November 17, 2019
Parkinson’s Disease: HSS

Parkinson’s Disease: HSS


In that case,
let’s switch gears, talk about Parkinson’s disease. The rest of the morning will be
spent on Parkinson’s disease, because that’s the most
common movement disorder. And basically, we’ll talk about
treatments and clinical trials and we’ll talk about
physical therapy, speech therapy for
Parkinson’s disease as well. So I’ll have some guest
speakers to join me. But first, let’s just
mention that this is the second most common
neurodegenerative disorder and it affects 1% of
people over the age of 60 in the United States. It results from depletion
of dopaminergic cells in substantia nigra,
that’s the area of the brain deep in the
brain, I’ll show it to you. And there are some
Lewy body inclusions. So not to be confused
as Lewy body disease. I want to make a
direct distinction. Lewy body disease is
not Parkinson’s disease. You can see Lewy body
in Parkinson’s disease, but only in specific
places of the brain, whereas in Lewy
body disease it’s a widespread distribution
of the Lewy bodies, everywhere in the brain. So, different disorders. And the prognosis is different,
treatment is different. So Lewy bodies can be
seen in certain cells of the brain in
Parkinson’s disease, but limited to certain
part of the brain. So characteristics. Dr. Kaplitt already mentioned
the stiffness, slowness, resting tremor– classic, but you
don’t have to have– 25% of patients with
Parkinson’s disease never have a tremor
in their life. So that doesn’t have to be. And there is a response
to Levodopa, also. Now that’s a picture
from the textbook, showing that you can have a
little bit of stooped posture, you can have reduced
arm swing, you can have a little bit of
shuffling going on, stiffness. You know, you might. You might not. So this is just kind
of a textbook picture with everything together. But this disease
is very diverse, so whatever happens
to one person doesn’t have to happen
to the other person. As Dr. Kaplitt mentioned,
no two similar patients in the world with
exactly the same thing. Other features can
include masked faces, decreased facial expression,
smaller handwriting, changes in blood pressure, and
depression, as Dr. Kaplitt also mentioned, can occur
in Parkinson’s disease. And in fact, there is a 2% risk
of developing depression per year for someone
who has Parkinson’s. Now, freezing and falls. So freezing can
occur as well, which is the when you have the
sensation that your feet get stuck to the floor. Falls can occur as well,
and physical therapy is very helpful. Medications do help for
stiffness, slowness, and a little bit of tremor. The medications don’t help for
the balance, unfortunately. So the non-motor
manifestations include– potentially, can include–
memory issues, not immediately, 20 years down the
road, you might notice some memory problems. It’s not Alzheimer’s
disease, you’ll never forget your relatives, it’s
just you might be a little bit confused. But it is not Alzheimer’s
disease, different type of memory problem. Constipation can occur. RBD stands for REM
sleep behavior disorder, kicking and screaming
at night, which can precede the motor onset of
Parkinson’s disease by years. So people might
notice that they’re kicking screaming at night,
and then 20 years down the road they might– they don’t have to– but they
might develop Parkinson’s. Drops in blood pressure as well. These are the existing
medications that we have now approved for these symptoms. So, for hallucinations,
psychosis, quetiapine, or the newer version
approved is called Nuplazid. For memory loss, it’s
rivastigmine, or Exelon patch, or donepezil. For orthostatic hypotension,
the new one is called Northera, or people can use
fludrocortisone and midodrine if you have drops
in blood pressure. For constipation, it’s
Miralax, and Linzess, recently was found to be very helpful. And for REM sleep behavior
disorder, clonazepam, that’s probably the only
one that helps greatly. Now let’s look at this slide. This is just to show you the
conventional, the old school treatment of
Parkinson’s disease. Motor symptoms, so L-Dopa
has been around since 1968, then dopamine agonists include
pramipexole and ropinerole. This is the actual
precursor of dopamine, it’s converted into
dopamine in the brain. This class is dopamine
agonists, they essentially mimic dopamine and stimulate
production of more dopamine in the brain. Selegiline, rasagiline, it’s
an MAO-B inhibitor– monoamide oxidase-B inhibitors–
they prevent degeneration or degradation of the dopamine,
both your own dopamine, and from the medications, so
the dopamine stays around longer and works stronger. Entacapone and Tolcapone,
these are COMT inhibitors. So they also do similar
things that MAO-B inhibitors do, they prolong the action
of carbidopa and levodopa. And Trihexyphenidyl,
very old medication, could be used for tremor
