Hi everyone and welcome to the Davis Phinney
Foundation's Parkinson's OFF seminar: What is it and how to manage it. My name is
Dr. Lauren Costantini and I'm a member of the Scientific Advisory Board at the Davis Phinney
Foundation and I'm really looking forward to this conversation because we're going to talk
about an issue that is relevant for nearly everyone living with Parkinson's and that's OFF
times. So welcome Dr. Torres-Yaghi and thank you for agreeing to be our guest today.
My pleasure thank you for having me.
Just to tell you all in the audience about Dr.
Torres-Yaghi, he's a movement disorder specialist, an assistant professor in the department
of neurology at Georgetown University and co-director of the Lewy body dementia
clinic spearheading an initiative to care for a growing population of aging
patients with neurodegenerative conditions. He has a broad background in clinical research
with specific training and expertise in Lewy body dementia and atypical parkinsonism
and has been an integral member of numerous clinical trials. So let's get to it. So
first question, is what exactly is OFF and what are the different types of OFF?
This
is an amazing first question. So off is something that first of all you need to be on the same
page with your patient about. I still remember 34 years including preschool is how long it
takes to become a movement disorder specialist and I was in my 33rd year doing my first year
of my fellowship which is, you become an MD, then you do your neurology residency,
then you do a two-year fellowship if you want to do clinical research and in movement
disorders. I still remember my first patient, what off meant to me was different than what my
patient would off meant to my patient. Actually off to my patient meant that the Parkinson's
was off. So my patient was explaining to me, he said, I'm off at these times of the day and I
said well you know we have to fix that because he sounded happy he said I'm off all the time it's
just amazing and I said okay well that's great and so I left the room and I said oh well you know
my patient's doing you know very happy but but he's off all day and I so I came back in the room
I said wait hold on a second so when you set off you mean Parkinson's off right for a movement
disorder specialist when we think off we think a return of Parkinson s symptoms right so that
means that your medication has worn off or it hasn't really kicked in yet and people feel that
their Parkinson's symptoms are back in action, their tremor, rigidity, stiffness, slowness and
movement, is all present and that can come in all shapes and forms and they can enter our lives
differently from moment to moment. It's not always the same, not all OFF episodes are equal and so
you can have it in the morning.
For example, morning OFF means I wake up in the morning and
it takes me a long time to get ready. What that means to me is that it's been many hours since
your previous dose of carbidopa levodopa, right, so maybe you took your last dose at 8 pm and
hopefully you wake up at 6 am or maybe even later, if you don't have a three-year-old like me and you
wake up later and you say, you know I've taken my medicine and maybe it you know it takes a little
bit of time before it kicks in. That's a morning OFF. Now wearing off just in general means you've
taken your medicine it's kicked in, it's working, maybe it works for three four hours, maybe your
next dose is due five or six hours after your previous dose was given and you have about a
one or two hour period of time where you feel those symptoms re-emerge. That can happen just
after your dose is given three to four hours for example. It can happen precipitated by actually
eating. So if you eat a high protein meal like let s say at lunchtime, you're doing the right thing
you're eating you know some some protein which is good for your body but it reduces the absorption
and the effectiveness of the carbidopa levodopa, so that can happen.
The other piece here
that's really important is understanding that OFF also includes the time it takes after you
take your medicine. So that medicine kicks in, sometimes that can be on average sometimes 60
minutes. So people might say you know doctor I take my carbidopa levodopa and I feel worse
for about an hour right after I take it and I say well I don't we have to investigate but
it's possible that what you're experiencing is that time it takes before that carbidopa
levodopa takes effect. That counts as OFF time. One more, because look you know 30, 40 years
including preschool, we have to identify these OFFs because how you communicate with your team
is very important. The healthcare team that takes care of you, let's not forget, nighttime. Let's
not forget 2, 3, or 4 am in the morning. Our patients might wake up and feel restless, it might
be hard to turn in bed, maybe their Parkinson's symptoms are bad, maybe their Parkinson's symptoms
wake them up but then they have to urinate. That could be an OFF episode, right. So sleep
fragmentation in the middle of the night is also something that we always need to screen for to
make sure that we're not missing that aspect of OFF. That can happen at any moment throughout the
day.
And it sounds like these different types of off can happen within one individual at any time,
is that right?
Very good question and I think it can happen differently it can be predictable or it
can be unpredictable and then another feature can be tolerance right? They can be tolerable OFFs and
sometimes intolerable OFFs and so that's a very very important question. Every time in the back of
my mind when I was being trained to really analyze OFF as a as a movement disorder specialist with
sub-specialized training thinking about the more modern advanced therapeutics we always
need to figure out first of all, is this happening predictably? Can a patient tell me,
you know it's really happening every three hours after taking my previous dose? That's a pattern,
right? If there's a pattern that's helpful for us to know. Or like we said eating, if you eat and
and you feel like you wear OFF of your medicines more easily that's also an important pattern
and then that morning OFF that can be a pattern, right? And there's different ways to analyze
how to treat those different OFFs.
