Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. So if you missed it, we had a fantastic discussion last time about Parkinson's disease, particularly having to do with the clinical features and the new diagnostic tools and so forth. We had our terrific guests, Dr. Meredith Spindler and Dr. Nabila Dahodwala. And they are back here again today to talk to us more about Parkinson's, but this time with a focus on treatment, basically what we can do to make people's lives better. So, Meredith, Nabila, thanks for coming back.

Meredith Spindler, MS: Thanks for having us.

Nabila Dahodwala, MS: Thank you. It's a pleasure to be here.

Host: I think your first podcast is going to get a lot of interest because you gave us a lot of pearls and talked over some things that probably many of us didn't quite understand in medical school in terms of the difference between the various tremors. And so, I want to thank you for doing that. I already gotten some positive feedback. But let's start talking about Parkinson's from the perspective of what a patient can expect, but also what we can do to improve their lives. So, let me just start with a scenario where a patient comes in, they're a newly diagnosed Parkinson's patient. What are you telling them in terms of what to expect? And also, what should they start to focus on?

Meredith Spindler, MS: There isn't a cookie-cutter answer to this. It really depends on how they're feeling in terms of their symptoms and what they really want to know about what to expect, because not everybody wants to know everything about what to expect. So, I really try to ask them what they want to know and ask them what their priorities are.

So if I've got a patient who's feeling pretty poorly, it's not just like a little tremor and they want to know what it is. It's, you know, they're having symptoms and they're feeling pretty poorly, and they do want to know what to expect. I'm going to be telling them that we have treatments that really do help the symptoms, and that if we start a treatment, they may be feeling a lot better actually in the short term.

And I kind of start with that, and I explain how people often feel better six months, a year after starting treatment than they did before they got the diagnosis and before they started treatment. I'm also going to tell them about the importance of exercise, whether they want to start treatment or not. I'm going to tell them that the only thing that we have that slows progression of disease is physical exercise; that, unfortunately, we don't have any pills right now that do that, although there are many smart people working on that and there are many clinical trials going on to change that. But that everybody with Parkinson's should be exercising, and I'll go into what kinds of exercise I recommend or we recommend.

And then, you know, I may ask them what more do they want to know about what to expect in terms of do they want me to tell them how they'll be in three years, five years, ten years, fifteen years? Like, what do they really want to know? Because sometimes they really kind of don't want to know. And if they do, I give a big caveat that, "Look, there's a lot going on in the research world. I don't really know what treatments may be around in five years, let alone ten years, that may change the trajectory of the disease compared to what people are dealing with now and in the last ten years."

And then, I maybe give some pretty crude numbers, because I really don't know for certain, but just that they may be having more walking problems and needing a walker or something probably ten years or more down the road, that they may be noticing, like, reduced efficacy of medication, needing to take their pills more often, maybe five to ten years down the road. And I'm probably not going to get into, like, dementia, hallucinations, dysphagia, falls, unless they specifically ask about those things, and then I may get into that and how far down the road that might be.

Nabila Dahodwala, MS: Yeah. I definitely try to frame it in a more hopeful and optimistic way just to highlight what we can do. That it's slowly progressive. So, I think a lot of people worry, like, about the future when they get this new diagnosis. Like, how, what do I need to plan for? And I just try and set expectations that this isn't something that changes, like, day to day, week to week, or even month to month.

It's more on, like, a year's timeframe. And then, if they want, I can give them, like, what Meredith talked about, like, a 5 to 10-year timeframe, 10 to 15, even longer timeframe, and really try and emphasize that everyone is very different with this, and they're probably going to see things on the internet, and you can go down rabbit holes. I usually give them some websites that I think are really very good, especially for newly diagnosed patients. And let them know that there's a lot of symptoms you might read about, but most people don't develop all of them. Like, we just talk, ask you about all these questions to just see who you are with this, and that really this is a journey that we'll be on together.

Like, I really try and tell them that, like, they're part of the team now, and we have a lot of resources to support them both at our center and in the community. And as symptoms come up, we'll manage them. And that's mainly what we focus on, is managing symptoms. We don't have anything to slow it down other than the exercise that Meredith talked about, which is really, I think, a nice way to empower patients.

Like, these are things that you can do to take charge of this new diagnosis, which is, like, generally quite upsetting for people. Although some people are expecting it. They have a family member with it. They're, like, thinking the worst thing possible, and then they come in, and they get the diagnosis. I try to, like, set the expectations around individuals being different and, like, taking things in small chunks, because it's not going to all happen at one time.

Host: So, something you said struck me as being somewhat remarkable, and that is that exercise is the only thing that slows the progression of illness. And we're going to talk about a lot of medications, and there's this long list of potential medications that you can put patients on, but none of them are going to do anything to slow the progression of the disease, only exercises.

So, let's just take a moment and talk about exercise specifically. What do you mean by exercise? I know there's this Rock Steady Boxing. I see places advertising it near me, you know, just private gyms. But also, just the magnitude of effect. I mean, how much can people get? How much can you slow the progression with exercise?

Nabila Dahodwala, MS: We don't have the answers to all of that. People always want to know, like, what exercise should I do? How often? At what intensity? And those are all questions we don't have the answers to. What we do know is that most exercises are helpful, at least in the short term, in terms of reducing falls, improving quality of life, even maybe reducing how much medicines people need to take.

And the evidence that it slows the progression of disease is still like in the animal models and in the basic science. Not yet in, like, clinical trials of humans. Although I don't think anyone is going to argue that point, just because the evidence is pretty convincing that it helps promote neuronal health.

