's neurotransmitter abnormalities
involved in that as well too well.

Speaker 3 (01:17:13):
And it's also not just that anxiety is.

Speaker 4 (01:17:16):
I think that living with a rare disease and chronic
disease on its own comes with anxiety that may not
be just down to the path of physiology of that disease.

Speaker 1 (01:17:26):
One hundred percent. Yeah, absolutely, absolutely, absolutely, yes, it's so
it is so much bigger than all of that, But
I think it's an important kind of piece to highlight
is that it is important to get the correct diagnosis,
and when it comes to stiff person syndrome and other
rare disorders, it can be very difficult to get there.
And so in terms of where do we go from here,

(01:17:48):
I think it's it's really hard to say to try
and estimate like what is to come. I think there
is no doubt that when a celebrity comes out as
having a disorder or even bringing something like a rare
disorder to the spotlight in one way or another, it
really does put a type of spotlight on that disease

(01:18:12):
that most other diseases don't get. So the question really
now is like, is that going to lead to more funding,
Is that going to lead to more research or is
it not. I hope it's going to I think that's
the big hope, or just.

Speaker 4 (01:18:25):
More awareness, which in itself could then lead to more
diagnoses and more like name recognition for that.

Speaker 1 (01:18:33):
Yeah, and we might have very different epidemiology numbers in
years to come simply because of increased awareness. And I
think one of the things that at least for me,
watching that documentary highlighted that I hope that we as
a society continue getting better at when it comes to
rare disorders, but also when it comes to a lot

(01:18:54):
of these what we call like invisible illnesses and really
just anything things that people are dealing with. Is like
understanding that these are all affecting people and you have
no idea what it is that another person is going
through when you're looking at them. And I think that
that is one of the big things that for me,

(01:19:15):
at least, that documentary really highlighted, and I think that
we need to do better at in medicine and beyond
medicine is recognizing that, like, these are people, their symptoms,
whatever if whether they have a name for their diagnosis
or not, Like just believing people, I think, and giving

(01:19:35):
grace and understanding that like you don't know what another
person is going through. And I think that that, like
that empathy building is very much needed in medicine and
beyond medicine. We've highlighted and mentioned Aaron the organizations like
the National Organization for Rare Diseases that are doing a
lot of this advocacy work. There's also I want to

(01:19:56):
shout out the Stiff Person Research Foundation, which does a
ton of work in raising money and doing research on
stiff person to try and better understand it, to try
and come up with cures. And Alison, the provider of
our first hand account for this episode, also works with
a number of other people living with stiff person syndrome
who have a couple of other organizations I wanted to

(01:20:17):
give a shout out to. They have an Instagram page
called Bent Not Broken Autoimmune and then a YouTube channel
called Stiff Person Syndrome Heart to Heart. So if you
would like to learn more about stiff Person syndrome specifically,
you can absolutely check those out, and check out the
National Organization for Rare Diseases as well to learn more
about so many additional diseases besides stiff person syndrome. But yeah,

(01:20:39):
that is what we've got for this episode.

Speaker 4 (01:20:43):
And we've got a lot more that if you would
like to read further, there's plenty. There are plenty of
sources out there, so let's go ahead and go through
a few of those. I've got a whole lot I'm
going to shout out too, in particular that I think
are really interesting and we're helpful to kind of my
head around this. The first is that paper by Asher

(01:21:03):
called a Woman with the stiff Man Syndrome from nineteen
fifty eight. I do think it is a really interesting
presentation of this person's experience, sort of fitting this into
that retrospective diagnosis and some of that self awareness.

Speaker 3 (01:21:17):
And then on.

Speaker 4 (01:21:18):
The topic of rare disorders and rare diseases, there is
an essay from the Lancet published in two thousand and
eight by Schapati at all, and it's titled why rare
diseases are an important medical and social issue. There's a
whole lot more.

Speaker 1 (01:21:36):
I have a few papers. The couple that I want
to give a special shout out to are one by
Hadavi at all from twenty eleven called Stiff Persons Syndrome
in the journal Practical Neurology, and then another that was
also titled Stiff Person Syndrome from Neurologic Clinics in twenty
thirteen by Chicato at all. I'm almost certainly pronouncing that wrong,
and that I apologize. I had a number of other

(01:21:58):
papers as well too. There was that one that really
looked at the stiff person syndrome and psychiatric comorbidit ease.
That was from twenty twenty one, but we'll post all
of the sources from this episode and all of our
episodes on our website, this podcast will Kill You dot
com under the episodes tab A.

Speaker 4 (01:22:14):
Big thank you again to Allison for being so open
and willing to chat with us and share your experience
and your story. It really we appreciate it. The words
cannot express Yeah.

Speaker 1 (01:22:27):
Thank you, thank you, thank you. Thank you also to
Bloodmobile for providing the music for this episode and all
of our episodes.

Speaker 4 (01:22:33):
Thank you to Tom Bryfogel and Leanna Squalacci for the
amazing audio mixing.

Speaker 1 (01:22:38):
Thank you to everyone and Exactly Right Network, and.

Speaker 4 (01:22:41):
Thank you to you listeners. We hoped that you learned
something from this episode.

Speaker 1 (01:22:46):
And a special shout out as always to our patrons.
Your support means the world to us. Thank you so
so so much.

Speaker 3 (01:22:52):
Truly truly. Well until next time, wash your hands, you
filthy animals.

Speaker 2 (01:23:04):
Bum bumba, buba

Speaker 5 (01:23:15):
Buba bu

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.css-14f5ked{margin:0;word-break:break-word;display:-webkit-box;-webkit-box-orient:vertical;box-orient:vertical;-webkit-line-clamp:2;overflow:hidden;}Ep 155 Stiff Person Syndrome: A rare disease in the spotlight