Thank you so much for
that lovely introduction.
So again, I'm Veronica
Santini, and I'm
so happy to speak with you.
I really caught the bug
of loving and learning
about the disease of
Huntington's disease
when I was in my fellowship.
And I treated over 100
patients during my fellowship,
and really got to
know and appreciate
the disease for what it was.
I am, as mentioned,
the codirector
of our multidisciplinary
clinic at Stanford.
And I codirect this clinic
with Dr. Sharon Sha,
who's helped to put this
talk together with me.
Unfortunately, she
couldn't be here tonight.
So what are you going to
expect from this talk?
Well, we'll talk a little
bit about the historical
perspectives, give
you an introduction
into Huntington's disease,
talk about the genetic basis
of disease.
We'll also talk a little bit
about the pathophysiology,
but we're going to try and
not get too much into that.
We'll talk about who
gets this disease
and where it comes from.
What the clinical features are.
And, finally, we'll talk a
little bit about the therapy
and different stages of disease.
So let's talk about the
historical perspectives first.
Neurologists love talking
about historical perspectives
of disease.
So what we know is that
Huntington's disease
may have been first described
by the alchemist Paracelsus
in the 16th century.
And he termed this the
most prominent feature
of the disease, which is a
dance-like movement, chorea
naturalis.
Then, if we head over
into the colonies,
the American colonies, we
know that in the 17th century
the term Saint Vitus
dance, or that disorder,
was used by the English
colonists in New York,
Connecticut, Massachusetts.
And in the 19th century,
Johan Lund, in 1860,
publishes his first detailed
description of this disease.
And he, actually,
is one of the first
to describe it as
being hereditary.
Then, in 1872, George Huntington
wrote his landmark paper
about adult onset
Huntington's disease.
What's interesting
about all of this
is it's not until the
20th century, so 1959
that poor Johan Lund, actually
gets a little bit of credit
for his observations.
So we'll ignore that fact and
head to the landmark paper
that George Huntington wrote.
This is a picture of the
gentleman right there.
He is actually the father
of a son-- he is actually
the son of a physician.
And he spends his days sitting
outside of his father's office
and watching the people walk by.
And he notices--
through observation,
he notices that there are people
who have unusual movements.
And what he really
notes, which is
the most important
part of his manuscript,
is that it's hereditary.
And not only is it
hereditary, but it
hits every single
generation in the family.
We call that an autosomal
dominant pattern
of inheritance.
We also know that
George Huntington
was able to describe both
the neuropsychiatric features
of the disease, as well
as the cognitive features
of the disease.
So beyond just talking
about the abnormal movements
that may come about.
And also, notably, he notes
that there is an elevated risk
of suicide in this population.
And this is actually the first
time that that's described.
I'm going to digress
just a little bit,
and I want to talk to
you about something
that may not
historically be proven,
but often is talked about.
So, in 1692, I think we all
know of the famed Salem witch
trials.
And there is a question
in the mind, I think,
of many neurologists of
whether these movements,
along with Huntington's disease,
may have been the cause.
And so people misinterpreted
this, and perhaps
thought they were
possessed by a spirit.
And certainly there
were no treatments
for this kind of
disease at that point.
So in more recent history,
let's fast forward quite a bit,
and we're going to go
straight to the late Maracaibo
region of Venezuela.
So actually we know in
1955, Americo Negrette
was able to find this hotspot
of Huntington's disease.
And this led to the
US-Venezuelan Huntington's
Disease Collaborative.
This is a project that was
started under the direction
of Nancy Wexler.
I'll show you an
image of her here.
She's here with some of
the people in Venezuela
in this area who are
affected by the disease.
And it's actually really
been her life's work
to learn about
the disease, learn
about the genetic
basis of disease,
and help people as
much as possible.
So Nancy herself is actually
quite an interesting woman.
She is at risk for Huntington's
disease herself, growing up
in a home that, I believe,
which her father was
afflicted with the disorder.
And actually her sister, Alex
Wexler, is a famous novelist,
and wrote a book called Mapping
Fate about her upbringing
in this environment.
In 1983, about 3,000
individuals were genotypes,
we say-- so we did an
analysis of their genome--
and, through this
pedigree analysis,
we were able to localize the
disease to chromosome 4p.
But it was a full decade
later before we were actually
able to figure out which gene
and which area of the gene
might be involved.
And when we did we called it
interesting transcript 15.
Scientists are very creative
people, as you can tell.
And this was actually a
very paramount finding,
because it was the first
obvious autosomal dominant gene
to be identified in this way,
through these genetic linking
studies.
Now we know that many diseases
can be identified in this way.
And it's been quite
helpful to further
our understanding
of genetic diseases,
especially in this vein.
So our current
understanding is that it
is an autosomal
dominant condition,
meaning it does hit every
generation, typically,
of the family.
And we know that it's
caused by a repeat
of three proteins in our DNA.
There's a certain number of
repeats that we can all have.
But when it's expanded,
we know that that
creates an abnormal protein.
And we know also that
that's on chromosome 4p16.3,
in case you wanted to
look in the genome.
[LAUGHS] So what is the exact
function of the normal gene?
We have no idea.
OK?
So this is one barrier
to our understanding
of the disease itself.
We do think it's thought to
be crucial for development.
And the reason why we think
that is when you take a mouse
and you knock that
gene out completely,
so don't have any of those
protein repeats, what we find
is that the mouse can't survive.
And so we think
that it's absolutely
crucial for development
and survival.
The other thing that's
interesting about this gene
product is that it's
conserved across species.
So when we see
something like that
that's conserved across
species, in general,
we believe it must be a very
vital and important protein.