And it, in other neurodegenerative diseases, is also helpful. So in Alzheimer's disease, it actually improves memory. And I think a lot of these pathways are similar across neurodegenerative conditions that have accumulation of an abnormal protein that the similar kind of lifestyle modifications and preventative measures work across the conditions.

Meredith Spindler, MS: I'll offer what I tell patients in terms of what I mean when I say, you know, exercise slows progression of disease, here's what you should do.

I believe that the evidence that's been the most compelling in the animal models has been with aerobic exercise. And so, I recommend what the American Heart Association recommends for goals for aerobic exercise, which is 150 minutes a week of moderate intensity aerobic exercise, split up how you want to.

And so, I say, "I acknowledge that that's a lot," but I say that this is what I recommend for that benefit. But also, adding in weight training about twice a week to keep your muscles and bones strong, and also stretching daily to keep you limber because there can be rigidity with this. So, that's what I sort of recommend as like the foundation of an exercise regimen.

Also, they'll ask me, "Well, what kind of aerobic exercise?" I say, "Whatever you're going to actually do, and whatever is safe, of course, too." So if you're having a lot of balance problems, maybe don't go for a run. And if they really want more input on this, I may recommend meeting with a physical therapist to develop their exercise regimen.

And you, earlier when we were talking, brought up Rock Steady Boxing, which I think is a wonderful exercise program for Parkinson's disease. It integrates aerobic exercise, boxing, balance exercises, large amplitude exercises, which have been shown separately to be beneficial for Parkinson's patients.

And in addition, there's like social and cognitive elements, because you're cognitively a little challenged with the movements, and you're in a group, and so there's additional benefits that way. And I think that's been a really popular exercise class. And so, I'll recommend that as well if it's feasible for someone.

Nabila Dahodwala, MS: What I love about Rock Steady is the socialization part, because they tend to become a community of people with Parkinson's who go to the same class, and then they become friends and share just their experiences. It's almost like a support group. And they're informed by Parkinson's disease, so they include these specific exercises to help with balance and movements. But also, the voice can get soft in Parkinson's disease. And so, they even work on projecting voice and speaking loudly, like counting while they're doing their exercises.

I think it's a pretty well-researched exercise. But I'll agree with Meredith that really there's a lot of different exercises that are helpful and that have been studied, like dancing. I don't know if there are articles in The New York Times about tango. That, again, incorporates more cognitive skills and learning the dance movements and balance, and it's with a partner, so you have like intimacy and socialization dancing. Tai Chi has been studied, which includes a lot of balance. Bicycling, which removes some of the impediments to, like, people getting stuck. There's some, like, amazing—I think it's a case in the New England Journal of Medicine with a video of someone who's totally frozen who can't get started with their movement. But on a bicycle, their legs just are cycling around.

So, I talk to them the same. I give the same American Heart Association recommendations for how much exercise to incorporate, cardio or aerobic exercise along with balance, strength, and multitasking. And then, try to tailor it based on who they are, what their interests are. You know, if they have back problems, I might recommend a recumbent bike, or if they have balance problems. But really, any exercise is good.

Host: You know, it reminds me of a lot of conversations I have with patients, because frailty is becoming an increasing issue in patients, partly because we're doing a good job at treating the other stuff, you know. So, people are living longer, and then they're hitting issues of frailty. And the only way to stop frailty from getting worse is to exercise and to develop those skills early. So, it's a very similar conversation to what we have with patients all the time.

So, I think all of us, going back to medical school, know about the drug Sinemet, which is the trade name for carbidopa/levodopa. We all learned the cool thing about why it's a combination med, about being able to get the levodopa to the brain and and so forth. I had that on a board test, you know, at different stages about that cool drug. But it's actually a very interesting drug. And to me, it's not straightforward because it comes in a lot of different formulations. What's your approach to starting this medication? How do you use it long term?

Nabila Dahodwala, MS: I'll take a first stab and then you can add on. So, I generally set expectations about why we're starting it, which is to improve quality of life. It really can be quite effective for managing the motor symptoms in Parkinson's disease: the tremor, the stiffness, and the slowness. And I typically start with just the standard immediate-release Sinemet, which is carbidopa/levodopa. I usually start with the 25/100 milligram dose, and I slowly titrate up. So, I start with, like, a half tablet twice a day. And then, every three days, add a half tablet until they're at one tablet three times a day. Some people can get away with one tablet twice a day because the half-life can be especially early on, like, a little bit longer, six to eight hours. But typically, it's four to six hours and people need the three times a day dosing.

And just talk a little bit about side effects when they're first starting at the low doses, like the one tablet of the 25/100 mg three times a day is kind of a low starting dose. So, it may or may not help with their symptoms at that level, but that's kind of where I stop and check in. "How are you feeling? Are you having nausea with the medicine? Are you having sleepiness or orthostatic symptoms from the medicine?" And then, depending on how they're feeling, some people, I would say with early Parkinson's, like straightforward, like, mild symptoms, most people feel better with the one tablet three times a day. Some people need to go up to two tablets three times a day, and rarely the three tablets three times a day. It's a pretty, like, straightforward, just keep increasing to tolerance and symptom benefit. If they're running into problems, that's when you kind of have to, like, step back and think about some of these other formulations and other options to manage their symptoms.

Meredith Spindler, MS: Yeah, I agree. I do the exact same thing. One situation that can happen that I'll just mention, tremor specifically can be a little bit stubborn if the person has like a relatively high amplitude tremor, and they are very bothered by it, and they want to get it under control. You might see someone, you know, at two tabs three times a day just being like, "It's not helping. It's not helping." And that doesn't mean it's not Parkinson's. If the tremor is classic for Parkinson's, it still probably is, and they may need a higher dose, even three tablets three times a day. Rarely higher, but sometimes higher.