in Parkinson’s disease. In fact, it works for tremor
better than anything else, but it has those
limiting side effects. So namely, you can
have memory problems, you’re going to
have constipation, you can have dry mouth
as a side effect. So in older people, meaning
anybody over age of 50, I wouldn’t use that medication. Amantadine is a
dirty drug, it has a lot of mechanism of action. It was approved for Parkinson’s
disease, used for tremor, occasionally for any symptoms. But we don’t use
it now for anything except for involuntary body
movements, called dyskinesias. So for these it is helpful. Now before we talk about
new medications that are newly approved, and the
ones in clinical trials, I just want to mention
something about wearing offs. So wearing offs is
after a few years, levodopa stops lasting forever. Meaning the duration
of action shortens. So it only lasts for, let’s
say, four hours, or five hours, and then four hours,
and then three hours. So that’s considered
wearing off. So what we traditionally
have been doing, I mean, you can ask someone to
take levodopa more frequently, or you can switch to longer
acting version of levodopa, such as the newly approved
medication called Rytary. You could add any of
those previously mentioned classes, dopamine agonists,
and the inhibitors of the degradation
of the dopamine. That will increase
duration of the action. Increasing each individual
dose of levodopa is not going to
make it last longer. It will just be
stronger when it works, but it’s not going
to last longer. So it’s not the way to do it. Polypharmacy is
used in treatment of Parkinson’s disease. What do I mean by that? So instead of pushing that
those through the roof, I would rather use a little bit
of that, a little bit of that, a little bit of that, or
even a little bit of that. So the reason why, is because
you will get less side effects, because I’m using just a small
dose, but different classes of medication to attack the
disease from different angles. You know what I mean? So polypharmacy is
considered to be a good standard of
care in treatment of Parkinson’s disease. Also, if I don’t use very
high doses of levodopa, I will prevent these nasty
things called dyskinesia. Dyskinesia is involuntary
body movements. You might have seen
Michael J Fox on TV, he’s doing this business,
and that because he’s been taking levodopa
for 20 years and that’s the result, that’s a
side effect of the medication. So I received through
email a question about when does it develop? What do we do about it? And does the dose matter? Yes, yes, and yes. After five to seven years of
someone being on levodopa, dyskinesia is usually developed. So it showed that
after five years, 50% of patients taking
levodopa develop some degree of dyskinesia. At 10 years, it’s like 80%. But these are all averages. So there are some patient
related risk factors, such as younger women. Younger women tend to develop
more dyskinesias than men. The older you are,
the less likely you are to develop
involuntary body movements. So that’s all averages. So someone who is 80, is
unlikely to develop dyskinesia as much as if they were 50. So that’s why Michael J
Fox has so much of it, because he was 30 when
he developed the disease. And the higher the
dose of levodopa, the more likelihood of
developing dyskinesia. The study showed that beyond
400, actually, not 300, but 400 milligrams
daily, that results in exponential increase in the
risk of developing dyskinesias. And management, Amantadine,
that’s a traditional, but now we have a new version,
long acting Amantadine, Gocovri and Osmolex ER. I’ll mention about them
a little bit later. Other treatments for
dyskinesias and other things could be medicinal marijuana. So medicinal marijuana is
being studied for Parkinson’s disease, and the data is mixed. So there are two studies. One of them showed
some improvement in tremor, anxiety, sleep, and
REM sleep behavioral disorder, meaning kicking and
screaming at night. The other studies
showed that there is a possible improvement
in slowness, stiffness, and involuntary movements. In my experience,
my patients who have been taking medicinal
marijuana, their anxiety, sleep, and dyskinesias
get better. The stiffness and
slowness, I’m yet to see improvement
in those two domains. But some data shows
that it does improve. I do not prescribe
medicinal marijuana, so you need to see
a pain management doctor who can do it. There are two ways. You can either take
just CBD oil, that can be helpful for sleep, and it
doesn’t have that THC component that gives you a high. So that for sleep
it’s good enough. If you want to improve your
tremor and involuntary body movements, you have to have
a little bit of that THC component in your
mixture of CBD. And the pain management doctors
usually do prescribe that. I can give you names of
those who do prescribe, if you want to give it a try. Now, let’s talk about the