And so when the
gene is expanded,
it does lead to a protein
that folds in an abnormal way,
and then becomes basically
a substrate to be cleaved.
And all kinds of toxic
fragments may build up.
We don't exactly know
why this happens.
But our thoughts are, when
the protein is abnormal,
we may have difficulty
having inter--
the cell may have difficulty
interacting with other cells
and also within the cell.
It's interesting because
this protein is actually
expressed in every
single cell of the body--
so in the testes, in the brain,
in other tissues as well.
But we know that it
leads to brain cell
death in a certain
area of the brain
that we call the striatum.
And most importantly,
and something I really
want you to keep in mind as
we talk about this disease,
is that it has a clinical triad.
What that means
is that there are
features of the disease
that most people have.
So it is, number one,
usually a movement disorder.
So people have abnormal
involuntary movements,
or have difficulty moving.
In addition, it is a
cognitive disorder.
What do I mean by that?
Well, people have difficulty
with memory and with thinking.
And also it's a
psychiatric disorder.
So many people have difficulty
with psychiatric disease
as well.
And often that precedes
the motor symptoms.
So let's talk a little bit about
the genetic basis of disease.
So I think this is a
very helpful chart.
And what you can see here
is that, if there are more
to more than 40-- I don't
know why this isn't working--
if there are more
than 40 repeats
of that triplet protein, then
we know that the person will
develop disease.
That's a definite.
For people who have
less than 26 repeats,
CAG repeats, we know
that they're not
at risk of development
of the disease.
So those are our two
absolutes in this chart.
But let's spend a
little bit more time
on those middle ranges.
So, from 36 to 39,
we know that there
is an inverse, length dependent
correlation with development
of disease.
So what does that mean?
That's a lot of words.
Who knows what that means?
What it means is that,
the more repeats you have,
the higher probability you have
of developing this disease.
If-- so, for instance,
somebody with 36 repeats
has less of a chance of
developing the disease
than somebody with 39 repeats.
Now, let's head
over to the, what we
call the intermediate alleles.
So these are repeats
within the 27 to 35 range.
And these are also called
normal mutable alleles.
We think that
individuals in this range
do not develop disease.
However, there are
quite-- there are
a number of case reports
in the literature,
so there are a number of patient
reports, that actually show
that the patient had symptoms.
And, unfortunately,
when they passed away,
we were able to
study their brain
and see the pathologic
markers of disease.
And so we do have confirmation
that people within this range
may develop disease
characteristics.
In addition, we believe that
people within this range
may actually have
behavioral abnormalities,
psychiatric manifestations,
of the disease.
Furthermore, and
this is probably
the most common scenario,
that people in this range
don't develop disease.
However, when a father
transmits-- usually
a father-- but when a
father is able to transmit
this number of repeats
within this range,
he may pass it on
to his children.
And so we know that people who
have this range of CAG repeats
may actually pass it
on to their children.
OK.
So what is the age
of onset of disease?
Well, it's really
difficult to determine.
And the reason it's
difficult to determine
is because most studies
have difficulty identifying
what the age of onset is.
So many studies will
say the age of onset
is the time that somebody
develops motor symptoms.
And often times that is the
time where somebody is going
to come to the doctor's office.
So it might be the first
time it's identified.
We also know that behavioral
and psychiatric manifestations
of the disease actually
may come before that.
And so, because of that,
we're not exactly sure what
the age of onset of disease is.
But in our mind we
think that the CAG,
and in fact we can prove this,
that the CAG repeat length
actually-- the longer the length
of the repeat, the younger
age of onset you may develop
symptoms of the disease.
We know that the most severe
juvenile forms of the disease
can be with greater
than 60 repeats.
And we also know that
the number of repeat
can also correlate to
late stage outcomes.
And what I mean by that is
time in which a person may need
to go to a nursing
home, or may need
to get a gastric tube to feed.
But that doesn't
tell us everything
about the age of
onset, and so we
think that there's also modifier
genes and environment that
may make a difference as well.
All right.
So.
Now, let's talk--
epidemiology, we're
just going to talk about
who gets this disease.
Where do we find it?
Well, it's rare.
It's a rare disease--
we know that.
But it's found worldwide.
And the age of
onset is typically
between the 30s and the 50s.
Definitely we see older
and younger onset forms.
I unfortunately diagnosed
someone recently in their 70s
with this disease.
So we know that it can
be a very broad range.
We also know that about 90% or
more is inherited from someone.
But there's also this
percentage of people who
may have spontaneous mutations.
And we'll get back
to that actually.
So the prevalence, we know
that it's only about 5 to 10
of 100,000 people
get this disease.
And we know that that is in
Western Europe and in Canada,
but there's much
higher rates in places
like we've already talked
about, like Venezuela, also
in Tasmania, the Northeast
of England, and in Scotland.
And, this comment here,
maybe it's a founder effect.
So some of these areas,
we think, perhaps,
that somebody with the
gene or carrying the gene
traveled to that
area, and then that's
how the hotspot was created.
And then people in that area
maybe didn't travel very much
outside.
We know that the lowest
rate, or the lowest
prevalence of this disease,
is in African blacks.
Which is interesting because
juvenile Huntington's disease
is actually two to four times
higher in African blacks
than in white.
So it's an unusual
correlation that,
in adult onset Huntington's
disease, very low
rates in African blacks,
but quite high for juvenile
Huntington's disease.
And the reason for that
is unknown currently.
And, but we do know that
there's no difference
between the number of
repeats or the age of onset
between different ethnicities.
So we know that there's not a
genetic basis for that as well.
So now we're going to get into
the symptoms of the disease,
the different stages
of disease, hopefully
we'll get to talk a little
bit about treatments as well.