I'll also just quickly mention, you know, because I think this can get confusing, there is a 10/100 milligram tablet of carbidopa/levodopa that we don't typically use as a starting medication. It just is going to kind of not get quite as much levodopa into the brain because there's not as much carbidopa. It may not prevent nausea as well. Usually, that's saved for when people are on a lot of pills and the pharmacy doesn't like people exceeding 200 milligrams of carbidopa in a day. Or very rarely, if someone's super sensitive to a 25/100 pill and gets like dyskinesia from it later on in the disease, maybe they like a 10/100 better. But we use the 10/100s pretty rarely. And we usually don't start with a 25/250. That's probably going to cause nausea if you start with that. We might use that later if we get up to high doses.

I'll also mention about taking it with food or not, because that's a very common question. So, I actually usually start it with meals, with food, because that's going to reduce the chance of nausea. But inevitably, somebody comes back and says that they went on the internet and learned that they're supposed to take it not with food, and that's because protein can compete with levodopa for absorption in the intestine. Theoretically, it can reduce the efficacy of the medication.

In my experience early in the disease, this isn't noticed to be that much of a problem, so I worry about this less early on, and I'm a little more worried about nausea when they're first exposed to the drug. So, I just say take it with meals. Later on, that can become an issue, and we may start having patients take their pills an hour before a meal or two hours after a meal if we think that sometimes the doses aren't working because they're taking it with a meal.

Host: The 25/100 formulation, you start out one BID, go up to TID, and then eventually...

Meredith Spindler, MS: Half a tab BID.

Host: Half a tab BID, you start with.

Nabila Dahodwala, MS: Start, and then every three days I have them take an extra half. So, they'll be like half three times a day, then one full tablet, half, half, then one. I mean, I make like a calendar and I hand it to them so they, they know how to do it. Otherwise, it can be confusing.

It probably is okay if you start at like the full tablet two or three times a day. But what we see—and it might be because we're more specialized—are people who tried it and then felt bad, and so stopped taking it. And then, they come to us and they're like, "Oh, this Sinemet didn't work," but they didn't really take it. So if we start low and kind of slowly titrate up, it's much more tolerable.

Host: And tolerability, you've mentioned nausea a couple times. It's nausea, right?

Nabila Dahodwala, MS: That's the big one with starting low. Yeah. Some people do get sleepy after they take their medicine. Some people get orthostatic with the medicine. But the most common is nausea.

Host: And when people have a successful response, and it sounds like you'll go up until people are feeling like they have a successful response, for lack of a better word, just looser, right? I mean, movements are more fluid. They feel more comfortable. They feel more balanced, that kind of thing, right?

Nabila Dahodwala, MS: I would say, like, not uncommonly people say they feel like they're normal. Like, they feel like most people don't think they have Parkinson's disease. They're, like, doing their regular life, and they just have to take their medicine. That's like the typical response.

Meredith Spindler, MS: Yeah, whatever the symptom was that brought them in, or symptoms, whether it was their walking, their foot was dragging, their hand was not cooperating, they weren't writing as well or typing, any of those things, shaking. And sometimes some non-motor stuff, too. Some people feel, like, an internal jitteriness or some sort of non-motor sensation. That'll often be better as well.

Host: So, I want to ask a question that goes back to sort of when I was in residency and rotating in a Parkinson's clinic, something that was the practice at that time, and that was to hold off on prescribing carbidopa/levodopa, because the idea was that it doesn't work forever, and you wanted to sort of wait until symptoms were severe enough that you could do it. And then, people would have a longer time with the medication more at the back end, if you will, you know? And then, we would use some of these other meds early on. That does not seem to be what the practice is now, right?

Nabila Dahodwala, MS: It has changed. I mean, I think we're about the same age. That's what I learned too in medical school. And the practice has changed, I think, for several reasons. One, there have been several large randomized, like, comparative effectiveness trials looking at the early initiation of carbidopa/levodopa and comparing it to other medication classes that might have a lower rate of dyskinesias, which is what people were quite worried about early on, or even no treatment and the levodopa group has better quality of life for a longer period of time if you start it early.

I think the second thing is we've learned that some of these alternative medicines that we're using to kind of spare the levodopa actually have a high rate of side effects. So, the dopamine agonists, so like the ropinirole, pramipexole, rotigotine, that whole class, less impulse for impulse control disorder. Somewhere up to 20% of people can have, like, excessive gambling, hypersexuality, overspending, like going into debt and not realizing it's from the medication. And also, just higher rates of hallucinations, psychosis, hypotension. Almost all side effects are greater in the dopamine agonists. So, we just really moved away from using them as first line. We still use them sometimes, but I use them less and less, I feel like, as time goes on.

And as we have now more formulations of the carbidopa/levodopa, like more extended release, we have inhaled levodopa, we have a pump. There's just different ways we can manage symptoms that arise from how they're getting the medicine. So, we're just less likely to use the agonists, which had a role, but I think they're becoming—although there's a new one coming out. It supposedly has fewer side effects, and we'll see if that's true.

Host: And so, the drug does wear off in its effectiveness over time because the disease is progressive and people are losing dopamine.

Nabila Dahodwala, MS: That's exactly what's happening. So, it's not that the medicine loses its efficacy, it's that the disease is progressive.

Meredith Spindler, MS: I mentioned this actually in the first episode, where as the disease progresses, you're losing more of those dopaminergic neurons, which not only produce the dopamine, but also take up the dopamine that you took as a pill and store it for later. And if you have fewer of those cells around, they're not there to buffer the peaks in the dopamine that occur after a dose, and they're not there to hold onto dopamine and supplement later when your levels are no longer high, and then you notice your pill wearing off.