Interesting. So what types of symptoms might a
patient experience when they are OFF besides the ones that you had just described?
You know
that's a really good kind of neuroscientist question because you got it, the brain is
complicated, as Dr. Costantini knows. The brain is not, it's not a straightforward
organ. Unfortunately for all of us, right? You know, it's a very important organ but it
controls a lot of aspects of our body, right? It controls our neurologic state right?
Our neurologic state's very important, our brain capacity, our memory, our cognition,
our alertness, right? It also controls our ability to move right? There are certain centers of the
brain like our Parkinson's circuitry that can be affected, we might see tremors, rigidity, slowness
of movement, gait impairment, falling, those are the motor symptoms that might happen. But also
the brain can control our psychology, right, anxiety, depression, right? This is an
organ that it can affect our behavior, our neurologic state, our movements, and so it's
very different, it's unique in that in comparison to the other organs of the body. Also there's
a nervous system throughout our body, right?
Our nervous system controls our other organs
so it really is a multiple system type of condition especially OFF episodes because it's
those non-motor symptoms, not the motor symptoms, those non-motor symptoms that also can be hard
to detect and those are the things that we talk about, things that are very under detected
based on research are things like pain, right? Pain can be a symptom of wearing OFF
and that's something very very important to detect. Brain fog. Some patients might feel like
I'm just cognitively slowing down, it's like my cognitive agility isn't at its full capacity. As a
Parkinson's specialist that also handles cognitive patients with cognitive impairment, I see that a
lot that I need to be able to distinguish between true cognitive impairment or a cognitive effect
from a wearing OFF episode if it can happen episodically, panic, anxiety, depression, all of
these things can be part of wearing OFF. Sweating can be part of wearing OFF. So all of these things
we have to combine them together to understand hey is it just one a la carte thing that's
happening? Some patients might experience just a little bit of anxiety. That could be a
symptom of wearing OFF and sometimes those non-motor symptoms do not necessarily happen in
combination with the motor symptoms and sometimes they happen solely motor symptoms that occur and
sometimes it's a combination. So this is a very intricate conversation, I'm so happy that we're
having it.
It sounds more complex than we had originally thought. So you had mentioned earlier
L-dopa, does this have to do, do OFF episodes have to do with the types of medication you take and
your medication schedule or both? Obviously, a lot of patients are taking more than just one type of
Parkinson's medication, does that play a role?
Yes, and you got it, you're just nailing it with
the questions, because it's carbidopa levodopa you know we think of carbidopa levodopa as
our dopamine repleter right? When I teach, I m an academic neurologist that's why I'm
stuck in the river, the Potomac River here, with Georgetown behind me, but when we teach
our medical students, residents, our fellows our goal really is to teach them
about what it is that we're doing, our role as a physician is to identify a
problem and think about the therapeutic solution to that problem. So wearing OFF
occurs traditionally when we think about it in between our doses of carbidopa levodopa right?
It can either happen like we said in the morning, in the evening, in between, due to diet, etc,
and so when we think about it, it's traditionally thought of you know as a function of the medicine
either not being absorbed as adequately as it could in patients maybe with constipation or
because of diet or it's wearing off early, the effect as it's in your system wears off too
early, but the way we practice as you mentioned is to combine therapies right so we think of
carbidopa levodopa and we give that multiple times a day, but there's a lot of reasoning behind
adjunctive and combination therapy.
We call that rational polypharmacy. Not irrational
polypharmacy, that's not what we want right? We don't want our patients on a million medicines
you know although that sometimes happens, we have our patients on so many meds but the idea is, how
is it that we really kind of combine and create a cocktail approach? We use adjunctive medications,
and those families of medicines can be monoamine oxidase inhibitors, dopamine agonists, and there's
different medications within each category. You can think about other formulations of
carbidopa levodopa, extended-release formulations, to help potentially extend the duration. You can
think about COMT inhibitors, which are medications that might prolong the duration of effect of
carbidopa levodopa, and now we have multiple other avenues right? We think about the medications that
are derivatives of amantadine, which can help with wearing OFF and dyskinesias and then we have
other medications like A2A receptor antagonist, those are adenosine 2A receptors antagonist,
that's another family of medication, those are the medicines that we combine together.
And now we have as needed therapies right? We have medicines that can be given as needed for patients
that need an on-demand or an as needed way of rescuing them from an OFF, to get them from an OFF
state to an ON state so that they feel better.
Excellent, fantastic. So I'm a big fan of
nutrition and hoping to change the body through what we eat. As you know, things that
we put in our mouth every day play a role in our physiology as well as our disease state, so are
there any nutritional choices, like hydration that can play a role in OFF times and improve or
even cause a problem and increase OFF?
