>> Our third and final
speaker this evening is
Dr. Robert Pascuzzi.
He's the chair of the
department of neurology
at IU School of Medicine.
The neurosciences are one of
the school's highest priorities.
We have national expertise in
Alzheimer's research, traumatic
brain injury, neuroimaging
and genetic factors,
and neurological diseases.
Dr. Pascuzzi is a national
leader in research that
focuses on therapeutic trials
and neuromuscular diseases,
including ALS, myasthenia gravis,
and Lambert-Eaton syndrome.
He served as the director
of the American Board of
Psychiatry and Neurology
and has been selected outstanding
professor in neurology
by the graduating medical
school class at Indiana
University on 26 occasions.
We look forward to
his talk this evening.
Please help me in welcoming
Dr. Robert Pascuzzi.
>> Thanks, Aaron.
I appreciate that.
I'm looking for my
advancement tools. Hey,
thanks. I appreciate it.
It's a pleasure to be here
and talk for a few minutes
about a couple of things.
I want to talk about creeping
paralysis, and so pretty be clear
what is creeping paralysis?
That's the word on the street in
the hills, going back 100 years
for Lou Gehrig's disease, ALS,
amyotrophic lateral sclerosis.
When you see somebody who has a
family history from 60 years ago,
or someone who had creeping
paralysis, that's what
they're referring to.
It's a horrible disease.
Hopefully, in the next
few minutes, we'll learn
a little bit about
it, but we'll also come away with
some enthusiasm for getting to
a point where we can actually
treat this a whole lot better than
we have been up to
this point in time.
I'm also going to put in a
joke unless this gets cut out
by the dean or somebody else.
It's one of the best
medical jokes out there.
I know we have a big audience
of medical personnel, so has
to do with Count Dracula.
Goes something like this,
three vampires walk into
a bar in camel, and
a bartender thinks
that's a little creepy.
The first vampire says,
"I want a glass of blood."
He writes it down, the
bartender does, and looks
at the second vampire.
He says,
"I want a cold glass of blood."
He writes that down and turns
to the third vampire and
says, "How about you pal?"
The third vampire says,
"I want a cold glass of plasma."
Bartender writes that down,
scratch his head. He thinks
this is really weird.
He said, "Okay, let me get this
straight. It's going to be two
bloods and one blood-like.
[laughter]
Is that okay?"
Anyway, you can at least
take that with you.
Let's talk about the
creeping paralysis.
Disclosures, my only
disclosure is I'm an IU person.
I went to IU for everything
except for some neurology training
and been around here
for many decades.
IU is my home, and that's
my inherent bias. I'm going
to give you a case here.
This is intended to help
make people less anxious,
and particularly since
we have an audience
of clinical people.
This is something that
I get consulted about
a couple of times a month,
typically by a physician.
In this case, one of my clinical
colleagues called and said that
since Friday [inaudible]
because the hand's
twitching, it's flickering.
I said, "Well, can you show it
to me?" They sent me a video.
Look at the hand. Now you
see it flickers. It twitches.
The inside of the hand
twitches. The little finger
on the side it twitches out.
It looks like there're twitches.
In between the thumb and the index
finger, it's twitching a bit.
The little finger is twitching.
It turns out that when physicians
see these twitches and flickers,
everybody gets
twitches and flickers.
As long as you don't know
what they are, they don't
really bother you that much.
Your eye twitches,
that sort of thing.
When physicians get this,
oftentimes they know too much
and they understand that muscle
twitches are fasciculations,
and fasciculations are
something that one sees
in Lou Gehrig's disease, in
amyotrophic lateral sclerosis,
it's a natural fear.
We just worry about these things.
It's a reason to get checked out.
The good news is nearly always
when somebody comes in to see
a physician and their chief
complaint is twitches and
fasciculations, it's
not Lou Gehrig's disease,
Lou Gehrig's patients
present with other things,
have other findings on exam,
but it's our job as clinicians
to try to make the distinction
and be very clear about it.
Anybody out there
listening, if you get
muscle twitches and flickers,
particularly if
you're a physician and
you worry about this stuff,
you should be in pretty good
shape, but feel free to call me.
We actually have the patients
come in, we take a look at them,
we conduct a complete
exam looking to establish
a reason for the twitches
and fasciculations.
We'll come back at the
very end and try to
diagnose this individual.
Let's talk a little bit about
Lou Gehrig, The Iron Horse.
I think he is a very
interesting figure, not
so much because of his baseball
accomplishments, which were huge.
He went to Columbia.
He didn't go to IU.
He went to Columbia and New York
and was going to be an engineer.
He played football,
also baseball.
He played in the Summer League,
which was not allowed then, so
he got in some trouble.