And there was a concern early on that levodopa may have actually been hastening the development of these complications, the early wearing off of the dyskinesias, and that there was some toxicity from it. This is a difficult thing to study, but there has been some data that seems to suggest that if you were to wait 10 years to start levodopa and then you started, you would develop the dyskinesias and fluctuations very, very quickly, because it has more to do with the stage of the disease than how long you were taking the levodopa. We feel pretty confident about that at this point. And so, you're not really saving yourself anything by waiting to take levodopa.

I would say that there are going to be some patients who come to you as a brand-new diagnosis who really aren't bothered by their symptoms, and then they really don't have to take medication. They can just exercise. But if you've got somebody who's bothered enough by their symptoms to take a medication, then yeah, I think we're doing the best thing for their quality of life, their ability to exercise, their ability to lead a normal life by giving them carbidopa/levodopa at the start.

Nabila Dahodwala, MS: And just one plug for research. We are always conducting clinical trials of new therapeutics, including therapeutics that might be disease-modifying or neuroprotective. And for some of those studies, we ask for people not to be on any treatment at the start of enrollment. But I tell patients there's always going to be a study for you, so you don't have to first manage your symptoms and how you're feeling and then think about research.

Meredith Spindler, MS: Just to kind of potentially maybe confuse things, unfortunately, there is a new dopamine agonist that is being reviewed by the FDA now and has a decision date for early 2027. And it is designed to not cause the impulse control disorders. Now, it still may cause some of the other side effects, but it was designed specifically to stimulate a different ratio of dopamine receptor subtypes that's less likely to lead to impulse control disorders.

And if that's true, simply for convenience sake, we may start using dopamine agonists a little bit more in the beginning because they can be takenor that specific one, tavapadon can be taken just once a day, and I can imagine patients asking for that in order to avoid the three times a day dosing. So, stay tuned for how that changes our practice. But right now, pre-tavapadol, it's carbidopa/levodopa.

Host: We could go into the formulations, we don't have to go into detail. I know there's a lot of tools in this toolbox in terms of different formulations. And Nabila, you had alluded to that. But I do want to ask about the role of long-acting carbidopa/levodopa and when that fits into the discussion of treatment.

Meredith Spindler, MS: So, there's an old long-acting carbidopa/levodopa controlled release that came out in the 1990s. And where that factors into my practice is in two ways. One is that it has a lower peak in the bloodstream, and therefore I use it in people who are having trouble tolerating regular carbidopa/levodopa. So if they're getting too sleepy or too lightheaded, and even sometimes too nauseous, I may try using it instead. I also may use it at bedtime to last a bit longer in their system overnight.

However, in other circumstances where someone's carbidopa/levodopa is just not lasting long enough, that isn't my first choice. Because in clinical practice, patients don't necessarily notice it being effective enough in a reliable and predictable way during the day. So, it's not our favorite for that purpose.

There are two other extended-release formulations of carbidopa/levodopa that have come out much more recently. There was Rytary in 2015, and then there was Crexont just last year. These are more reliably effective, I would say, reliably and predictably effective than that old Sinemet CR, and they will not cause less side effects. If you've got a patient on regular Sinemet who's having side effects, these will also cause those same side effects, perhaps in a more sustained way because they do last longer. and I would start using these in a patient whose carbidopa/levodopa immediate release is not lasting long enough, meaning maybe it's wearing off at four hours or less. I would consider using one of these.

It's important to note, and this will have implications for some people more than others, but sometimes insurance companies will not pay for these extended-release formulations if you haven't already tried some of our earlier, more affordable adjunctive medications for the wearing off phenomenon. So, we have a number of drugs that can be used that are not super expensive because they've been around a very long time, that help your immediate-release carbidopa/levodopa last around longer. We've got the MAO-B inhibitors, including rasagiline, selegiline, and safinamide. We've got entacapone, which you take with each dose. We've got the dopamine agonists, which you could add on low doses of dopamine agonists that can also help off time, and side effects are less likely at low doses.

Host: That's rapirinol, peramapexal...

Meredith Spindler, MS: Yes. Right. Exactly. Ropinirole, pramipexole, rotigotine. And then, we've got amantadine as well, which can help with off periods and dyskinesias. And a lot of insurance companies are not going to want to pay for those extended release formulations if you haven't already tried and failed these. And so, I will often use some of those older ones before going to the extended release formulations.

Host: So, those drugs, just to hover on that because I wanted to talk about those drugs that you just mentioned, the MAO inhibitors, selegiline and so forth, the dopamine agonist, pramipexole; actually amantadine, the old flu medication That's how I remember it. They're adjuncts that are boosters, I guess, to the effects of the carbidopa/levodopa—or, at least, that may not be quite the right way to describe them—partners like the Robins to the Batman, right? That's their role, right? And they're always used with Sinemet. They're not replaced necessarily replacements for Sinemet.

Nabila Dahodwala, MS: So, the MAO-B inhibitors, they are MAO-B B, so they're selective, because the only reason I mention that is because you get a lot of messages from the pharmacy that they're also on an SSRI or there's this risk of serotonin syndrome. But with the MAO-B, we have never seen— and there have been actually studies looking to see whether serotonin syndrome could happen, and not at the doses that we give them. It would really have to be at high levels of non-selective MAO-B, MAOs with high doses of SSRIs. In any case, that was an aside, and you can edit that out.

But the MAO-Bs centrally block the monoamine oxidase enzyme that would break down levodopa in the brain. And by blocking it, you just have sustained levels of levodopa just for a little bit longer. And you can be only on an MAO-B inhibitor without levodopa at all. So, it's your natural levodopa that your brain's making it, prevents the breakdown of it.