Great. Yeah you know I think it's a very important topic,
you know, thinking about the condition that we all deal with in our world, our dopamine deficiency
condition, thinking about it holistically and not just you know, I'm talking a lot from an
MD allopathic lens talking about modern therapies, therapeutics, but there's so much more to life
than medication right? Sometimes it doesn't feel like it because we have all these you
know wonderful medications at our disposal, but it has a lot to do with lifestyle and diet and
exercise and so these non-pharmacologic measures can make a difference in our life. Exercise
is important, diet is important, sleeping is important, hydration is important, you know
especially in patients with Parkinson's disease we might actually feel low blood pressure.
So low blood pressure actually can be part of Parkinson's not necessarily part of OFF,
but you can see blood pressure changes, this volatility of blood pressure, especially
with OFF episodes we might actually see sometimes the blood pressure come up and so it's
important to manage all aspects of our body. Hydrating is important in terms of recommendations
we try our best to adequately hydrate. We usually say it's kind of that old adage, you know, eight
ounces of, eight glasses that are eight ounces of water in a day right that's 64 ounces,
a little bit more than half a gallon. And then our patients say but wait but then
I have to urinate a lot and I say I know, that's the drawback, right?
We do unfortunately
have pluses and minuses to everything. The other thing we say is that diet is very important,
you know diet actually can dictate how we sleep, the better we sleep the more deeply we
sleep, the better our days are going to be, but we usually say for a good brain healthy
diet we consider the Mediterranean diet right, so the Mediterranean diet is something that
is usually high in vegetables, it's a very colorful plate right, maybe half of your plate has
color, might be fruits, vegetables, whole grains. You actually have a lower carbohydrate amount as
part of that diet, and you do in fact have things like fats and and protein as part of that diet
but then that leads us to the second part of Dr. Costantini's question is are there any drawbacks?
And I mentioned that we alluded to it earlier but protein can unfortunately reduce the absorption of
carbidopa levodopa and I don't want to overdo it because I don't want people, because what ends up
happening is, when you're on a medicine multiple times a day like a carbidopa levodopa pill or in
any formulation oftentimes we're on it multiple times a day and patients might say but when do I
eat? You know how am I supposed to eat when I'm eating, and I'm supposed to space my medicine
away from food, so that's a very individual conversation and so it's important to know but I
don't want it to alter our way of thinking.
And then one last point on diet. Constipation is one
of the non-motor symptoms of Parkinson's disease and so imagine, we have our upper GI tract and our
lower GI tract. Constipation is something that we suffer from but also esophageal dysmotility,
sometimes it's hard to bring food down, our stomach does not always empty into the small
intestine and so that kind of dysregulation makes it even harder for us sometimes to rely on the
pills that we take orally, so that they take us into an ON state from an OFF state and that's part
of the problem of wearing OFF and so that s one of my first questions, whenever a patient calls us
and says you know it feels like my my carbidopa levodopa isn't working as well as it used to
or our medications to help us with movements, they're not working as well as they used to, the
past three days has been really rough.
You know the first question I'll ask, the first question I
ll ask is, are you constipated? And patients will say, wait hold on a second, and they'll think,
and some will say no and I'll say wait, what do you mean you're not constipated? They'll say well
I had a bowel movement today and then I go even deeper I say wait, is it a, was it a full, did
you fully evacuate? If you didn't fully evacuate, if you're straining, if it's hard to go and you're
noticing even if you're going that still is sub optimal bowel movements, so our goal really
is, it's a multimodal approach. If we can have you eating properly, hydrating properly, that's
where hydration is a major piece right? If you're hydrated, your colon is going to move that stool
down. Hydration is important for bowel movements, exercise is important for bowel movements,
so all of these things come together.
Excellent, perfect. That was another question
is what about OFF episodes and exercise? Sounds like that just exercising is going to help some
of these other problems like constipation but could they have a direct effect with OFF episodes,
exercise in general?
Wonderful, wonderful question because it's a, that is a tough one
you're right, you know making that connection is a tough one and it's a very higher-level question
because you got it, so exercise is very important, and we kind of talked about the reasons why
exercise is important for your GI system. Exercise is also important to help increase endorphins.
Endorphins are good for your muscles, good for your brain, it's good for your alertness, it's
also, when you exercise based on animal models and based on what we know, if you see and if you study
the chemicals that are elevated there's something called a neuronal growth factor that is increased
with exercise. That's very very important for your overall functional state and it might be really
good that neuronal growth factor might be very good at maintaining the health of your nerves and
your brain. And then the third part about exercise that's important is that there's a concept called
neuroplasticity, kind of retraining the circuitry of your brain, right? We have different circuits
that lead to movement. In Parkinson's disease we have our basal ganglia circuitry that might be
affected but there's different circuits that help us move and so you can kind of strengthen the
other circuits and the circuits that are affected in Parkinson's disease so that we can walk and
move and be more functional and in a more smooth fashion. So the more we exercise, the better we're
going to feel and that may have a positive effect on the amount of OFF time that we have.