newly approved treatments. So Rytary, so that’s a
long acting levodopa that was approved, and
some people like it, some people don’t like it. So you still take it
three times a day, but instead of taking
it seven times a day, you might be able to
take it five times a day. Or instead of five times
a day taking levodopa, you might take Rytary
only three times a day. Now it’s the same
medication as levodopa, just formulated in a way
that it lasts longer. Inbrija, that’s a newly
approved medication. It’s inhaled levodopa, used
for not freezing episodes, but off episodes. So it’s not available
in pharmacies yet, but they’re taking
prescriptions already. Next month, in March,
it will be available. So if you suddenly notice
a medication stops working, and you need a rescue
dose, conventionally, we ask people to take additional
dose of levodopa and chew it. And that does help, but
takes maybe 45 minutes to an hour to kick in. This one shows
that in 30 minutes, you have significant
improvement. You also have improvement as
early as 10 and 20 minutes, but 10 and 20 minutes
were not statistically significant from placebo. So the 30 minute improvement
was statistically significant from placebo. That’s the data. But it is approved now, so
I can start prescribing it, if you want to give it a try. Xadago, some of
you are on it, it’s a newly approved
MAO-B inhibitor. The older version was
Selegiline and Rasagiline. There is no head-to-head
data comparing the two, I cannot tell you is that Xadago
is better than the generics. All I can tell you is that’s
its a once a day treatment, doesn’t have any
dietary restrictions, and it can be taken together
with anti-depressants, as opposed to Selegiline, where
pharmacists always flags that and call me, oh, patient
is taking anti-depressants and you’re giving them
Selegiline, how can you? It’s OK as far as I’m concerned,
but officially it’s a red flag. Gocovri, it’s a long
acting Amantadine, and so is Osmolex ER, these
are competing two drugs. Once a day, instead
of three times a day– regular Amantadine is
taken three times a day– that’s just once
a day formulation. Northera is used for
drops in blood pressure. It’s also a newly
approved medication, and that prevents drops in
blood pressure, apparently. Can be combined load with
fludrocortisone, but not with midordrine. Nuplazid was approved
two years ago, it is an antipsychotic
approved for treatment of the hallucinations
in Parkinson’s disease. Starts working at week six,
so basically for six weeks it’s just kicking in and people
having continuous symptoms, so that’s a limitation
of that drug. There is also a patch
called Neupro, that’s the dopamine agonist patch. I didn’t mention it here
because it’s not new. Even though it’s a brand name,
it’s been around for years, and some of you are on it. But it’s not that new– new,
I mean in the last two years or so. So we’ll talk about that. You can ask me questions about
that, for the sake of time, I just want to mention a
couple of words about DBS. So he already mentioned to you,
Dr. Kaplitt what it entails is basically they put one or two
electrodes in the deep portion in the brain connected
to the battery. And this is what
the battery looks like, it’s embedded in under
the skin like a pacemaker. That’s from Medtronic but
the similar looking battery can be obtained from St. Jude’s,
as someone asked earlier. And that’s what I wanted
to concentrate on, because Dr. Kaplitt
I don’t know if he had time to explain it to you. So you have to have
a clear diagnosis of Parkinson’s disease. So if you have
atypical Parkinson’s, such as multiple system atrophy,
or progressive supranuclear palsy, these are
rare, very rare. You would not get better
from that surgery. So it has to be just a
regular Parkinson’s disease, with or without tremor, and
I’ll be able to tell you that. Now you should demonstrate good
improvement of your symptoms with levodopa, because
that would prognosticate your improvement with DBS. Improvement, not
necessarily in tremor, but stiffness and slowness. If it gets better, than DBS
is a good thing for you, potentially. You might have problems, such
as motor fluctuations, disabling tremor, intolerance
to medication– some patients just
get nauseous and they can’t take levodopa at all. They do get better from it,
they just can’t tolerate it. So that’s what the
deep brain stimulation would be helpful for. So to continue on the good
candidates, stable cognition. So if someone has dementia,
or cognitive impairment, and we do DBS, the dementia
will get much worse. So for your own sake,
you don’t want to get DBS if you have cognitive issues. And we screen everybody
through neuropsychological testing before we
do this surgery, so that would not be missed,
but you should be aware of that. Now realistic expectations
and good family support is very important. I had one patient who had DBS