And usually, it's the most helpful if it's going to be used by itself in early, very mild symptoms of Parkinson's disease. Entacapone medicine that Meredith talked about, which also it's in a class called COMT or catechol-O-methyltransferase inhibitors. There's another drug in that class called opicapone. But those are blocking the breakdown of levodopa in the periphery. So, that you have to take with Sinemet because that allows more of the Sinemet to go to the brain, more of the levodopa to get into the brain without being broken down in the periphery. So, opicapone and entacapone can only be used with Sinemet, and there's even a combination drug called Stalevo that has all carbidopa, levodopa, entacapone in one tablet. And then, the agonist work can also work independently without levodopa because they just work directly on the dopamine receptors.

Meredith Spindler, MS: And amantadine as well. Amantadine can be given as monotherapy as well. In terms of relative efficacy, I think all of them are more modest than carbidopa/levodopa, which is why we tend to just go straight to carbidopa/levodopa. But you can use all of them but the entacapone for monotherapy

Host: Meredith, in our sort of pre-discussion before we turned the recorder on, you had kind of given an overview to me of just how you think about the course of treatment for Parkinson's disease. Can you kind of go through that? I found that really helpful.

Meredith Spindler, MS: In early disease, first of all, as I already said, there may be a period where patients feel they don't need any medication at all. They're functioning just fine. They'd prefer to exercise. Once a patient knows they would like medication and they're noticing impacts on their quality of life from their symptoms, I typically start with immediate release carbidopa/levodopa.

And often, because it's early in the disease, it lasts long enough that they can take three daily doses and not really notice any kicking in or wearing off of the doses. They just kind of feel normal all day or pretty good all day. And when we first start it, that's when we try to find how many tablets per dose do you need to feel good.

For some people, even just a half a tablet is going to be enough per dose to make them feel good. For other people, they're really going to need two tablets maybe or two and a half tablets to feel good. And they're going to take that three times a day, and they're going to have a pretty good period that sometimes we call a honeymoon period, where they just are feeling pretty normal for a while.

And then, the next thing that's going to happen, which could be a few years down the road, is that their doses start wearing off. And that's when I start either moving the doses closer together, adding these adjunctive medications we just talked about, maybe trying the extended release formulations. And then those, what we call motor fluctuations, which is the wearing off and the dyskinesias, those start kind of getting worse and worse. And it's in that group of folks that we start thinking about advanced therapies like the pumps or like deep brain stimulation, which we can get into more detail about later. This is all happening over the course of years and years, okay? Like, we might already be 10 years in at the point that I'm at now.

Eventually, what starts happening is people start developing the more very advanced disease stage symptoms like dementia, hallucinations. They may start falling a lot or getting orthostatic hypotension, or the meds start making them very, very sleepy. Any of these things may start happening, not all of them all at once. But unfortunately, a lot of those symptoms are made worse by the medications. And so, then, we actually start doing this pull back on our medications, where we start taking off all those adjunctive medications and trying to go down to just levodopa. Because in terms of all those things I just mentioned, cognition, hallucinations, orthostatic hypotension, levodopa's sort of the least bad, like the least offender, least of an offender of all these drugs. And so, we'll pull away our amantadine, or our agonists, or our entacapone, and then try to reduce our levodopa to the minimum necessary to just not exacerbate the psychosis, the orthostatic hypotension, et cetera. So, that's sort of my trajectory of medication use over the course of Parkinson's.

And it's just important to realize that in late stages, the answer may be less medication, not more. It's not that the farther along you get, the more medicine you need. That's not always how it is.

Host: So, one of the things I noticed in reading and prepping for Parkinson's, it was a little disappointing, is that there wasn't a lot that was new in the 20 years since I've been rotating. But there is some new stuff, you know? So, I think there's been an evolution of, really, how to best use the medications that are available and so forth. But one of the things out there is deep brain stimulation. And Meredith, I know you are sort of the director of the program for deep brain stimulation. Can you tell us more about that?

Meredith Spindler, MS: It's one of my favorite topics. So, deep brain stimulation is an incredible surgical therapy that actually has been FDA approved for Parkinson's since 2001, and FDA approved for tremor from Parkinson's or essential tremor since 1997. So like you said, it's not a new advance. It's been around a very long time. But it is still an incredible therapy.

It involves the surgical implantation of two thin electrodes into the brain, targeting either the subthalamic nucleus or the globus pallidus interna for Parkinson's. And those leads are connected to an extension wire that's tunneled under the scalp and under the skin and attached to a battery pack in the chest. And electrical stimulation is delivered continuously, and has been shown to dramatically improve certain symptoms of Parkinson's, as well as essential tremor and dystonia.

So, I think of good candidates for this procedure who have Parkinson's as falling into three main symptom buckets. One of which is the one I kind of just mentioned, which is your patient who had an initial wonderful response to levodopa, still has a good response to levodopa, but it's just not lasting long enough and they're getting terrible dyskinesias, people in that group who have those symptoms and the symptoms that are better with levodopa are motor symptoms, so tremor, stiffness, slowness, shuffling, walking, dexterity problems, et cetera. Those people make great DBS candidates. They generally experience a significant increase in their on time, which is the time during the day that their pills are working well without troublesome dyskinesias and a reduction in their off time. So, that's one symptom bucket.