One last
point on that is it's not uncommon for patients of ours to do what they're supposed to do, they're
all they're trying their hardest, they're trying to feel better, they're trying to exercise,
they're trying to go to their physical therapy, we know how important physical therapy is, and an
OFF episode stops them from being able to do that. So it goes both ways. We need to tackle OFF in
order to exercise and we need to exercise in order to kind of beat OFF and so both of those
things are very important that that piece of if OFF impairs our ability to exercise or OFF
impairs our ability to go for our physical therapy session, that's an important point and we have
to be able to have maybe an on-demand strategy in case that were to happen in an unpredictable
fashion because I don't want my patient to miss their physical therapy appointment. I want
them to be able to feel better if they if they're in an OFF state maybe we can get them
back in and ON state so they can exercise.
Yep, mind body connection, it's important. So
one question here from a patient is are there safe ways to extend the life of your carbidopa
levodopa so you have less OFF time? Sounds like the goldmine question there.
Yeah, you know and
that is a debated question. Yeah, it's a gold mine question so you know it's a tough question because
there's different ways of looking at this because it's a very much, it's very much an individual
conversation and it's a personal one in many ways to everybody, but the way I kind of describe it is
we want people to feel as functional as possible. And so as we mentioned, we don't want our patients
not to be able to move, not to be able to walk, we want them to be at their optimal capacity, so
that they can exercise, so that they can walk, so that they do maintain functionality over time
and how we do that is to try and maintain what we call dopaminergic tone. We want that tone to be as
steady as possible given our oral medications so that our patients can feel that stability and so
it's very much I believe, it's very much dependent on each person, but we don't want also, we don't
want to overdo our dopaminergic tone, right? There is a therapeutic window that, our goal is
to stay within that therapeutic window so we don't supersede that threshold into dyskinesia and
then so that we don't undershoot so our patients are experiencing multiple hours of OFF time in a
day and that's where that multimodal approach to therapy comes in. There are ways to extend our ON
time you know with therapies, exercise, lifestyle modifications, that can, all of those things
can help kind of extend that duration of effect throughout the day, but the overall longevity
of that effectiveness from our medication is very much dictated by the way the condition
progresses.
So if the condition progresses, that's the true function you know when you think
about the the function of of the cause I think the idea that medication may not last in terms of
longevity, in terms of effectiveness, over many many years is very much based on how the condition
itself is progressing.
That is the, you led me right into our next question on the list here. Do
OFF times increase when Parkinson's progresses, is this a function of the progression of the
disease? Or because the medications are no longer treating symptoms as effectively?
Yeah, great
and I, you know, there's a lot of ways of looking at this and there's data out there you know about
the utility of using dopamine sparing medications versus just using dopamine or levodopa, dopamine
sparing strategies. Now more recently there's been a lot of scientific and clinical discussion
about kind of this continuous dopamine type of therapeutic strategy, kind of keeping everything
as continuous as possible and so there's different ways of thinking about it, but what we do know
is that over time as the condition progresses, we know that the overall amount of medication that
is needed can increase in order to provide benefit and we're seeing more and more OFF
time as the condition progresses and so anywhere between five to 13 years after
either disease onset or the time that we start our medications right there's different start points
that have been studied, but ever since because when we think about the progression of the
condition, because it is a progressive disorder, we have to think about the more and more need to
address OFF as the disease progresses over years usually 5 to 13 years after, we might see more
and more OFF time start to develop and and another way of kind of categorizing OFF time is actually
talking about it just as return of symptoms right, peeling off that extra layer, just saying return
of symptoms in between doses does tend to progress become more pronounced and the duration of
those time periods does tend to get worse.
Yeah, so what are the most effective ways to treat
OFF currently? Pharmacological, you mentioned a couple I think people want to hear a little
more specifically about some of those on demand, and are there any non-pharmacological
or even surgical ways to treat OFF?
Yeah, you got it. So this is the joke is the 34
years including preschool, this is why you know neurology has become so sub-specialized right?
Clinical neurology has become so sub-specialized that a movement disorder specialist can be very
helpful in analyzing these sorts of scenarios, similarly an MS specialist for multiple sclerosis
would be much better suited to be able to handle a 2021 case of multiple sclerosis because
of the advancements in therapeutics both in movement disorders and multiple sclerosis
and so this advancement in therapeutics has kind of paved the way for the need for more
sub specialization within neurology. So the positive about all of this is that, hey, look
at all these medicines that I mentioned right? Dr. Costantini was like wait I just asked one
quick question and you're talking too much with all these things, but you got it there's so many
families of medications and now there's different categories right you said we want to hear more
about those on-demand therapies, hey, look, just since 2017 you know there's been this development
of on-demand therapeutics.
