Dan Keller 0:02 Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research, the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

Off episodes are a troubling aspect of Parkinson's disease. They can be sudden and unpredictable, or gradual, such as when medication is wearing off, causing a return of motor or non-motor symptoms. They can start early on with the disease and usually increase in frequency over time as the disease progresses. Today's guest, Dr. George Kannarkat, a movement disorders fellow at the University of Pennsylvania, describes some of the causes of off episodes and how they manifest, and he suggests a variety of ways to help minimize them with a look to what new medications are here now and what's in development. Basically, what are some of the signs and symptoms of an off episode?

Dr. George Kannarkat 1:31 With off episodes, there are both motor and non-motor manifestations, so that means when we have motor off periods, you may experience some of your Parkinson's symptoms come out—things like slowness, stiffness, tremor, shuffling gait. And there may be other non-motor symptoms, so things that are not associated with movement, things like anxiety, feeling tired, feeling just kind of an internal sensation of slowness with thinking. So those are the symptoms that people often experience with off episodes.

Dan Keller 2:05 Broadly speaking, when in the course of Parkinson's disease do off episodes become more troubling or more prevalent?

Dr. George Kannarkat 2:13 Typically, people in early stages respond really well to dopamine replacement medications, and it's really over the course of a couple of years—two to three years in the literature—that people start to experience these off episodes. Initially they happen infrequently, but as the disease progresses, and as people have more moderate and advanced disease, it can be up to even 40 to sometimes 50, 60% of the time that someone is spending in an off episode throughout their waking hours.

Dan Keller 2:42 How suddenly do they come on? How quickly does the medication wear off?

Dr. George Kannarkat 2:46 There are a few different kinds of off episodes. So there are certainly the sudden off episodes, but the majority of the time what people experience is "wearing off," and this means that as the levodopa, or whatever dopamine replacement is being used, is metabolized and wears out of their system slowly, the Parkinson's symptoms re-emerge—both the motor and the non-motor symptoms.

And then there's a subset of people that experience these unpredictable or sudden offs. These also fall into a few different categories. Sometimes it can be that you take your medication, the medication starts working as usual, but then you're going along doing your normal routine, and then all of a sudden your off symptoms come on without any warning. There are other types of sudden offs where the medication that you normally take, you take it as you normally would, but it just doesn't work for you at all after you take it. And then there are kind of partial offs, where you take your medication as you normally would, but you don't get that good "on" as you typically would expect. So, those are the different kinds of unpredictable or sudden offs.

Dan Keller 3:53 Are there identifiable factors that affect the occurrence of off episodes?

Dr. George Kannarkat 3:59 The underlying mechanisms for why off episodes happen are not entirely clear. There are a few ideas that we understand in the Parkinson's community. So, the first one is that as the dopamine-producing neurons in the brain die off, there are just fewer of them around to kind of use that extra buffer of dopamine that we provide through the gut.

The other idea that is out there is that actually, in people that have more advanced or severe Parkinson's disease, they just don't absorb the medication as well or less reliably. This can be due to a multitude of factors, but the main ones are delayed gastric emptying—so slowness in how your stomach moves along food into your intestines—and then also actually how food is absorbed and passed along once it reaches the intestines, too. And so this changes the way that the medication is absorbed into the bloodstream, and then as a consequence, how long it takes to get into your brain, and it may be at irregular intervals.

That's what we understand about why these off episodes may occur, and really the way that we target or deal with these off episodes, the first is to try to make sure that we have a more reliable spread of dopamine replacement over the course of the day. This can mean either taking your carbidopa/levodopa more frequently, sometimes at smaller doses if you have side effects at higher doses—such as getting dyskinesias at high doses—so putting the medication into smaller doses, taking it more frequently. And then oftentimes we have to add on other medications to help provide a more continuous level of dopamine supplementation, and this can be through medications like dopamine agonists—medications like ropinirole, some people may use—and then other medications that change the metabolism, so the breakdown of carbidopa/levodopa in the bloodstream, to make it last longer. And so these are medications like COMT inhibitors, a word that you've heard, so those are the main strategies.

And then we can talk a little bit about some of the things that are coming down the pipeline even, that are exciting to help treat the off periods. So, and now that I think about it, I can also tell you about some of the medications that are already out there that treat these more sudden off periods. There's one, an inhaled form of levodopa, that's often used when people have these sudden off periods, and it's really like an inhaler that you use whenever you have an off period, and that can be used as a rescue medication. There's an injectable form of a medication called apomorphine, and then there's also one that you can place under the tongue of that same medication, apomorphine. So, those are both used as rescue medications for those sudden off periods, but initially the goal is to kind of even out the dopamine supply or dopamine replacement over the course of the day.

Dan Keller 6:45 Once someone takes levodopa, is it possible for any other medication that they take later or food to interfere with it? Or once it's in your system, it's in, it's okay.

Dr. George Kannarkat 6:56 So that's a great point. And so that's something we think about often. Levodopa is an amino acid, and so what that means is that if you take levodopa with other foods that have proteins in them, that protein is competing for absorption with the levodopa. And so we know that it reduces the absorption and makes it less reliable if you take levodopa with particularly protein-rich foods.