As we go forward, I want
you guys to just think
about the clinical triad.
So, remember, a
movement disorder,
a disorder of the thinking, and
of psychiatric or behavioral
disorder.
So the prodromal almost
stage-- this is typically
considered a stage where
there are no obvious abnormal
movements or extra movements.
And so, like I said,
typically no motor symptoms
at this stage.
But we do know
that some symptoms
can come on 15 to 20 years
before the motor symptoms.
So some of those
might be considered
the cognitive symptoms
of the disease.
And usually that is
mild executive problems.
Yeah, mild executive problems.
So what I mean by
that is people have
difficulty with higher level
thinking, multistep tasks,
and things like
doing your finances,
for instance, or even
making a cup of coffee.
This occurs in
about 40% of people,
but that increases
as you get closer
to the diagnosis
and the motor onset.
We also know that there are
psychiatric changes ahead
of time as well.
So this is just, we know that
not only executive systems have
difficulty, probably, quite a
few years before the disease
onset or the motor
onset, but we also
know-- there were some studies
done-- and if you look at this,
we ask patients basically
to learn a list of words
and then be able to
repeat those words,
or at least identify
them from a list.
And we know that this
declines as we get closer
to the diagnosis.
So even 15 years, 10 years,
5 years before the diagnosis,
that is declining.
OK.
So moving on, we'll
talk a little bit more
about prodromal stage.
7% of at-- so I just
told you that people
in the prodromal stage don't
develop motor symptoms.
But what I'll tell you
now is that actually
7% of gene carriers may
actually develop motor symptoms.
And the motor
symptoms are subtle.
So eye movement abnormalities,
something only really
your neurologist may pick up.
Changes in the walking
and the difficulty
with coordination of the hands.
There also can be a
decreased sense of smell
this is something we see
in other neurodegenerative
conditions, such as Parkinson's
disease and Alzheimer's
disease, as well.
People with Huntington's disease
in the prodromal stage-- so,
again, no obvious
motor symptoms--
may have irritability,
they may be more sensitive,
they may have difficulty with
interpersonal relationships--
and also, at times,
feel apathetic or as
if they don't care.
There is very rare but
occasional psychosis
in this stage of
disease, as well.
And these symptoms can
really increase over time
until the time of diagnosis.
Interestingly, there are two
peaks in the suicide rate.
The first peak in
the suicide rate
is right before the diagnosis.
And we believe that patients
may feel something is abnormal,
feel like something
is wrong, not
be able to necessarily
identify that.
And, very interestingly,
right after the diagnosis,
the suicide rate drops
fairly dramatically.
So is it comforting to get a
diagnosis and know what's going
on?
Perhaps.
So are there any signs
that we can learn about?
Is there anything
we can identify?
Maybe we can use earlier
without genetic testing.
Well a lot of people
have looked at the MRIs.
And what we can see here is
there is a lot of brain tissue
right around here.
It's what we call the
head of the caudate.
However, in a patient
with Huntington's disease,
even in the prodromal
stage, we may
see that this area is
much, much thinner.
So it is a possible
thing to take a look at.
And these changes can happen
sometimes 16 to 20 years
before the diagnosis.
There are also subtle cognitive
changes that can happen
or thinking changes.
And we wonder if maybe we
could identify patients
a little bit earlier.
Having seen quite a few patients
with Huntington's disease
I'm not sure that
the MRI findings
are going to be something that
we can really hang our hat on.
They are present sometimes,
not always present.
And it's hard to choose an
earlier diagnosis stage.
So now let's move on to early
stage Huntington's disease.
This is generally when we think
about the involuntary movements
starting.
So early motor signs
of Huntington's disease
are chorea.
Chorea is a dance
like movement that
is continuous,
irregular, unpredictable,
and flows from one
body part to the other.
It can sometimes
be confused when
it's just very early stages
as being a little bit fidgety,
a little bit restless,
maybe a little agitated.
And also people can
suppress the movements
for a short period
of time often.
And, in addition,
movements often
flow into a purposeful movement.
So maybe there's
a little movement,
and then it flows into
a purposeful movement
that the person wanted to do.
And so sometimes
it can be confused
with voluntary movements.
Or it can be confused
with the person trying
to hide the movement.
In reality it's just flowing
into a purposeful action.
Many patients are not
aware of this movement.
And so, not only in
Huntington's disease,
but often in other diseases,
chorea for some reason
is something that patients
oftentimes are unaware of.
And it doesn't bother them.
But that is obviously not
the case for everybody.
So we also know that this
can cause incoordination,
this can cause
difficulty walking,
and it can also cause changes
in facial expressions.
We often think of a
characteristic eyebrow
raising that we see in
Huntington's disease.
There's also early
changes in mood
similar to what we've talked
about, anxiety, depression,
irritability,
apathy, impulsivity.
So that's a big one, and we
think that it contributes
to the elevated suicide rate.
Also people can have
obsessions and compulsions.
There's also early
cognitive changes.
So people can have
memory loss, and, again,
that executive function.
So this is a test where
we're kind of testing
somebody's mental flexibility.
We give them a bunch of dots,
and we say, connect these dots.
And, in each, square connect
the dots differently.
And you can see, although this
patient, try as she might,
kept connecting the
dots the same way.
So there's a mental
rigidity there.
Again, that impulsivity can
get people into trouble.
There can be trouble with
organization and with planning.
There's slowed processing speed.
So perhaps in a conversation,
it may take a little bit
longer to process.
There are working
memory problems.
What that means is when
we take in information,
we try and manipulate it,
and kind of spit it back out.
That can be very,
very difficult.
Attention can be decreased.