So let's start there, right, so on-demand therapeutics so traditionally
what we may have done back in the 1970s and 1980s is, hey, take an extra dose of
carbidopa levodopa. Hey that's a way of thinking about treating an OFF episode, right? In between
your doses if you're having an OFF episode maybe you can take an extra dose, right? Here or there
and that's again very individual so it has to be planned by your healthcare team and each
individual person. That's one way of thinking. Now, but that still doesn't bypass the problems
that we that we run into with the gut dysfunction, right? And so you might be doing the right
thing by taking your medicines orally but what are the medication options that are
on-demand therapies that, as needed therapies that might help us bypass that GI tract. We have
injectable apomorphine right? Apokyn. We have an inhaled option with Inbrija or Inbrija, right?
I've been told Inbrija because it's supposed to bridge you to your next dose, depends if you're
what coast you're on but I guess I say Inbrija but it really kind of has this idea of bridging
you till your next dose because you're using an inhaled option in an on-demand way for OFF.
And we have a sublingual apomorphine that's helpful, it goes under the tongue, and it can get
you from an OFF to an ON in a more reliable way than using those oral therapies um that we that
we traditionally used to use. I'll stop there and and clarify any answers Dr. Costantini has.
Are there any non-pharmacologic or even surgical approaches for OFF? Specifically? I don't think in
my knowledge that there is but
Yeah, so well you can think about them as maintenance therapies
right, so surgically yes, those surgical treat, we call them surgical treatment modalities,
right, you got it so that's exactly kind of where we there's a now a a continuum right? So
we think about the condition as a continuum. If we are experiencing motor fluctuations or
wearing OFF and and we're at a stage where we need to consider surgical treatment modalities there
is a medication infusion port that actually gives carbidopa levodopa intestinal gel on a reliable
and consistent basis through a medication infusion port directly to the small intestine where the
carbidopa levodopa gets more effectively absorbed and that's pumped it's a pump basically that
infuses medication on an hourly rate and that allows us to fine-tune you know the amount that
we're actually giving by 0.1 ml increments, which equates to two milligram increments. Imagine being
able to titrate, go up and down, by two milligrams per hour. That's an infusion port. What we have
also at our disposal are three kinds of deep brain stimulators, right, so there are the different
kinds of deep brain stimulators that we can place, and you put them in different parts of the brain
depending on what sort of condition we're dealing with. There are three main targets, there's more,
but three main targets that we think about when treating tremor and Parkinson's disease for deep
brain stimulation.
Excellent. Okay well we're about halfway through our timing and we want to
now switch over to questions from the attendees so Leigh is is typing them out for me here we've
got five questions so far, so I encourage all of you listening to start typing in your questions
in the chat, so first question from our attendee is what is your experience with the Neupro
patch and does it help with wearing OFF?
Yeah, so, great question. So Neupro is a dopamine
agonist right so it's a patch it's transdermal, we call it transdermal, through the skin, and
what makes it um unique in comparison to the other dopamine agonist is that it is a patch but also
that it's an extended release formulation right? So we think more extended release, right, we think
about more extended-release carbidopa levodopa. We like to use perhaps um depending on each case but
extended-release formulation of dopamine agonists but the Neupro patch is a helpful tool to help
kind of think about you know creating some sort of stabilization of benefit so it could, yes,
dopamine agonists like Neupro could be helpful in extended-release form to help reduce wearing
OFF, that's the short answer. There are risks and benefits to each drug class right and so we think
about dopamine agonists as their own drug class different than the other drug classes but
really what dopamine agonists are and so we can conceptually think about them as a pharmacologist
right if we put on our pharmacology hat what they are are molecules that they're like dopamine
imposters. They sit on dopamine receptors you know these are receptors by the way or like
little cups and then the molecules sit on those receptors on the neurons and act like dopamine
would act they they are not dopamine. Levodopa actually enters the neuron and converts
into dopamine. Dopamine agonist might be used adjunctively or as monotherapy on
their own without any other medications to provide benefit and reduce symptoms.
Excellent, great. Another question from one of our webinar attendees is does strenuous exercise
quote on quote burn through the carbidopa levodopa quicker which invokes OFF quicker? Can
you actually burn through that and cause the medication to be metabolized quicker if you're
intensely exercising?
Well I can tell you in my clinical experience I hear that from patients,
that on days where they are expending more energy, right they might actually note that they're
wearing OFF potentially more. It's almost like, yeah, I have not uncommonly heard this from
patients and that's kind of more clinical experience kind of what I've heard from just
having we have 12,000 patients in our clinical practice, very big Parkinson's center, we're
very busy we have a high volume and you got it. I've heard that and it's not uncommon for
me to hear that now it's possible that maybe when we're trying to exert ourselves we're
noticing that maybe we're wearing OFF rather than if we were just sitting there not really
exerting ourself, maybe we wouldn't necessarily feel that wearing OFF effect as strongly or
it's possible you're right with expenditure of energy you know your metabolism you're using
your cells are using the energy that you have and our medications help us but it's possible that
we are kind of somehow in certain cases kind of exhausting some of those energy that some
of that energy capacity that we have.