So one of the other things that we recommend is to try to keep in mind, are you taking the levodopa with food? If you are able to tolerate it by spacing it out—so either 30 minutes before a meal or an hour after you eat—sometimes the off periods are reduced in that way. And then there are other tricks that have often been helpful for individuals to help speed up absorption: actually crushing at least the immediate-release carbidopa/levodopa in your mouth as you swallow it, so that it gets absorbed more quickly. That can also help with sudden off periods, and also to help get it absorbed into your system more quickly during a regular dose.

And then there's also another strategy where you can mix the crushed carbidopa/levodopa tablet in acidic or carbonated water; that also helps the carbidopa/levodopa get absorbed more quickly into your system, so those are a couple of tricks that you can try.

And then the last piece of advice I'd add is there's literature on gastroparesis—so delayed emptying of the stomach—and how that can play a role in decreasing the absorption of levodopa in a consistent manner. There's a little bit of controversy. We rely on our gastrointestinal doctor colleagues to help us with treatment of gastroparesis, but that's something that you can talk to your physician about if you're concerned that you're having symptoms of gastroparesis or delayed stomach emptying, which are often bloating and belching and lots of nausea immediately after you eat.

Dan Keller 8:45 And I guess we should note that levodopa in your stomach doesn't do you any good; it has to make it to the intestine to be absorbed.

Dr. George Kannarkat 8:52 Yeah, that's absolutely right. That's absolutely right.

Dan Keller 8:54 What about people planning ahead not to have an off episode? Say they're going to be at an event or something like that. I know Michael J. Fox says when he goes on TV, he has dyskinesias—he's twitching and whithing—because he doesn't want to have an off episode, so he kind of over-medicates.

Dr. George Kannarkat 9:11 That's a great point. I will often advise my patients to actually have some extra carbidopa/levodopa on hand when they're going to a wedding or to an uncertain situation where they need to be in an "on" state. As long as you know that you're not going to have a side effect by taking an extra dose—such as dyskinesias or sleepiness or nausea—it's often okay to just take that extra dose, a tablet or half a tablet, to prevent an off period or to make sure that you're really on when you need to be.

The other consideration for that is to make sure that you're also reliably doing the things that you would do on a normal basis, you know, making sure you're not taking it around food, you know, when you're at an event. And then the last thing I will say is that anxiety and stressful situations are commonly reported in individuals to bring out off periods or make medications feel like they don't work as well.

Dan Keller 10:03 Paradoxically, can higher doses of levodopa raise the risk of wearing-off phenomena more than normal?

Dr. George Kannarkat 10:12 So, there are some reports in the literature, and Stanley Fahn, one of the grandfathers of the movement disorders field, will often mention that there are some individuals where they've been on high doses of carbidopa/levodopa for a while, and then they start to have wearing-off episodes, or even episodes where they just go completely rigid. And then actually, reducing the dose of carbidopa/levodopa will help—they feel better with reducing the dose. So that's something we'll often try if we notice that it's an individual that's been on high doses for a long time, but I think that's more of the exception rather than the rule.

Dan Keller 10:46 If someone is noticing or experiencing off episodes, when should they report it to their movement disorders neurologist, or should they do it right off the bat to fix it immediately?

Dr. George Kannarkat 10:58 I think you should definitely let your movement disorders neurologist know as soon as you experience one, because I think there are probably simple things that you can do, and then they can provide you advice on that to just help reduce that off period. Because we want to make sure that you're living life at your best and have the best quality of life that you can, and so that means minimizing those off periods. And another term that's often used is having your best "on" periods, too—so that can mean titrating your medication, moving it around, changing the dose.

And often what's helpful is actually keeping a diary for your movement disorders neurologist. You can find these diaries online, so through the Parkinson's Foundation, through the Michael J. Fox Foundation, they have some templates and outlines for how to do that, but it helps us know what times of day these off periods are happening. Does it correlate with a meal, with other medications that you may be taking? And so that can help us guide you on how to change your medication regimen, or if we need to make any changes or additions.

Dan Keller 11:57 What about when it gets to the point where someone is considering or having deep brain stimulation? Do they still experience off periods, or can you just turn on the deep brain stimulator and overcome it?

Dr. George Kannarkat 12:10 So, deep brain stimulation can certainly reduce off time and reduces off periods, but may not eliminate it completely. There are individuals who can certainly reduce medications, and in some cases even come off of medications completely after deep brain stimulation surgery. The goal is to reduce overall off time, but sometimes people still need to be on some level of medication to reduce their off time.

That prompts a good point of another reason to tell your movement disorders neurologist about when you're having off periods, because one of the indications or the reasons to have deep brain stimulation is to treat off time and off periods. So, noting that may prompt that discussion of we should start thinking about DBS, or whether you're a good candidate for DBS in the future.

Dan Keller 12:56 Where does exercise fit in? Does that help with off periods or not?