And also there's
other early symptoms
of Huntington's disease.
So people can have
speech changes.
I'm sorry that this
slide came out so funny.
People can have speech changes.
They can also have
trouble swallowing.
And there's something
very characteristic
behaviorally that people
with Huntington's disease do.
Sometimes they quickly put food
into the mouth, so shovel food
into the mouth, and
then don't really
know what to do with
it once it's there.
Creates kind of a
chipmunk cheek problem.
And also there's other
non-neurologic symptoms.
So muscle atrophy, meaning
that the muscles shrink.
There can be heart problems.
There can be thyroid problems.
There can be bone thinning
and bone cell problems.
And we think this is because the
Huntington protein is expressed
in every cell of the body.
There's also weight loss.
And this is something I'm
pretty vigilant of in my clinic.
It's somewhat
unexplained we think
that because the cells lining
the gastrointestinal system
are also involved, we think
that may have something
to do with it.
So now we're going to move
on to moderate stage disease.
And in moderate
stage disease people
can have worsening chorea.
So chorea's interesting
because some people
don't have any chorea at all.
Some people have chorea just
for a short period of time.
And some people have
chorea that gets worse
in moderate stages of disease.
I find that interesting
because everybody associates
this disease with that movement,
and certainly that movement
can bring people to
diagnosis earlier.
But it's not always the
main feature of disease.
Chorea does cause
trouble as it gets worse.
It can interfere with
walking and lead to falls.
It can interfere
with coordination
and disrupt daily
activities, and this
can be very frustrating.
There is also a difficulty
with maintaining actions.
So you see Einstein
there sticking his tongue
out having a great time.
So one thing that
we like to look for
is motor impersistence.
And what that means is that
an action cannot be sustained.
So, for instance, we
test this in the clinic
by sticking the tongue out.
And I like to count out, one,
two, three, four, and go to 10,
and see how long the
tongue can come out.
That can be difficult. For
multiple reasons, but one
of them is this difficulty
maintaining action.
Also the speech
becomes more difficult.
And people can have trouble
understanding a patient
with Huntington's
disease, and that's
going to lead to frustration on
their part-- on the patient's
part.
And then also people sometimes
notice a faster decline
in their motor abilities
during this stage of disease.
Again, this adds to frustration.
So this is-- so you can see
the picture that patients
start to become very frustrated
in moderate stages of disease.
Their thinking becomes
more impaired, as well.
It interferes with
their driving abilities.
It can interfere with
gainful employment.
Psychiatric and behavioral
symptoms might also increase.
And, again, these include
irritability, apathy,
impulsivity, lack of insight.
And then there's poor sleep,
and that-- everybody knows,
poor sleep worsens everything.
So worsens your thinking.
I don't think I slept
very well last night,
and I was searching for
words all day today.
It worsens psychiatric feelings.
So if you're feeling
depressed, you're
probably going to feel
more depressed if you
haven't gotten good sleep.
And it can worsen
motor features.
And this goes across the
board for many, many movement
disorders, including Parkinson's
disease tremor, other things.
Now, what do you guys
think this all leads to?
You have a loss of
independence, loss of driving,
loss of gainful employment,
perhaps progression
of psychiatric and
motor symptoms,
and difficulty with speech
leading to frustration.
So this is where we see the
second peak in the suicide
rate in moderate stage disease.
It's actually four times higher
than in the general population.
Some of the
psychiatric literature,
actually, quotes rates as
high as 10 times higher
than the general population.
It is the third leading cause of
death in Huntington's disease,
and this is a shame.
Again, loss of independence
physical independence,
increasing frustrations, loss
of driving, loss of employment.
But there's other things as
well like, social isolation
and a family history of suicide.
Those last two
factors are actually
major risk factors for
anybody who commits suicide.
And so if you compound that
with the disease itself,
then you definitely lead
to an increased risk.
There's also,
typically, many people
who have Huntington's
disease in their family.
They may have grown
up with the disease.
Perhaps their home
life wasn't the best.
Sometimes, when people
suffer from dementia,
they can't take care of
their children properly.
And there can be
financial hardships.
So this all also leads
to increased risk
in this population.
We're going to move
on to advanced stage
Huntington's disease.
So we see further changes
in the motor symptoms.
So, remember, up
until this point,
we've basically been talking
about too much movement.
But what we really find
is that, in the advanced
stages of disease, the
movement calms down.
Again, this isn't for everybody.
But, in general, the
movement calms down.
And people develop Parkinsonism.
So what's Parkinsonism?
Well, it's slowness, stiffness--
they can have abnormal muscle
contractions.
So some people develop
teeth grinding,
such as you hear
sometimes overnight.
There can be forceful
eye closure at times,
and abnormal limb
postures as well.
And then, to make matters
worse, all the medicines
we've been giving
for the chorea,
for the extra movements,
also cause Parkinsonism.
So it's absolutely vital
that the clinician,
that the physician,
treating the patients
is always thinking about this.
Are we making things worse with
the medicines we're giving?
Walking also worsens.
And people develop an inability
to maintain upright posture.
So remember we talked
about the tongue,
having difficulty
holding the tongue out
or maintaining positions.
Well, the same can be with
maintaining upright posture.
And, again, this
can lead to falls.
Increasing falls can therefore
lead to serious injury,
and can even lead to death.
We talked a little bit
before about causes of death
in Huntington's disease,
and certainly falls
with brain bleeds can be
one of those causes-- one
of the highest causes, in fact.
You also have change-- in the
advanced stage of disease,
you continue to have changes
in the cognition, the thinking,
and the behavior.
So speech output becomes
more and more difficult.
The thinking actually can remain
kind of at the same progress.