Another one is patients who have a terrible tremor, and we're just trying high doses of levodopa, maybe we're adding amantadine, we're adding other adjunctive meds, and their tremor just won't quit. DBS can be even more effective for tremor than medications are. So if you've got one of these patients, this is often an excellent choice for them, and they often present a little earlier for DBS than the people with motor fluctuations. They often discover within the first five years of their disease that, like, the meds are just not going to cut it for their tremor

The third bucket is the least common, and that's people who can't tolerate levodopa at all. This is quite rare, but there are some people who even despite adding in antiemetics and using controlled-release levodopa like I mentioned, they're vomiting from the medication or some people get extremely somnolent from the medication and we try adding modafinil or methylphenidate and they're just so somnolent. Those people also can be good candidates for DBS.

So, those are the three types of patients that DBS can be very beneficial for, provided they don't have any of the red flags that can be sort of like a risk factor for a worse outcome, which would be that they're developing cognitive problems enough that we're getting worried about dementia, that can be a red flag that they may not do so well with surgery; balance problems where they're falling a lot, that's not great because stimulation can actually worsen balance, or a lot of speech and swallowing problems because DBS can also worsen speech problems. But these are relative contraindications. It's always sort of weighing the risks and benefits in each individual

Host: Can you tell us what the procedure actually is and how it's done? Is something left in the body?

Meredith Spindler, MS: Oh, yes. I'm sorry if I didn't make that clear. Yeah, absolutely. The electrodes and the extension wire that's under the skin and the battery pack in the chest, all of that is hardware that's left in the body. It is done by our functional neurosurgeons. It's done in a couple of stages, actually.

They take you to the OR, and they implant the electrodes first. They use stereotaxy with an MRI with fiducials to guide and a stereotactic frame that's in place during the surgery to guide them, as well as electrophysiology. They actually use microelectrodes to record neuronal firing and use the neuronal firing patterns to tell them what structure the tip of the electrode is in, so they know that they're putting it in the right place. It's incredible. And then, they actually wake the patient up after lead placement while still in the OR, and they turn on the stimulation, and they test whether the stimulation is having the intended effects. Is it helping tremor? Is it helping rigidity, or is it causing some side effect they don't want to see, which would require them to replace the electrode? So, that's the first stage of the surgery.

And the second stage of the surgery is a week or two later, where they tunnel the extension wire from the lead down, under the scalp behind the ear and then under the skin and place the battery pack in the chest and connect everything. A couple of weeks later, they come into the office, and we turn on the stimulation,. And we test several levels of stimulation and come up with parameters that we think are the best stimulation settings for them and then allow them to adjust it at home, go up for symptoms, go down for side effects. And it's kind of like a four to six-month optimization period of testing settings to get the best settings for their symptoms.

Host: So, that's remarkable. And I mean, dopamine's a neurotransmitter, so it's bridging a gap, and I gather you're sort of somehow bypassing that when you're putting in the deep brain stimulator and delivering an electrical impulse, right?

Meredith Spindler, MS: Right, right. It's not like the electrical impulse is generating dopamine and that's all that's happening. It's not like that. It is sort of bypassing the dopamine need and just generating the benefit electrically.

As far as how it truly works, like electrophysiologically, we really don't know. It's interesting to look at the literature. Needless to say, many, many electrophysiologists have tried to tease this out and they get confusing results. Every theory has been tested and like there'll be some data showing that that's correct and some data showing it's not. And so, it's really not well understood. We say that we're normalizing an abnormal firing pattern because we think that's what we're doing, but that's as far as we can get.

Host: How long do you anticipate improvements to last?

Meredith Spindler, MS: So, it kind of depends on improvements in what. So, improvements in tremor are going to be lifelong. I mean, there's people who, 20 years down the line, if you turn off their stimulator, which we sometimes have to do for certain procedures and tests, their tremor is incredibly bad. I mean, they're absolutely getting benefit from their stimulator.

The same can be true for motor fluctuations and dyskinesias, although not always. But the disease does still progress. I think that their bradykinesia, like their fine motor skills and their walking can progress kind of beyond the capabilities of the stimulator, so that even though they'd be worse with the stimulator off, they're still not so great even with it on. And then, of course, the balance issues, the dysautonomia, the cognitive issues all continue to progress.

Host: It sounds like a very useful tool too.

Meredith Spindler, MS: In the right patient.

Host: In the right patient, yeah. So, the other thing I wanted to ask you about is sort of how to manage some of these symptoms that we both share, both in primary care that patients come to us with the autonomic dysfunction, depression, sleep issues, cognitive issues, and so forth. You shared with me before we started recording that, for the most part, you guys are using the same medications we are. But I wanted to ask you about two areas in particular, and that is sleep, but also the autonomic dysfunction. For the autonomic dysfunction, is it just midodrine? I mean, is this all we got, or what else do you use?

Nabila Dahodwala, MS: I would break down autonomic dysfunction into orthostatic hypotension, constipation, urinary symptoms, which are usually urgency, frequency, and to some degree incontinence. Sometimes even temperature changes, like sweating at times when they're not actually hot. Those are probably the main ones that I hear about.

So for orthostatic hypotension, we use everything. We use Florinef, we use midodrine. I'm going to just take a step back. I don't usually go right to medicines. I try to limit drugs that are causing that orthostatic hypotension, one of which is the levodopa. So if we can cut back on their levodopa, I will do that. Some people who have had a diagnosis of hypertension for a long time, now their blood pressures tend to normalize, and they don't need the level of control that they did. Although some people continue to be very labile, which is challenging because they need a lot of kind of as-needed medicine based on where they are at the moment that they're checking their pressures.

If we're getting past the medicine reductions not working, then I'll do some lifestyle changes. If their blood pressures are kind of consistently low and get lower when they stand up, I'll add a salt tablet. Water, obviously, they should always be drinking water. You still have to remind them, even though that seems more obvious. People don't like to do that, especially if they're having urinary symptoms. And then, the compression stockings I haven't had. The data I don't think is very good that it actually improves symptoms. But the abdominal binder can be quite helpful, although it is uncomfortable. I have a few patients that swear by it and continue to wear it, because it does help. And did I say salt?