In the professional league,
he had an extensive career
for over a decade of hitting
over 300 year after year. His
durability was incredible.
He became known as The Iron Horse
as his nickname until 1938 when
his batting average
dropped below 300 for the
first time in a decade.
Then earlier that year in 39, then
his performance really was poor
at the beginning of the
season. He went to the Mayo
Clinic to be evaluated.
They evaluated, or they
determined that he had
amyotrophic lateral sclerosis.
While we call this Lou Gehrig's
disease here, most of the world
calls it Charcot's disease.
Charcot was the
father of neurology.
He worked at the
Salpêtrière in Paris.
He trained a generation
of neurologists.
He's the one that first
observed this condition.
His description of it is
the basis for the clinical
diagnosis that's made today.
What is the disease?
It's basically an adult.
It can be any age, more common in
older people than younger people.
They typically have the gradual
development of weakness, loss
of function, loss of muscle
in one arm or one hand.
That's where it starts,
on one place in the body.
It could start in a leg
with a foot drop, very
gradually developing.
It's painless. There's no
sensory loss, just a gradual
decline in function.
Muscle tends to
shrivel up and atrophy.
There are muscle
fasciculations and twitches.
Over time, over months to
years, the weakness progresses
gradually and spreads.
If it starts in the left arm,
it spreads to the right arm.
If it starts on the left
arm, it also eventually
spreads down the left leg.
Then it spreads up into the
bulbar area. If it starts in a
leg, it gradually spreads upward.
In some patients, it starts in
the speech and swallowing muscles.
In those patients, it
gradually spreads down into
the neck, shoulders arms.
It's like it creeps along in
the central nervous system
with a regional spread.
Patients tend to progress fairly
steadily at a steady rate.
What limits their survival to
about two to five years on average
is when it spreads to involve
the diaphragm muscles.
The diaphragm is not
working well enough. You
can't breathe well enough.
That's going to limit your
survival unless you go on
a breathing machine, like
let's say Stephen Hawking
for a number of decades.
Two to five years is the
typical timeframe it takes
for most patients to reach
a point where their
breathing is that critical.
For some patients, it's a
more rapidly progressive
downhill slope.
They don't survive a
year. For other patients,
it's a very slow course.
We have some patients that
have had it for 30 years,
so it's progressing.
They're just losing ground a
couple of percent per year.
Whatever slope you're on,
is the slope you stay on
for the most part.
That's what it looks like. There
are two different kinds of motor
nerves in the brain and spine.
The two sets typically are
both affected in this disease.
Lower motor nerves go from
the spinal cord straight out
to the muscle and make
the muscle contract.
If the lower motor nerves
malfunctioned, the muscles shrink
up atrophy fasciculations.
Upper motor neurons begin up in
the thinking part of the brain.
When you want to make
your arm move, you have
to initiate that by triggering a
signal in the upper motor nerve.
If it's in the right side of
the brain, it sends a signal
down a wire, the axon that goes
down to the bottom of the
brain, crosses over to the
spinal cord on the other side.
It goes down the
spinal cord and stops.
That upper motor nerve
then hooks up with
the lower motor nerve that
goes out and serves the muscle.
Any muscle you want to use,
you have to have a hookup between
the upper and lower motor
nerve like two electrical
wires hooked up in series.
If the upper motor nerves in
the brain malfunction, patients
have different findings on exam.
They get stiff and
tight, called spasticity.
They get real jumpy reflexes
when we tap on their reflexes.
These are features of an
examination that one can see.
Neurologist findings are
typically a combination
of widespread lower motor
neuron findings, widespread
upper motor neuron signs, and
a slow progressive course over
time. Yet sensation is spared.
Cognition is typically spared.
Eye movements are spared.
Bladder and bowel function are
spared. That's the clinical
presentation that leads
a neurologist to say, "Well, this
is amyotrophic lateral sclerosis.
That description comes
courtesy of Charcot.
It's not a common disease
in the sense of Alzheimer's
or Parkinson's, but it's
more common than you think.
It affects 1 in 10,000 living
people. There's probably 700
patients in Indiana now.
One's lifetime risk of getting
it is actually about 1 in 500.
It has to do with the fact
that the life expectancy is
limited with this disease.
It's a progressive problem and
eventually becomes very difficult
to manage for patients
and their families.
There's pretty much nothing
good about the disease.
Pretty much nothing good.
I think that's where we're at.
We have Charcot to thank for
teaching 100 years of neurologists
how to make the diagnosis.
We're at first base in the
baseball metaphor.
We know how to make the
diagnosis. Neurologists do it.
It's a neurologist disease.
Here's just a brief example
of what happened to a patient.