Excellent, good. This is not in the clinical
journals but you're hearing it first here folks from clinical experience. So, next question
is when OFF time occurs late in the afternoon would adding a late afternoon dose of
levodopa be as effective as switching to an extended-release dopamine?
So yeah,
so there are different ways of evaluating OFF time right and if we're seeing that throughout
the day we have a predictable experience, where we are wearing OFF of our medicine or we're feeling
like a certain time of day we can predictably say, hey, I know I know I'm wearing OFF, right, this
is it, I found it, this is the time, it's not unpredictable, it may or may not be intolerable
right? Those are the two factors that kind of when we have those two questions in the back of
our mind about how we, when we add therapies. You know it's not uncommon for us to do two things at
once right, it's a dynamic condition and sometimes we need a dynamic strategy. So we are thinking
about now that we have all these categories, definitely, hey, how do we improve our OFF
time, improve our ON time, reduce our OFF time. Extended-release formulations of of carbidopa
levodopa for example right those are those are ways that we can help prolong duration
from our previous dose. Data has shown that uh the more extended-release formulations of
carbidopa levodopa like if you think about Rytary, it actually can show based on clinical data
extended duration after each dose in comparison to the immediate release carbidopa levodopa if
dosed right and done properly. Now what about patients that we have that in the back
of our mind where we're thinking about extended release formulations of carbidopa
levodopa, maybe we've added an an adjunctive to reduce OFF time right? These ON extenders or ON
augmenters, the different families that we mention but we're also maybe thinking in the back
of our mind well let's have an action plan similar to what an asthmatic might have right? You
have, or a diabetic person might experience right? How do we combat these sugar fluctuations that
despite being on multiple formulations of medicine that might tackle diabetes, we still might need an
as needed plan to kind of modify that sugar level, same goes for asthma, we might have our patients
on three or four different doses or different medications for maintaining or preventing asthma
crises but if you have an asthma crisis there's an action plan there to help reduce the symptoms.
Great analogy, yeah, now we can start using an asthma protocol for maintenance versus as needed
that's excellent. Looks like we're going back on our next question to diet, you struck a chord
with the protein and says how much time should you avoid protein before and after eating to
allow maximum absorption of the levodopa.
Yeah, so yeah, it's a good question.
Sounds
personal.
Yeah so, it's a good question and it's about so what we tend to say and patients
that might be experiencing that is protein if taken within half an hour to an hour of taking
your carbidopa levodopa may actually reduce the benefit from those doses and so we tend to say,
try and space your carbidopa levodopa half an hour to an hour away from eating a protein-packed
meal. What I tell patients though is if you're hungry and you gotta eat you eat right and maybe
think about that knowing that it's protein mainly try and find out you know what are those kind of,
those meals that may not have a lot of protein so that you can maybe eat something, but it may not
affect your absorption or benefit from carbidopa levodopa.
Yeah, have a big salad with lots
of vegetables and a little bit less protein.
Yeah, that's a good thought.
Next question is
about sun downing, so my father is having some evening symptoms that we thought were an extreme
OFF period, but an experienced in-home caregiver is suggesting maybe a sun downing effect, can
you speak to the difference between OFF symptoms and sun downing?
Yeah great, and they could
be the same. You know, it's possible just as, it's a multi-layered process right and that's why
it's possible that in the evening hours you know we might be seeing an increase of neurobehavioral
changes right. So it is important to distinguish sundowning from an OFF episode and it's possible
that there's a cycle there right? You know maybe anxiety and panic is setting in because of
a wearing OFF episode and that can kind of then trigger some neurobehavioral changes that seem
like confusion or brain fog. Those things can be, sometimes they're non-specific, so they could
be wearing OFF, but sundowning is an important an important topic to discuss because cognitive
change is also part of our condition in certain cases, and so it's important always to evaluate
your patient's cognitive state, their abilities, their cognitive abilities, their neurocognitive
kind of level. If there's cognitive impairment or if there's dementia, we may be more prone to
sun downing or confusion in the evening hours and it's important to know that because if we
have cognitive impairment detected on either an MMSE or a Montreal Cognitive Assessment
those are ways that we can determine our patient's cognitive status.
Let's not forget
psychosis, right? When we think about psychosis that is part, can be part of our condition and can
be made worse or caused by our medications and so understanding the cognitive overall, all those
components is very much a part of understanding our movement disorder. You need to know about your
cognition in order to help your movements and vice versa.
Yep, sounds like a balancing act. You
had talked about this a little earlier how much wearing OFF should you tolerate before
increasing your carbidopa levodopa? Do you worry about obviously dyskinesias caused
by the higher levels, how do you strike that balance or is it a very personal thing?