done and she perceived it– I don’t know if she was misled– she thought it was a cure
for Parkinson’s disease. She thought she
that she didn’t need to take any medications after
that, and it’s not true. So it did help her symptoms,
but after a few years, she needed to take a
little bit of medication, so she was devastated, it’s
not a cure, no it’s not. This is just surgical treatment
for Parkinson’s disease, but it’s not a cure. So you still will have
to be on medication. I think 50% reduction is
a little bit optimistic, I’m going to tell you it’s 25%
reduction in your existing dose depending on the
site of the brain. Some sites, such
as globus pallidus, you wouldn’t reduce
your medications at all. You will still have to be on
the same dose of medications. So, no co-morbid psychiatric
behavioral problems. So this is not really true. Before, back in the day, we
used that criteria to make sure you don’t have
atypical Parkinson’s that progresses much faster,
so that was to rule that out. We no longer observe
that five year rule. So, the window of opportunity. Question meaning, when is a
good time to have that DBS? Early on? Later on? Do you wait and
see what happens? So there is a window
of opportunity. Clearly, if your pinky is
just shaking and that’s it, you don’t need to run to
have the surgery done. If your medication is
controlling your symptoms fine, you don’t need to
have the surgery done. But if someone is
not able to walk, and their balance is so bad– DBS by the way, does not
help for the balance, and neither do the medications– and they don’t
have tremor, what’s the purpose of doing DBS? They can just as well
take the medications. So you want to do
it when you start noticing symptoms that
medications don’t help you adequately with. And if you have
wearing offs, DBS can give you up to four
hours of good time per day. So it will reduce
dyskinesia, it can be used to reduce dyskinesia,
and will reduce wearing offs. And it works beautifully
for the tremor. So there’s just one
video I want to show you. So someone is
turning off the DBS, and that gentleman has
Parkinson’s disease. So you see, stimulation is
off, and the tremor starts. That’s a resting tremor. It’s rare, not many people have
that bad of a tremor at rest, but some people do. Now the stimulation will
be turned back on again, and then you see gradually
the tremor subsides. Yeah. So, the other picture is this. It’s also similar, just
a different patient. They gave their consent
to be videotaped, and that’s part of the Movement
Disorder Society video library. So these are not my patients. Sorry. Appropriate candidates for
thalamic stimulation have disabling tremor from essential
tremor or Parkinson’s disease, which cannot be controlled
with medication. All types of tremor
can be treated with the thalamic
stimulation, including rest tremor, postural
tremor, and action tremor. OK. Expectations, I already
mentioned that these are all the symptoms. And by the way,
this presentation will be available online. This will be video
recorded and I’m going fast through the slides,
because we’re limited on time, but you can watch that later
and you’ll see all the slides. You can get improvement
in all these symptoms that are listed here,
including wearing off, stiffness, slowness,
some dystonic symptoms of Parkinson’s tremor as well. And the expectations
should be realistic. You’re not going to get
improvement in the following symptoms. Speech, balance, memory. So these three things
will not get better as a result of the DBS,
make no mistake about it. And autonomic system
symptoms, such as drops in blood pressure, also
would not get better. Now, maintenance
of DBS, we’re going to skip that, because
he already mentioned the battery lasts four years. Or you can do rechargeable
and you have to charge it, not every day, I think
once or twice a week. Now, complications. Hemorrhage. We talked about bleeding. 2%, not 1. 2% overall risk or
bleeding in the brain. Some of that could
be incidental, they just take a picture
after the surgery, they see a little bit of
blood, nobody knows about it, meaning it doesn’t
affect the patient. Or it could be bad,
as he mentioned, it’s very rare that it
causes weakness and so forth. Infection, he mentioned
about like 5%. I personally never saw
it, he had one incident. Device-related, if let’s
say, you have a trauma and you get in a car
accident, this wire that goes from the brain
under the skin to the chest can be broken. It would have to be replaced. And, so, that’s it. And we’ll talk more if you want,
I have a question and answer session about that. Then MRI guided ultrasound,
he already mentioned. Just one word
about that is this. The ultrasound is the
destruction of the brain. Deep brain stimulation
is the stimulation of the brain, which
can be adjusted. So what’s done is done. If you have ultrasound, you
burn that area of the brain, you cannot go back,