Not unlike our patients,
when Lou Gehrig got
diagnosed at the Mayo Clinic,
he went back to New
York and had his famous
speech at Yankee Stadium.
Then he said, "Well, somebody
has to know how to treat this."
They said, "Well,
we don't know how to fix this."
He said, "Well, is there
any research being done,
any clinical trials?"
He found a clinical trial in
New York done by Israel Wexler,
a very famous
well-known neurologist
at Mount Sinai who was studying
the effects of vitamin E on ALS.
There was a theory that
this was the source of it.
Lou Gehrig volunteered
for a clinical trial.
That's what our patients do
here. They say, "Well, how
do we fix this disease?"
We say, "Well, we have a couple of
things that slow down the disease
a little bit,
but we don't have a fix for it."
They say, "What's out there
in a way of research so we
can find something better?"
Patients are motivated, their
families are, and they're willing
to contribute to the greater good.
Lou Gehrig went into this trial.
It's interesting when he left
the Mayo Clinic, he signed
documents that prevented
the Mayo Clinic from ever
releasing his medical
records for decades.
When he was in this
clinical trial, this was
published by Wexler.
If you look at case number
4 of the 20 patients in the
study, this is Lou Gehrig.
Actually, his medical record
is published LG male, age 36.
[inaudible]
weakness in March of 1939.
If you go through the exam,
it basically describes
a widespread lower motor
neuron signs, widespread
upper motor neuron signs.
This description, there's
nothing else this condition
can be besides ALS.
What's interesting is the
very bottom part where it
says treatment with vitamin D
was begun in February
and continued to date.
The fibrillation, and that was
the term then for fasciculations,
have practically disappeared.
Walking is improved and
some power has returned, and
the thumbs the case may be
regarded as definitely arrested
and somewhat improved.
This is science clinical
trials published big journal.
If you read this, you say, "Well,
Lou Gehrig did pretty well.
He was basically had his
disease arrested and
he's somewhat improved."
In fact, you look at the
20 patients in the study,
most of them were improved.
Some were recovered,
marked improvement, marked
improvement, marked improvement.
The majority of these patients
did great in this trial.
The question then is why
is it this publication came
out virtually the same week as
Lou Gehrig's obituary came out?
How do you reconcile that?
I think that you can- This
is a good, helpful piece
of information deciding how
to conduct clinical trials
and clinical research.
I think the problem
here is several.
Number one, it's an uncontrolled
study, so there's no control.
You hear people talk about.
Well, do we have any controls?
Patients often say, "Why do we
have to have placebo controls?
Why can't we just all
get the active drug?"
I understand that point of
view, but if you really
want to know for sure
if something works or not,
it's good to have controls.
Then you need to have
blinding where the evaluators
don't know if the patient's
on the real drug or the placebo,
and the patients don't know
because we're all biased.
The very best clinicians
it's proven they're biased.
If they know the patient is on the
active drug, they want it to work.
They score the patients better.
Patients do the same thing.
If they know they're on a placebo
or active drug, they interpret
their situation differently.
In this case,
Wexler was a very kind doctor.
He had great interpersonal skills.
His patients loved him.
Some of them, the stories
are out there they didn't
want to let him down.
They didn't want to
let the old man down.
They knew that he's such a nice
guy. This is important to him.
They would tell him they
were doing better even
though they weren't.
This is, I think, a very
good example of why we have
to at least think through.
Do we have controls?
Do we have blinding?
Are we really sure that
the results mean what
in fact is reality.
We're at first base. We know
how to make the diagnosis.
We know something
about management.
We've got a couple of drugs
that slow the disease down
a little bit, not much
but a little bit, so
we got some options.
Management is the
village comment.
No one doctor can take
care of these patients.
They have trouble with
hands, arms, speech,
swallowing, breathing.
Some have trouble
with cognition.
We need a team. We need about 12
different types of professionals.
They have to work
collaboratively as
a team to make this a program
that provides effective
comprehensive care.
IU has a comprehensive ALS
multidisciplinary clinic.
It's recognized by the ALS
Association nationally,
and that's essential.
It's multi-departmental.
It's not just neurology, so
Physical Medicine Rehabilitation,
their team is in
there along with us.
That's essential to give
patients and their families
optimal management.
What we don't know for sure
is what the causes of disease.
You'd think that would be known,
but it's not known, except for a
few important exceptions.
Then we don't know
how to fix it.
That's the work that
needs to be done.
In terms of cause, whether
the causes known, really
comes out of the genetic area.
About 5% to 10% of
these patients have
a genetic form runs in every
generation, their family.
This is much like
Alzheimer's and Parkinson's,
where 5% or 10% are genetic.