Meredith Spindler, MS: You did say salt.

Nabila Dahodwala, MS: Yeah.

Meredith Spindler, MS: Yeah. Electrolyte drinks can also do the trick. Yeah, same idea. All that stuff.

Nabila Dahodwala, MS: And then, I'll go to medicine, which would be Florinef, midodrine. Those two are kind of the first line that I'll start with. And then sometimes, the two together if they're still staying low.

But the thing that we worry about is supine hypertension, that it helps them keep them up when they go from sitting to standing. But when they're lying down, their blood pressure is high. So, it really needs to be closely monitored with frequent blood pressure checks in sitting, standing, and lying down.

And then, if that isn't helping, droxidopa, which is specifically the one, I think, FDA-approved drug for orthostatic hypotension in Parkinson's. And that too can do the same thing, though you can still get supine hypertension with droxidopa. Although, I will say that in the people who I've used it in, who usually have to have failed midodrine and Florinef, I have seen some better success in getting their pressures higher.

Meredith Spindler, MS: I've also used pyridostigmine for orthostatic hypotension. And I'll just make a note that midodrine can worsen urinary retention, which has been an issue for some of my patients, because obviously they already have urinary just often. And I've also seen droxidopa kind of worsen confusion. So, just being aware that these drugs that we don't necessarily think of as being able to affect all these other systems, they sometimes can. I think Florinef can also sometimes cause confusion. So, just being mindful of that. But we use all of those.

Nabila Dahodwala, MS: For constipation, it's a lot of over-the-counter, a lot of water, fiber, Metamucil. Generally, I'm like quick to go to a laxative like MiraLAX because that can be quite effective. Although, again, they need to drink lots of water for that to be effective. When I'm like starting to hit a wall with the over-the-counter medicines, that's when I will ask for help from my GI colleagues for some of the prescription constipation medicines. But I don't know, have you prescribed them yourself?

Meredith Spindler, MS: Yeah. No, I do the same as you. I refer to GI. I'll just also make the point that this is so important because we know that constipation makes levodopa less effective. It's not absorbed as well, and it's less effective. So, this is actually something I ask about when my patients complain that their meds aren't working as well. Well, is it possible you're constipated? And then, I tell them for the 18th time to drink more water.

Host: Just two more questions. The last one is just a very specific question. Is there anything specific for sleep that you give them, and is there anything we should be avoiding? That's actually going to be my second question, is what do you want to tell primary care physicians not to do in this population? But let's talk about the sleep piece first.

Nabila Dahodwala, MS: Sleep is complicated, because there's a lot of different sleep disorders. And so, I try and get at what's happening. So, there's REM sleep behavior disorder, which is that acting out of dreams during REM sleep. I think we talked about that at the last podcast. So that, there's evidence that melatonin can be helpful and clonazepam.

And now, clonazepam is not the best drug in an older adult. So, we usually start with melatonin and kind of slowly work up to like a maximum of 10 to 15 milligrams at night. I usually start at one milligram and tell them to go up every week by one milligram.

Host: And then, you realize it doesn't work and you give them the clonazepam, which is what usually happens to me.

Nabila Dahodwala, MS: Yeah. Yeah. The thing with the REM sleep behavior disorder is it usually doesn't happen every night. So, some people are like, if it's happening once a month, maybe this is not bad. But I do talk to them a lot about safety, like putting a pillow between themselves and their bed partner, moving aside like a nightside table or lamp so they don't hit it. And, you know, if they can put their bed as low as possible and a pillow on the ground in case they're to fall out of bed.

But the most common sleep disorder in Parkinson's is frequent nighttime disruptions. So, they don't get like a solid night of sleep. So, they fall asleep, wake up, fall asleep, wake up, maybe they go to the bathroom, come back. There's like a lot of interruptions in their sleep. And I try not to necessarily treat that immediately. Like, I try to focus on getting eight hours of rest overnight, or like a roughly eight hours. Like, there's probably some people that only need six and some people that need more, but on average.

And the point being, like, you might not be asleep the whole time, and you're not going to have like the deep stage sleep that you had as a kid, but at least rest. But I will say for many people, it doesn't feel restful. They start to feel worried that they're not sleeping. They feel very restless. They're like tossing and turning. So if they're not falling back asleep very easily, I still try to work with like sleep hygiene and like cognitive behavioral therapy for insomnia. Like, a lot of the anxiety, I think, that's kind of interfering with them falling back asleep.

But then, I do go to medicine. I do not use like the—I'm going to get the class wrong—but like the Zolpidem class. Like, I think a lot of people with Parkinson's get parasomnias on these medicines. It actually like worsens their symptoms. But stick to things that I think can maybe try and consolidate their sleep, probably using similar ones that you do. I try trazodone. I try other TCAs. I will try clonazepam sometimes. I try and think about like other medicines they might need. So if they're also anxious and also losing weight, I might use mirtazapine, which I really like. But that also can cause parasomnias. So, they all can have like their benefits and risks. But an SSRI that's a little bit sedating, it seems like the least harmful.

Meredith Spindler, MS: There is some data for doxepin. So, I have used doxepin as well. I think there's some data for trazodone, which is why I use that one. If there's any hallucinations at all, Seroquel can be helpful.

Nabila Dahodwala, MS: Quetiapine. Yeah.

Meredith Spindler, MS: Yeah. That can be helpful. But I agree. I try to stay away from the Zolpidem class, if I can. Sometimes I have patients who come to me already on it and say it works very well, but I try not to prescribe it. This is a tough one.