you cannot increase it, you cannot decrease it, it
doesn’t cure the disease. It helps for the
symptoms for some time, let’s say four years. In four years, what do you do
when the symptoms come back? There is nothing else to burn. So if you’re younger and
you’re having symptoms, DBS would be the way to go
as opposed to the ultrasound, because with DBS, I can
always adjust the stimulation. Like I’m increasing your
doses of medications, I will increase the
parameters of this stimulation to match the symptoms. If someone is 90, they
have disabling tremor, they cannot go
through this surgery, it might be too much for them. So the ultrasound might
be a better way to deal with that, because they
go home right away, there is no incision,
no risk of infection. And you know, it definitely
would help them for five years. So as far as the
bleeding in the brain, the risks of
bleeding in the brain are identical in
both procedures. Even though in ultrasound,
they don’t cut your skin, even, because the beam of
the ultrasound burning the area of the brain
can, on its way, burn some blood vessels
and cause bleeding. Very rare, again like less than
2%, but it’s similar to DBS. OK, so I think for
questions we’ll combine after I
have my colleague. Promising clinical trials. So I think we have to talk
about that a little bit. We’ll have to cut
out something else, but I just want to go
through a couple of things before we take a break. So a couple of things to mention
are symptomatic therapies. So these are, again
the chosen trials that I chose for you because
you need to be aware of that. Instead of DBS, there is
a possible alternative. You can have a subcutaneous
infusion of levodopa. So what it entails is that
you have a little pump here on your belt, and it’s like
an insulin-like catheter, and the little needle
goes under the skin, and it continuously
secretes levodopa, and that results in
reduction in fluctuations. So right now, they
completed phase two trial– no, there’s at least two
ongoing, but they’re finishing, they’re not recruiting anymore. So watch out for phase three. When phase three is out
there, I would enroll. This is promising, because
unlike the Duodopa, which is approved, I wouldn’t
use that, because they put, actually, like a feeding
tube almost, in your stomach and infuse through that. The tube comes out,
it leaks, it’s messy. This one, if the
needle comes out, you just take it
and put it back in. It’s under the skin,
it’s very simple, as opposed to the tube– you
have to see gastroenterologist, go to emergency room,
have it installed again– this is much easier. So we will have phase three
starting pretty soon, I hope. The phase two is finishing up. So that could be
alternative, or, in patients who are really bothered, it
could be used in addition to DBS, potentially. OK, the other things. New Rytary is coming out, so
they are doing clinical trials. Phase three is on the
way for New Rytary, they will take it like
once or twice a day. Then there is a sublingual
Apomorphine that was being developed, it’s like
dopamine agonist– you put it under the
tongue and it melts– to unfreeze you, but it was put
on hold by the FDA months ago. So there will be a
delay in approving it. Neurocrine is coming out,
with the new COMT inhibitor. You might have heard of
Entacapone, some of you are taking it, so
they are developing Opicapone, which will make
levodopa last even longer. So that Phase three is
finishing, so it probably would be approved
either late this year or beginning of next year. Gene therapy, just to mention
a little bit about it, this is not for
cure of the disease. This is just to
prevent wearing offs. So what they do,
they do a surgery where they drill a
hole in the head, they put a little catheter
in there, and, sorry– the syringe, and
they inject that gene in the deep portion
of the brain. And that’s designed to
improve wearing offs and motor fluctuations in
Parkinson’s disease. So Voyager Therapeutic is
conducting these gene therapy trials. So, recruiting. But again, this is
not a cure for that, this is just to make
levodopa last longer. You still have to take levodopa. Non-motor trials are important. So Eli Lilly, they’re
recruiting for trials of Parkinson’s disease who
have dementia-like symptoms. So that’s the component, that
is the name of the drug they’re studying, it’s a Phase
two 12-week study they are recruiting. The Linzess, this study
was retrospective. They just looked
at the patients who were taking Linzess
comparing to just Miralax, and that’s Motegrity, another
constipation medication, and was found to be
superior than Miralax alone. So that is approved already,
and these two medications can be added today,
they’re out there. But they looked
retrospectively on patients with Parkinson’s disease,
there was no placebo because it was retrospective
study, naturally.

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