Dr. George Kannarkat 13:00 Exercise overall is good for Parkinson's disease. There's evidence that it may slow disease progression. I think a little less than a year ago, there was a study via the Fox Insight study—it was a survey of people with Parkinson's disease and what they did to reduce off times outside of taking medication. The overall majority said exercise was actually their way of reducing an off period. From individuals with Parkinson's disease, it is helpful to reduce off periods when we know that it may slow disease progression overall.

The other things that were reported in that study to be helpful for off periods were meditation and mindfulness practices, taking a break from whatever activity that was being done, and then there were a whole host of other things, such as stretching and prayer and things like that, that have also been reported to help with reducing that off period.

Dan Keller 13:49 So, in terms of sudden off periods, what is the nutshell recommendation, or the few things that people can do about it?

Dr. George Kannarkat 13:58 Yeah, so I think the bottom line is to think about, are you taking medications with food? Are you having symptoms of delayed stomach emptying or gastroparesis? Talking to your movement disorders neurologist about changing your medication regimen to help treat those off periods, and then using some of those rescue medications to try to limit the severity of those off periods when they do occur.

Dan Keller 14:22 Is there anything interesting or important to add that we haven't touched on?

Dr. George Kannarkat 14:27 There are some neat interventions coming down the pipeline that I think are really exciting—and at least I'm really excited about—that could change how we treat off periods. There are, in clinical trials, infusions of levodopa and apomorphine that are basically pumped underneath the skin. I know there's already an FDA-approved device, Duopa, that pumps a levodopa gel into the intestine directly, that does reduce overall off time as well, because you have a consistent supply of levodopa, but it does come with the caveat that you have to have a tube that goes into your intestine. Subcutaneous pumps—the only real adverse effect is some skin irritation that gets better with time, at least in the data that have come out so far—but it shows promise in actually reducing pill burden and reducing overall off times by giving a constant infusion of the medication under the skin.

Dan Keller 15:17 Would this be sort of equivalent to an insulin pump sort of setup?

Dr. George Kannarkat 15:21 Yeah, so they look quite similar to insulin pumps, and will be actually easier to manage than insulin because you don't need to titrate it to food or anything like that. You just set it at an infusion rate that works for you. There may be some initial setup in terms of finding that right infusion rate, and maybe changing it depending on if you have a higher activity level one day, for example, but overall much less complex than setting up an insulin infusion pump.

Dan Keller 15:46 And that would get around the problem of gastroparesis. What about nausea? Would that still potentially cause nausea too, or not?

Dr. George Kannarkat 15:55 For levodopa, it certainly will help reduce nausea, but the apomorphine nausea could still be a problem. But there are medications that we can prescribe to get around that, and for some people, the nausea does get better with time.

Dan Keller 16:07 Is that the big news coming along, or is there other stuff too?

Dr. George Kannarkat 16:11 I think those are the big things right now for sudden off periods that I'm aware of, but I know that's something that people are continuing to work on. And you know, even things like better targets for DBS are also underway, too—not necessarily specifically targeting sudden off periods, but better ways to target specific symptoms, such as freezing of gait, that can be associated with off periods but not necessarily treated very well with our current medications.

Dan Keller 16:34 Very good practical advice. I hope people take it to heart if they're having off periods.

As Dr. George Kannarkat mentioned, the first step if you are having troubling off periods is to discuss the problem with your movement disorder neurologist, since there are a number of medications and strategies that can help. Also, keeping a diary of when and under what circumstances they occur can give the doctor a better picture of the problem. Also, in a previous podcast titled How to Manage Parkinson's Off Time, Dr. Irene Malaty explains what causes so-called on-off fluctuations and how you can work with your doctor to manage them. You can find it in our list of podcasts at parkinson.org/podcasts. And if you come to our library at parkinson.org/library, you'll see a link to a fact sheet called Motor Fluctuations, which also discusses non-motor fluctuations with information on why both happen, treating them, and an overview of specific classes of medications.

April is Parkinson's Awareness Month, and this year we're going to "Take 6 for PD." New research shows that someone is diagnosed with Parkinson's disease every six minutes. Take six minutes this month to spread awareness and help create a world without Parkinson's. Visit parkinson.org/awareness to find out more.

News and updates about future events and resources are available by joining our email list at the bottom of our website's homepage. If you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts or wherever you get your podcasts.

At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Till next time, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO. That's 1-800-473-4636. Thank you for listening.

Dr. George Kannarkat is an MD-PhD trained physician-scientist who is currently finishing his Movement Disorders fellowship at the University of Pennsylvania. After fellowship, he will be staying at the University of Pennsylvania as an Instructor to continue seeing individuals with Parkinson's disease while concurrently working in the lab of Dr. Alice Chen-Plotkin. His research interests are understanding the molecular mechanisms, particularly those outside the brain, that contribute to initiating pathology seen in Parkinson's disease. His ultimate goal is to help develop technologies that identify and treat disease in early or prodromal stages. He completed medical school and his graduate training at the Emory University School of Medicine where he worked in the lab of Dr. Malu Tansey to work on peripheral immune mechanisms of neurodegeneration. He completed his neurology residency at Johns Hopkins Hospital.