Yeah,
you're right, and that's where it is personal and it's individual for each person but there's
different strategies. You know you you might be able to think about a strategy to help
reduce dyskinesias and improve OFF right? So there are medications that we might think about
for that, there's FDA indicated medications that are FDA indicated for both right. So a medication
like an amantadine derivative might be thought of during that time. So but but there's different
ways of thinking. You can even sometimes lowering the dose of levodopa and making it more frequent
thinking about extended release formulations, adding on extenders, those adjunctive medications
that we've talked about can be helpful, but sometimes then we push ourselves into that
threshold of more dyskinesias and that's where, whenever we're having a tough time with our
combination therapies or just our therapies in general, finding our way to thread that needle
into a narrow therapeutic window, where small changes make big impacts, that's a very important
conversation to have and understand because that's exactly when we start having that conversation
about surgical treatment modalities right? So it doesn't mean we're not going to still think about
optimizing our oral medications, but we might really start thinking and having that conversation
about, hey, you know these are the options for surgical treatment modalities. Which ones make
more sense you know given the individual?
Yep, personalized approach. So what meds may
be coming down the pike that can help with OFF? Anything in development that you've been hearing?
Your clinical trials or in your network?
So there's plenty of so this is one of my favorite
things is to talk about the momentum in clinical research, right? So as an academic neurologist
we have one foot in clinical research at all times and and we have to think about this as
an ever-changing field, as a dynamic field, and as a field that has all this research momentum
behind it and we've talked about everything that we can prescribe in clinic, but you got it,
there are there's so much going on. We have clinical research, multiple sites
throughout the country looking at an extended-release formulation already of
an extended-release formulation of carbidopa levodopa. We have so maybe a medication that might
be in the future taken less frequently but maybe you know successfully of course we still don't
know, but maybe we'll take it less frequently and and get similar benefits to a more immediate
release alternative that's given more frequently. We have different types of devices right we
have a dopamine agonist subcutaneous pump that is being studied in the United States and we
also even have a subcutaneous carbidopa levodopa device, that's subcutaneous meaning in the
skin, that might be able to deliver a continuous infusion of carbidopa levodopa. That's not
to mention all the other clinical trials looking at how to target the proteins within
the brain that are causing the problem and all the other clinical trials that have to do
with devices, that implantable devices, and where to target in the brain, so there's a lot here
in movement disorders and in neurodegenerative diseases that's being studied.
So exciting,
love it. A couple more personal questions I have OFF times when I don't move much for a long time
like when I'm watching a movie is this common?
Well you know what happens sometimes also in my
clinical experience that I hear8 from patients is that you know when we have long periods where
we're not moving, sometimes, we can kind of feel rigidity and stiffness set in and so it can feel
a little bit like you know to get moving again you kind of have to, to feel fluid again and
less stiff and rigid you kind of have to walk and stretch out those muscles and you're right
so you can you can combat that with exercise, stretching, core exercises, things like tai chi,
things that are gonna be good for your core. Stationary biking is something
that's both safe and effective but yes it also could be a wearing OFF episode,
right? So stiffness and rigidity can be a sole symptom of wearing OFF and that's where
a strategy of kind of writing down when you take your medicine throughout your day and how you feel
on an hourly basis can be very very effective, that's a nice effective communication tool to
be able to kind of hand your health care team a picture of what of what you might be
experiencing.
Ah interesting, excellent. My husband has fatigue when he is OFF what can
he do?
Yeah, fatigue is a symptom that may have many causes. So when we think about it, we really
have to kind of put it all together and try our best to determine that if fatigue is part of OFF
then we can target OFF and maybe fatigue improves. It's also possible that fatigue may actually be a
symptom of low blood pressure, right, so low blood pressure can happen in Parkinson's, might cause
fatigue. Fatigue can also be caused potentially by, if you eat a, it can happen to anybody.
If you have a big pasta meal at lunch time carbohydrates can make it so that all the blood
from your body goes to your brain to absorb all that food and carbohydrates are usually harder
to absorb and that can lead to fatigue too, so it could be induced by food. Another type of fatigue
can be caused by just overall tiredness right, low energy, that can be part of Parkinson's
disease, kind of hard to pinpoint, or we really really need to think about
remember I said let's not forget sleep, we think a lot about our day time but what
about our night time, remember Parkinson's patients might have sleep apnea and that might
make them feel fatigued or insomnia during the day they might experience REM behavioral sleep
disorder they might act out their dreams making them sleep less soundly. And then
that sleep fragmentation right if you're waking up several times at night because
maybe your dopamine levels are low right because that's what happened overnight or
you need to go to the bathroom a lot urinate that's going to contribute to daytime fatigue and
so you got it, it's so many factors and that's why you kind of have to think about everything
as a whole and get to the bottom of each one
Right and that actually leads to the next question
if insomnia is an OFF problem how is that treated? Yeah, so you got it, and so insomnia can be
an OFF problem. Restless leg you know can be something that we feel it's kind of like a
sensory issue that can happen um where we feel like like it's hard to control our leg or feel a
discomfort that could be a wearing OFF episode. So wearing OFF prior to bedtime sometimes can
contribute to sleep onset insomnia right and we have to distinguish between sleep onset insomnia
and then maintenance insomnia, in the middle of the night, sometimes our patients can fall asleep
easily but then they wake up predictably at the same time every night or maybe there is a pattern
there. Maybe their last dose of carbidopa levodopa was at 6 pm but they're going to sleep at midnight
right and that's been a long time potentially and if you're uncomfortable you're not going to sleep
you're not going to be able to fall asleep easily and then a third point is depression and
anxiety can very much affect our ability to fall asleep and stay asleep and so if we're
not screening for depression and anxiety then we might be in trouble because you kind of
have to in order to regulate your circadian rhythm you have to tackle anxiety and
depression too.