So what I often find is
that the processing time
is quite increased.
And so someone with HD just
may need a little bit more
time to answer you.
And so because of
the speech problems
and the slow processing speed,
just give them a second.
They're processing it.
They will be able
to respond to you.
I always assume in the
clinic that everybody with HD
understands me.
And guess what?
I follow quite a few patients
with advanced stage disease,
and I ask them very
clear questions,
I give them some
time, and they give me
very appropriate answers back.
So it's super important not to
assume that delays in response
means that somebody
doesn't understand you.
Also behavioral
symptoms may lessen
during these stages of disease--
the more advanced stages.
So there can be lower rates
of suicide and aggression
at this stage of disease.
The one thing behaviorally that
does happen in advanced stage
disease, although
somewhat rare, is
that people can have these
episodes of very significant
confusion, and they may scream
or have episodes of screaming.
So other bodily functions--
so swallowing can worsen.
And this may mean that it's
unsafe to eat by mouth.
And physical dependence
on caregivers
leads to 24-hour care needed.
And this is for their safety.
Some people at the
very end stage disease
may have severe fluctuations
in blood pressure
and in temperature.
OK.
So this is a typical
progression that we see.
We can see that right
before the diagnosis,
we have the, perhaps, the
first suicide attempt.
Earlier on, we're talking
about being at risk,
or maybe having some
positive gene testing
before symptoms develop.
And then this is, all
the way down here,
is where we're talking
about long-term care
facility or 24-hour care.
So let's talk about the therapy.
So the general
treatment principles
that I follow-- and I'm not sure
why my bullets keep coming up
this way, I apologize--
the general treatment
principles that I follow is
to address all aspects of care
so that we improve
daily functioning.
If you're only focusing on
one aspect of their care,
you're not giving
your patients all
of the life that they
could be leading.
Also I treat with
medications when
they're needed, when
people are at risk,
if they hurt themselves.
But otherwise I don't think
we need to overmedicate folks.
Nutrition, to me, is important
in absolutely all stages
of disease.
I don't want to see my
patients losing weight.
And I don't think anybody
should underestimate
conservative therapies.
So to me they're vital.
Get the physical therapist,
the occupational therapist,
and the speech therapist
involved early on.
We also want to utilize our
psychiatric services early on.
And understand that
the disease can
make it incredibly
difficult for a person
to take care of themselves.
And so caregivers are
so very important, even
in early stages of disease.
So what else do we know?
Well, care should be
multidisciplinary,
and in general it needs to be.
So it requires the
caregiver's involvement.
A neurologist-- and often
there are different types
of neurologists.
I'm a movement
disorder specialist.
My colleague and
codirector Dr. Sharon Sha
is a memory disorder specialist.
So we often need multiple
types of neurologists.
We also use genetic
counseling-- very important,
so that patients understand
the implications of getting
genetic testing, they understand
what the genetic testing means.
My clinic would
not run the way it
does without our
amazing social worker.
And this is absolutely
important, especially
because specialized care for
Huntington's disease patients
is hard to come by.
And so really having a
Huntington's social worker
makes a big difference, as
well as our Huntington's nurse.
All these conservative
therapists,
which I heavily utilize.
And then it's important to
discuss hospice care, as well,
at the right stage, if that's
something that a patient would
like to consider.
So we unfortunately do not
have a cure for this disease.
And we don't have anything to
slow the progression of disease
down yet.
We have looked into many, many,
many substance at this point.
This is not a
comprehensive list,
but this is a number of
things that we've looked into.
And unfortunately we haven't
gotten great results.
We were hopeful about coenzyme
Q10 that showed a trend,
and so now we're
doing a follow-up
study called the 2CARE study
to see if it can be helpful.
In addition, creatini--
creatine, sorry,
was studied in
the CREST-E study.
And, unfortunately, the study
was stopped due to futility.
What that means is a
data analysis was done,
and rather than
spending too much money
and continuing the
study, they realized
that the data that
they had so far
showed that there
was no difference.
There is a PRE-CREST study
going on right now looking
at the same thing.
But unfortunately we think
that the results are not
going to be much different.
So I like to use
combination therapies.
OK.
So why do I like to use this?
Well, why not use one
medication to treat
multiple aspects of the
disease, if we can, right?
Why expose people to too many
medicines if we don't need to?
So I really like
a medicine called
Depakote, or valproic acid.
It's an antiseizure
medicine, but it's
used for so many other things.
What I like about it is
that it's a mood stabilizer.
So those mood fluctuations,
irritability, labile
move-- those kinds of things
can be well treated with a mood
stabilizer such as Depakote.
Why else do I like it?
It causes Parkinsonism, so that
can calm down chorea, antics
as well.
We also can use
neuroleptic medications.
What those are are
antipsychotic medications.
Oftentimes, nowadays,
they're used
as antidepressive medicines.
And those can be used for
the same reasons-- mood
stabilization and as
well as the chorea.
I generally find the
Depakote a little bit better
for the mood stabilization, but
I think they both work well.
Those neuroleptics, the ones
we just talked about-- Ability
might be one that
you've seen a commercial
for on the television--
these cause weight gain
and they work against chorea.
So that's wonderful.
We want to cause weight
gain a lot of times.
So I use that for
combination therapy.
The creatine, could it slow
down disease progression?
Maybe, but it also
causes some weight gain.
And it's a great
source of protein.
And so I say use that as well.
And then, finally,
one of my favorite
medications-- a very, very old
medication-- called amantadine,
that works in multiple ways is
the only medication, actually,
that has very
special properties.
I like to use it when somebody
is complaining about chorea, so
the extra movements.
It can calm those down.