The genes that cause it are
known and they can be measured.
Those particular subgroups
of patients represent the
group that's probably
the most exciting
target for treatment.
If you have an extra piece of
DNA or unwanted DNA making
some kind of mutant protein,
it's possible to selectively
construct a piece
of interference RNA that will lock
up that stuff, the unwanted DNA so
it doesn't produce some
unwanted protein and free
up normal cell function.
That's the new wave of
trying to attack each
of these individual
genetically-based forms of ALS.
These are studies that
are currently ongoing.
They're starting up and making
progress in patients with ALS.
A couple of articles on the
superoxide dismutase patients from
The New England Journal of
Medicine from just a couple
of weeks ago showing that
there are some things you
can measure in patients
that suggests this could
be actually working.
This may actually work.
Very exciting.
For 25 years since 1995, ALS
clinical trials have been
conducted here at IU and these
are some that go back to '95.
Some of them were big multicenter
national or international studies,
some were conducted just
here, some were like
[inaudible] was here and Hopkins.
Some of them are not drug
treatment trials. One
involves art therapy.
We need to get some better
treatments. We're willing to look
at anything. That's the past.
The present is these are the
four clinical trials involving
medical therapies that
we're currently
involved with at IU.
The future includes us
bringing in some of these
very strategic protocols
for treating patients with
specific underlying types
of genetically-based
ALS, including the
antisense oligonucleotides.
We're doing studies to look
at metabolism of patients
to try to find the mechanism
of their vulnerability.
Is there something about
the environment that makes
them vulnerable to certain
toxins, the EXPOsOMICS.
We've got some studies in
neuroprotective drugs,
and a phase two study of
a drug that comes from the
beehives of New Zealand.
The propolis that makes the
beehives of New Zealand
hard to destruct and hard
to wear out has certain
constituents that have
neuroprotective properties.
Here at IU that has been
studied to demonstrate benefit
not only in mice, but now safety
in normal healthy
human volunteers, and
in phase I B studies
in patients with ALS,
with phase II studies coming up.
We think maybe this
disease has multiple causes
and has several different factors
that could come into play.
The same theory holds for
Parkinson's disease and
for Alzheimer's disease.
This is the missing piece of
the puzzle for the last 24
years up until a year ago.
This is Brian Pierchala. He joined
the faculty here in the past year,
and he's the Sherry L. Sonneborn
professor in ALS research. For
24 years, we had a bunch
of clinicians seeing patients,
involved in clinical trials,
trying to think of ways
to treat patients,
but to be fair,
the average clinician, the
average neurologist, we're
not basic scientists and
we can't be and we need
somebody who can really focus
on the basic science to
try to find out what's the
mechanism for the disease?
What are the various steps
that occur to make the
motor neurons fall apart
and age prematurely,
and how to identify the targets
that would be logical to go after
for therapeutic intervention?
Now we have basic science
here at the IU Neuro Science
Center with the clinicians.
This is only the beginning now
of a really new era of trying
to find the actual cause or
mechanisms for the disease
and then get some really
good options for treatment.
I was just showing
some of Brian's work.
He's able to show nerves,
the nerve-muscle interface,
the muscle itself, changes in
ALS patients in others, and
everything from inflammation
and the immune system to genetic
regulation and modification
in ALS motor nerves with a
variety of really important
insights that I think are going
to make IU central to getting
this disease where it's much
more effectively treatable.
The Sanaborns are
an amazing family.
Sherry was affected with this
illness and her wish was to find
something that would fix it.
If it's not going to
work for her in time,
for somebody else the next
generation people to get this.
They actually did the grunt
work at working with The School
of Medicine to provide
the funding necessary
to establish this endowed
chair for Dr. Pierchala.
Like a lot of things,
it's a teamwork, it's the
patients, it's their family,
the community, The School of
Medicine, basic researchers,
clinicians, everybody working
together to get to a point where
we've got something better.
All right, here's the patient.
The good news is that this doctor
has fasciculations in the first
dorsal interosseous muscle
that's one between the thumb and
the finger and the little finger.
These are muscles supplied
by the ulnar nerve.
It's not uncommon if you're
a hardworking person, your
elbows are on a table.
Your elbows are resting
to irritate the ulnar
nerve at the elbow,
and those are the muscles
that will twitch and flicker.
This patient had no
weakness on exam,
no reflex abnormalities, no other
findings for something serious.
This was a benign form
of fasciculation, which
it nearly always is
if the main complaint that brings
someone is the fasciculation.
We're not at the home
plate with this disease.
We're about, I'd say, second
base with what's coming along.
I think the next five years are
going to be huge trying to get us
so we're closer to get into home.
Thank you very much.