Absolutely. Next question is does chewing medication help
decrease wearing OFF, do you have any suggestions as to what to take levodopa
with to enhance efficacy prevent or help with OFF episodes and this person
has said I've tried vitamin c, orange juice as well as carbonated drinks which sometimes help. So
how can they take their medication differently?
Yeah you know I'm not sure necessarily about
the the true clinical trial data but you got it you know we we use strategies right we
think about it like so in carbidopa levodopa s case/immediate release, maybe we tell people to
chew on some carbidopa levodopa, maybe think about taking something with it like orange juice or
lemonade right because maybe there's something in terms of that acidity or citric acid that might
help with absorption potentially right, maybe, so that's something that we used to try. There are
different formulations like Parcopa sometimes that patients might feel, the oral disintegrating
tablet of carbidopa levodopa, but again still goes down the GI tract so we're still even though
we are doing those strategies with oral therapies we sometimes you know we're still reliant on
that absorption in the small intestine, so our GI tract does still need to be functioning properly.
Rytary is actually a medicine that's encapsulated that you can actually in patients that have
difficulty swallowing you can open the capsule sprinkle that into something like applesauce
and take it in patients that are having trouble swallowing but those are things that we think
about you know just in clinical practice to depending on each scenario we run
into.
Perfect. One question here, does OFF feel different if you're taking a
dopamine agonist instead of carbidopa levodopa?
Yeah, you know well the the answer I have is
you know I don't know, you know, I know that we know the half-lives based on clinical
research half-life is how long each medication administration if absorbed
properly is in your system right. So we know that carbidopa levodopa might have a
certain half-life and and so which means it's out of your system after a certain amount of time and
so it might not be giving you benefit. We also do know that about dopamine agonists. So you can
if you're taking an immediate release dopamine agonist the ones that are given three times a
day orally then you actually might feel those though that dopamine agonists wear OFF too just
like you would carbidopa levodopa but that's where potentially depending on each case of course we
really start thinking about more extended release formulations of both carbidopa levodopa and
dopamine agonists right or we think about those on augmenters or extenders those the newer
COMT inhibitors, A2A receptor antagonists, those combinations of how is it that based
on all the clinical research these adjunctive medications that are added to carbidopa levodopa
that might extend ON time and reduce OFF time.
Great and the last question we'll go with today
is, this is a general one get ready, please explain the three kinds of deep brain stimulation
surgical treatments.
Yeah, so yeah I'd love to. This is a three-hour lecture right Dr.
Costantini?
Saved the best one for last.
I can't believe it's the last question already
that time flies, so thanks for making it so fun everybody and Dr. Costantini, but you
got it so there are three right right now readily available in clinical
practice at least that I know of we have Medtronic, we have Abbott and we
have Boston Scientific and and we might think about the different technologies differently. So
Medtronic has what's called a closed-loop system that can help us actually potentially understand
some readings from the brain, potentially, so there might be some data that might be captured
by the device. Now what that data really translates into right now that's TBD right, to be
determined, but there is a capacity for Medtronic devices to actually capture some electrical
information from your brain after being placed. A deep brain stimulator like Boston Scientific
actually there are eight contact points so eight places to stimulate in comparison to four contact
points for alternatives so that might be something that might be seen in a Boston Scientific deep
brain stimulator and the Abbott device has directionality and they do remote programming
that's something that's newer to them is being able to program a patient remotely through their
tablet and so they do have approval to do that.
So each system has its pluses but their
effectiveness really you know is tried and tested through clinical research and before anything
is FDA approved of course they go through a huge vetting process of safety and efficacy, but each
each device may have different pluses and minuses at any given moment but of course technology
is constantly evolving right technology moves faster than this lecture right. Something new in
technology might have come out just in the past 50 minutes where we've been talking and so all these
all these different devices might evolve, and each company might have different things in comparison
to the other at any given moment in time
Excellent. Well thank you so much Dr.
Torres-Yaghi, this was so informative, and you made everything so easy to understand
you truly have a gift for teaching.
Thank you, thank you.
I hope everyone
got as much out of it as we all did so thank you so much again and hope you
all have a wonderful rest of your day