We utilize it in
Parkinson's disease
for drug induced chorea.
It also helps with Parkinsonism,
because of its actions
with dopamine.
And then finally it
gives people a boost--
it's a little bit of an
energizing medication.
And so it can combat
fatigue that patients often
complain about.
We're going to talk briefly
about the ther-- we're
going to talk a little
bit more about the therapy
in early and moderate
stages disease.
So keep those principles that
we just talked about in mind
for these next couple of slides.
So what do you guys think?
Do we need to treat chorea?
I say yes if people
are bothered by it.
So if they're
aware of the chorea
and they're socially
embarrassed by it,
or it bothers them in some
way, yeah-- treat the chorea.
Why should they be bothered,
embarrassed, by this?
However, that being said, many
patients are not embarrassed,
are not aware of the chorea.
And so if it's a family member
that's bothered by the chorea,
I don't think that's
a good idea to treat.
Why give medications
that have side
effects if the patient
is not bothered by it?
The other reason
that I treat chorea
would be if patients
are hurting themselves.
So if the chorea is making
you bang your arms into walls
and cause bruises,
if you're falling
and that can lead
to serious injury,
it's time to treat the chorea.
So what medications do we use?
Well, we use the
atypical neuroleptics.
Again, those
antipsychotic medications.
And these basically
blocked dopamine.
These are the ones
that have been studied.
And probably the one
that's been most studied
and has the best results is
olanzapine, also called also
called Zyprexa.
All of these others have
been studied as well.
I tend to like as gentle of
a medication as I can give.
I do actually like the
aripiprazole quite well.
The side effects are that you
can get a tardive phenomenon,
meaning that a drug
induced movement disorder.
You can have Parkinsonism.
And there's also a
very serious syndrome
that people can get called
neuroleptic malignant syndrome.
So other things that
have been studied, again,
amantadine-- we have
level B evidence for this.
Riluzole, I'm not sure that
I love the evidence for this,
but it is level B. I
shouldn't say I don't
love the evidence for this.
Practically,
anecdotally, in clinic,
I find it to be less effective.
And memantine has
also been studied.
Other medications that
have somewhat less
beneficial effects are
the ones listed below.
OK, so now let's move
on to tetrabenazine.
This is the only FDA
approved medication
for Huntington's chorea.
It is a dopeamine depleter,
and what that means is it
will not allow
dopamine to become
more available to the system.
And therefore it calms
down the movements.
So side effects with this
medication are dose dependent.
And very, very,
very importantly,
it may increase the
risk of depression,
particularly during
the titration
phase of the medicine.
So in a population that already
has difficulty with depression
and may have a
preponderance to suicide,
you have to be very careful when
prescribing this medication.
And make sure that
a patient and family
members will be in contact
with you should anything go on.
And this medicine can also
cause Parkinsonism as well,
so important to remember.
I think I'm going to just
skip ahead a little bit
for the sake of time.
Here's a nice review
of the medications
that we use for chorea.
And now let's move onto
medications for mood.
So, for depression, the class
of medications that's favored
is called SSRIs.
These are kind of the classic
medications we all know about.
Prozac is one of them.
And also SSRIs can also
help with irritability,
anxiety it can help a lot with,
and sometimes the impulsivity.
Again we talked about the
atypical antipsychotics
being helpful for mood as well.
And then the mood
stabilizers, such as Depakote.
For mania, again, we need to
use mood stabilizers here,
not antidepressants-- that
can actually worsen mania.
So, again, valproic
acid, or Depakote.
Keppra can be used as
well, and Lamotrigine.
And, whoops-- let
me just go back.
So we were just
talking about apathy,
that was on the
previous slide-- let
me see if I can just go back.
There we go.
And unfortunately
no clinical trials
have actually used this as
an endpoint in their studies.
So we don't know
of any medications
right now that work
that well on apathy.
Interesting thing about
apathy, who does apathy bother?
Not the patient.
It bothers everyone
else around the patient,
but not the patient--
because they're apathetic.
So medications for thinking.
Well, we've looked into
a famous medication
that we use in Alzheimer's
disease called the donepezil.
And unfortunately
when this was studied
in several small
studies it didn't
seem like there was
a consistent result.
So it seemed somewhat variable.
And then there was a little
bit better open label study
and, actually, eight
patients dropped out
because of side effects.
And then there was a 30 patient
placebo-controlled study,
which means that some people
got the pill and some people
got placebo.
And they, actually, did
not see any improvement
in any measures.
And what they were looking
at there is the UHDRS, which
we do in clinic-- their
functional scores, that
is-- the MMSE, which
is a cognitive score,
as well as Stroop and other
cognitive testing scores.
Rivastigmine is another
medication that's used,
and this has shown
variable results.
But this one study in 2007
may have shown some benefit.
So what about treating
the other symptoms?
Well, we're going to
treat the speech changes.
How are we going to do?
Well, we're going to send
patients to speech therapy
early and give them
the tools on how
to properly express themselves.
And you're also going to wait
for somebody with Huntington's
disease to finish.
I think our society is
always on fast pace,
but I think every once
in a while we can wait.
Also there's trouble swallowing.
So I think a lot of conservative
things can really, really help.
I like to tell patients meal
time is about meal time.
It is not about
chatting, it's not
about telling jokes or watching
TV-- it's about eating food.
And so what do we
do when we eat?
Small bites, put the
fork down, and take
a sip of water in-between.
And also using
swallowing precautions
that we can get from the
speech and swallow therapists,
and utilizing their
diagnostic tests
as well to tell us who's
having difficulty swallowing.
A way you can tell if somebody
is having difficulty swallowing
is by asking, do you cough
or choke when you swallow?