Host: Just in our primary care population, I generally try to avoid benzos, but they are very effective. And oftentimes for short-term situations where patients can't sleep because of some specific issue, they can be very valuable. So, what do you want us to not do? So, you're like, "Oh God, shocks, the primary care doc did this again" or they shouldn't be using this medication in this population? Is there something that—

Meredith Spindler, MS: I'll take this first just because I think it comes a little bit back to that trajectory that I mentioned, where I feel like it might not be realized how actually harmful our drugs can be in late-stage disease. And so, people may think, "Oh, you know, they need these for all their motor symptoms, so we're going to leave them on all of these," when really some of them should maybe be withdrawn.

I'll also bring up occasionally, this is pretty unusual, but I'll see the anticholinergics being used, Artane, which is trihexyphenidyl or benztropine, which can be very effective for tremor and even for Parkinson's symptoms. It is true that patients tend to find these to be very, very effective drugs.

The problem is that inevitably at some point they do cause a lot of cognitive problems, and they can cause urinary retention, obviously, and constipation. I have run into patients really where I struggle to get them off the drug, because they're kind of just not aware of how impaired they are on it, and there's family members who want them to get off it, but they feel like they're so much better with it that I have trouble getting off of it. I would just try to avoid using that class if you can, especially in later stage disease.

Host: I'm glad you said that, because we didn't get to that class in our sort of review of the medications. And so, I'm glad you mentioned that as a not-to.

Meredith Spindler, MS: Yeah. I also notice, and I don't know why this is just popping into my head, but, you know, someone will fail carbidopa/levodopa three tablets. Well, I'll never really get to three tablets. Maybe two tablets three times a day. And so, they'll stop it and they'll start, like, ropinirole 0.125 mg three times a day.

And I just want to bring up, like, the relative efficacy that for ropinirole to be as effective for symptoms as two tablets three times a day of Sinemet, you'd have to be at pretty high doses of ropinirole, like eight or 10 milligrams or something. So, just recognizing if you've got a patient who's just not responding to high doses of levodopa, like three tabs three times a day, I don't think you need a dopamine agonist trial. You're probably thinking about either DBS if it's tremor or an atypical parkinsonism if it's not.

Nabila Dahodwala, MS: Well, one, I would say you can never go wrong with prescribing physical therapy, occupational therapy, and speech therapy. Like, they can always use a refresher. If someone's struggling and they're, like, calling the office, home care, like, if they can't get to therapy, is usually a nice intermediate to just kind of bridge them to, like, figure out if really adjusting medicines is going to help improve what they're struggling with.

I was just trying to think, like, I don't really see things where a primary care doctor is like, "Oh, I wish they didn't do that." That would be very rare for me. I feel like I can always see that it's quite complicated, and I think some of the hard things are trying to figure out what is because of the Parkinson's and what's unrelated to the Parkinson's, and that takes some time and, like, diagnostic workup to figure out sometimes. And sometimes we can't tell them apart, and we just have to treat everything. Like, people always ask me about back pain, like, "Is it from my Parkinson's or..." I'm like, "You probably also have arthritis, but we're going to still treat your symptoms so that you feel better."

I will say, though, the thing that I have encountered that is a little tough to counteract is when another doctor, and it's not always a primary care doctor, but it's usually the referring doctor tells them they don't have Parkinson's disease, and then I'm seeing them. And I'm, like, not sure how that came up. But I feel like if you're not sure and you're going to refer them to us, then you can wait to hear our opinion about their diagnosis, because that sometimes is tough to counteract. Like, "Well, the other doctor has said I don't have Parkinson's." "Like, who do I believe?" And I'm like, "Well, I think part of the reason they sent you to us is to help figure that out."

Host: I think I might have been guilty in one of those circumstances. But it's really good advice. I was really confident the person didn't have Parkinson's. I don't think that was actually to you guys. But they went to somebody else, and they said, "No, you know, actually, these do meet the features." And I hadn't thankfully emphasized it to a great degree, but I have even written in my note I don't think they have Parkinson's. I don't think I emphasized it to the patient, though. But in any case, this is why we have you all to refer to. Meredith, you're going to say one last point?

Meredith Spindler, MS: The one thing I was going to say, and I don't think of this as being a problem, but what I think of is one of our colleagues, Allison Willis, actually looked into there's a large percentage of Parkinson's patients, Medicare beneficiaries who have Parkinson's in the country who actually don't have a neurologist at all, and their primary care doctor manages their Parkinson's.

And truthfully, our area, that is not what's happening. I don't see that happening a lot. But her data was just so interesting because unfortunately, the patients who were managed by a primary care doctor did worse, not because the primary care doctor couldn't manage their Parkinson's, but because it was sort of taking time away from managing their other primary care issues. Their diabetes, their this, their that. And so, just encouraging that you refer. Let us kind of take care of it so you can do the stuff that we need you to be doing. But I realize it's easier said than done because the wait times are so long. And that's the trouble. That's the rub. But we're here. Send us an email.

Host: My brother, who practices in rural Pennsylvania and is a far better doctor than me, and has almost no sub-subspecialty help, I always think about him when we're doing these podcasts, because you guys have given a lot of information to those primary care physicians who are trying to manage these patients. And it's hard. If I were in that situation, this podcast would be really useful, and I really appreciate you doing that, to kind of go over all those issues and the details of how you prescribe Sinemet and adjust and everything, it's really helpful.

I guess with that, I'll end the Penn Primary Care podcast. Both of you have been terrific. Thanks so much, Nabila and Meredith. Maybe we'll have you back again to talk about some other issues related to Parkinson's in the future. With that, I want to thank the audience for joining the Penn Primary Care podcast. Please come again next time.