OK.
And also, again, this
issue of weight loss.
So as soon as I
see that somebody
may be losing weight it's time
for some high calorie shakes,
ice cream, pizza--
whatever it is you like.
And also sometimes
the medications
we use to treat chorea, again,
they make you gain weight.
So anybody who's
unfortunately had
to take an atypical antipsy--
or an antipsychotic medication
can sometimes suffer
from weight gain.
It's a very common side
effect of those medicines.
All right.
So let's move on to the
advanced stage disease
and what therapies
might be available.
So this is the stage
of disease I oftentime
think about withdrawal
of medications.
So a lot of those
medicines we've
been putting on for the extra
movements, it's time for us
to reduce those medicines
because they give
side effects of Parkinsonism.
We often-- I really like
the use of amantadine.
I think it's very helpful
in this stage of disease.
But there are other
antiparkinsonian meds
we can use as well.
You have to be careful
with these meds
because they are
dopamine promoting,
and therefore can lead to
behavioral issues as well.
So what are the
end-of-life issues?
Well, I think these things
should be addressed early.
I don't think that we
need to be afraid of them.
I think it should be
an ongoing conversation
that you have with your doctor.
I want to talk to patients
when they can talk to me.
When they can fully express
themselves and tell me what
their wishes are.
And then I want to readdress
it, because guess what?
As you go through the
course of disease,
or as your life circumstances
change, as with anybody,
your ideas about what you want
for end of life may change.
I also really, really
like this Aging
with Dignity Five Wishes packet.
It goes through several
concepts, which I
think are really, really nice.
And it is a really
nice way for somebody
to take a packet home
with them and discuss it
with their family members in a
calm, comfortable environment.
You know, it might
say things like,
if I can't care--
the time of my death,
I want my family to know
how much I love them.
It doesn't even have to cover
sometimes, oh I want the tube,
or I don't-- or I
want CPR, or I don't.
We can talk about just things
we want with our family.
I want to pass away
one day at home.
So things like this,
and then it also
addresses the important issues.
If I can't eat for
myself, do I want
to place a tube to eat for me?
If I can't breathe for myself
and I get an infection,
would I want a
tube placed for me?
Let's talk a little
bit about caregiving
in Huntington's disease.
I think this is an
incredibly important issue,
so it's worth at
least one slide.
And basically we
have to understand
that there are many emotional
and physical demands for taking
care of somebody with
Huntington's disease.
Eventually 24-hour
care is needed.
It can be a financial
stressor, right?
Because there's loss
of gainful employment
and full-time employment
for the patient,
as well as the caregiver.
So really not a fair situation,
and very, very stressful.
In 2012, we were able to
add Huntington's disease
to the compassionate
allowance listing.
And what this does
is it expedites
disability coverage for patients
with Huntington's disease.
Caregivers can also apply
for caregiver status,
and it does provide
some compensation.
Not a ton, but some compensation
is better than none.
So I like to really
be careful and watch
for caregiver burnout.
This can happen in any
neurologic disease.
Many neurodegenerative diseases,
people have caregiver burnout.
And I can always identify it,
because usually the caregiver
comes to the office and
starts yelling at me.
And so I say, OK.
They're stressed
out, and I think
they're leading to burnout.
And that's something we
really have to address.
So why is that so
important to address?
Well, we use our social
workers to help, absolutely.
And it's so important
to address because it
affects everybody in the house.
It affects the caregiver.
And if the caregiver
doesn't have
good health, who's going to
take care of the patient?
It affects the patient, because
actually caregiver burnout
is very serious and can lead
to abuse of the patient.
And also, not just physical
abuse, but emotional abuse.
And certainly nobody wants
to live in that situation.
So it's our duty to help
support the caregivers as well.
So I just wanted to thank you.
I wanted to put a little plug
in, this is my codirector
Dr. Sharon Sha.
You see my picture over there.
And this is our entire team.
We have an amazing nurse
coordinator, Victoria;
our genetic counselors; our
neuropsychiatrists, we're
very lucky in our
clinic to have that;
as well as our social
worker, who's indispensable.
There is a Palo Alto support
group that is held monthly
and it's-- I believe monthly--
and you can contact Andrea
[? Quann, ?] who could give you
more information about that.
I just wanted to
say one last thing.
Neurodegenerative
diseases are diseases that
are still not understood well.
Part of that is
because we can't simply
just take a piece of the brain
and say, what's going on here?
And so it's really vital
and extremely important
that people participate
in research,
and that scientists are
interested in answering
these questions
that are unanswered.
It doesn't just take people
who have Huntington's disease
to participate in
research, but we
need those normal controls
as well-- those people
to compare them to.
So if you have an
interest, we certainly
would really appreciate it.
And I know that it would
help further the field.
So that's the end
of my talk now.
I would love to open it up to
questions, if anybody has any.
Yes, please.
Yes, um, I'm here because
a friend of mine has
Huntington's.
And I was talking
to him-- actually,
just recently, I
saw him last month--
and he was talking
to me about there's
research being done
in Great Britain
about the genetic
manipulations and stuff.
Have you heard of that?
And, if you have, could
you comment on it?
So genetic manipulation, as
in, changing the genome itself?
[INAUDIBLE] genetic [INAUDIBLE]
that kind [INAUDIBLE].
They do it in Great Britain.
Yes, so absolutely.
In fact, there's quite a bit
of basic science research.
And what basic science
means is, sort of,
in the absence of the
human being themselves.
In fact, this can
be considered what
we call translational
research, because it's
usually taken from a
blood sample or swab
to obtain the DNA.
I think, as far as I
know, those studies
are still in fairly early
stages of development.
I think that would be a
wonderful treatment, if it
does come out to be something.
So we're hopeful.
Things like that,
stem cell treatments,
these are still in early stages.
Actually, stem cells are
a little bit more advanced
than that.
There's a study that's
just about to start,
I think the pilot study is
now closed for recruitment,
at UC Davis looking
at stem cell therapy.
Any other questions?
What would be a good place to
learn about stem cell therapy
and different opportunities
around the world?
Yeah, so that's
a great question.
Where I would start--
so the question was
where's a good place to look
to learn about stem cell
therapies?
I am a bit hesitant-- I'm a
little bit more conservative,
but I'm a bit hesitant about
going to other countries
to get therapies such as that.
I think, if there's interest
in that kind of therapy,
joining a clinical
trial-- for instance
at UC Davis with the
amazing Dr. Wheelock--
would be a great place to start.
This is going to
ensure that there's
a rigorous scientific
process behind it,
and I think most importantly
looking at safety.
And so we really
want to make sure
that we're not doing harm just
because we're desperate to look
for experimental therapies.
Does that make sense?
What are the main sources
of funding for research
in Huntington's?
So that's a great question.
One of the main
sources of funding
comes from the
Huntington study group.
There are some of these study
groups in the community,
especially for
neurologic diseases.
And this is a group
of scientists--
I'm part of that
group-- who want
to be able to explore
different therapies
and also understand the
basis of the disease itself.
So I'd say that's a very
primary source of funding.
There are other
sources of funding
that come directly from
the government as well.
And then there are usually
smaller pilot programs
that some collaborative
groups may support.
So, for instance, Dr.
Nancy Wexler she--
it's escaping my mind right now,
the name of her organization.
But she has an organization
on hereditary diseases,
and she does give small funding
opportunities for that as well.
Yes, please.
Could you clarify the time
frame of first manifestation?
Absolutely.
Yes--
And, part two-- do people
go all the way to the end?
Or can, through medication
and other therapies,
you curtail the development
of symptoms at, say,
early stage, as opposed to
progressing to advanced stage.
So that the holy-- so the
questions are twofold.
So one is, how long do
you have the disease?
Is that basically
what you're asking?
And two is are
there diseases that
can help to slow the progression
or curtain the disease so
that one doesn't progress
to advanced stage disease?
And, unfortunately,
that's the holy grail
of our research in many
neurodegenerative conditions.
We want to be able to identify
diseases early, and stop
their progression.
Unfortunately, you
can see challenges
when we don't even really know
what the normal protein does.
So, unfortunately, we
just don't have it.
And remember that slide,
maybe I can pull it up.
That slide that I showed
you-- let me go back.
Oh, it might take
a little while.
So these are all the things
that have been studied.
And this isn't even
a comprehensive list.
So this is absolutely the
holy grail in our research--
we really want to be able to
slow, at minimum, slow disease
progression down.
Now, how long do people
have the disease?
Around the time of
diagnosis-- remember
that diagnosis is often the
motor symptom starting--
but perhaps people have had
symptoms before this for years
before.
So at the start of
the motor symptoms,
generally when people
get a diagnosis,
it's about a 15 to 20
year course of disease.
So it is a chronic and
progressive disease.
Yes.
Other than suicide are there
risks associated with death
from the disease itself?
Yes.
Yes, absolutely.
So sorry I didn't
go back to that.
I meant to towards the
end of life slides.
So what we see is one of
the main causes of death
can be aspiration, meaning
swallowing food into the lungs.
And that's because of the
difficulty with swallowing.
And so eventually people
usually need feeding tubes,
if they choose to have them.
So I have patients who have
decided they absolutely
do not want that.
I respect that
decision [? 100%. ?]
And basically we have
a conversation-- I say,
right now there's quite a bit
of food going into your lungs.
And if it gets into your lungs.
You could have a very
serious infection
that we may have difficulty
fighting against.
And that's usually when I also
may have a conversation about,
again, is a breathing
tube something
you would want, knowing that
perhaps you couldn't get off
that breathing tube.
So these are very frank
conversations to have.
And I think patients generally
feel relieved that somebody
will talk to them
about these issues
and not keep it as a bottled
up secret and something
to be ashamed of.
I have many patients who
have very different opinions.
I have patients who say
I will leave the state,
and I will utilize
physician suicide.
I have patients who
say I want to fight
with everything I possibly can.
So it's a very personal and
individualized decision.
And I want it to be
what the patient wants.
Does that answer your question?
OK.
And did you have a question?
Yeah, real quick.
Regarding sleep--
Yes.
--is there anything you
recommend for the patient?
So with sleep, in general--
so neurodegenerative diseases
definitely cause sleep
issues-- and in general
you have to identify exactly
what the sleep problem is.
Are they having chorea that
keeps them up at night?
And then you need
to treat the chorea.
Is it insomnia?
Do they get to bed,
but wake up later?
Are they anxious and that's
what's keeping them up?
So I always think that
it's very, very important
to take a very
thorough history when
it comes to sleep difficulty.
Because you can throw a
bunch of sedative meds
at somebody, but if that's
not what the issue is they're
not going to sleep any better.
Does that make sense?
Does something like a
high dose of melatonin?
Oh!
So I'm a big fan of melatonin
if that's appropriate.
But, for instance, if it's
chorea keeping people up,
then we need to
treat the chorea.
If it's anxiety, then
I think maybe it's time
to treat that anxiety.
Does that make sense?
So the question was, sorry--
the question was with sleep
are there good treatments,
good medication, options.
And there are, but identifying
what the sleep disturbance is
is very important there.
Are there any other questions?
OK.
So I think that's it.
And thank you very much.
