Stuart Isaacson, MD

 Dan, you mentioned this idea of motor and nonmotor symptoms. Do you try to link them when you educate your patients and their caregivers on what symptoms first occur? Tremor is often notoriously difficult to link to OFF, because sometimes it can occur just going ON. How do you educate patients who tell you in relation to motor and nonmotor symptoms?

 I definitely discuss that with patients because we find that many patients have concomitant nonmotor and motor symptoms. Oftentimes the nonmotor symptoms will precede the motor symptoms. It’s common for patients to describe a sense of dread, mental fogginess, and fatigue. Then they’ll note after that, “My tremor is reemerging; I’m having difficulty getting out of the chair; I’m freezing”—things like that. The key is to ask the questions, and they can be open-ended. “Tell me about what happens. Do you experience any strange feelings before you see your tremor?” A lot of times the patient will note the motor symptom because it’s obvious to them, but they may not link the fact that they have this anxiety or dread, or sweat before the motor symptoms emerge. I like to say, “Tell me about a typical episode,” and link it that way.

 Do you tend to rely on some symptoms or usually wearables? How do you educate patients of what they should report to you? Do they keep notes every single day of the month or only a day before they see you? Do you have observing in the clinics?

We have patients who bring in notes from every single day. I don’t necessarily encourage that, but we use written diaries in some cases, especially if there’s confusion and especially trying to sort out dyskinesia. Plenty of these patients have dyskinesia as well as the OFF-time, and the dyskinesia can interfere frequently with managing the OFF-time, especially with trying to make longer-acting medications.

We use written questionnaires sometimes, but it’s largely based on interview. I haven’t started to use wearables in clinical practice. We do that in research, but I’m not sure if people are doing that clinically yet.

 How is the diary used in research programs? Are there symptom diaries that patients can check off? What types of diaries do you use?

 Symptom diaries are probably the easiest ones where you can check off a symptom when you experienced it, and write down when you have symptoms and what it looks like. The simple diaries downloaded from the Internet have a 24-hour clock at the top, and you can edit it if you need to by checking off the medication and writing down the medication you took, for the most part some form of levodopa preparation. You can write down the other ones, but many of those are moved to once a day. You check off when you take that medication and eat—you can put M for meals, and O for OFFs. Extra medication is O for OFFs and M for meals.

They can take 3 or 4 days’ worth of that information and give it to me, preferably on 1 or 2 sheets that I can review quickly, so that I can see across multiple days. But there’s something between diaries and wearables that we haven’t discussed. Wearables are something kind of the promised land that’s coming up, and hopefully we’ll have the ability of it outside of research and diaries.

Videos are typically underutilized. Almost every 1 of our patients has a cell phone with a camera. If they’re not sure what OFFs look like, I want to see what OFFs look like. The same thing applies to tremor, though that’s beyond the scope of our conversation. When you say he or she has bad tremors, what does that mean? My definition of that is different from yours. I ask them to do a specific maneuver to find out when the individual is having an OFF. I have the house or caretaker do a get-up-and-go test.

I want them to sit in a chair and get up from that chair, go across the room and come on back. I want to see what that looks like during an OFF so that I can say that it’s an OFF, unless it might be obvious that it’s an OFF. Then video when you feel the medication is working well, and we can compare side-by-side, and I get to see exactly how difficult it is.

The main limitation is that you may have videos that show only part of the view. They may not be good-quality videos. A little education can help with that. The videos may just be motor based. Nonmotor components don’t get captured as much on videos.

The other thing I encourage is getting one or two 30-second, 1-minute videos to help illustrate how bad your OFFs are, because when we see patients in our office, the majority of the time they’re ON. The only times they’re OFF is when somebody else is taking care of their medications and responsible for their transportation. Virtual visits have given us a little more of a window, but 80 percent of my patients who complain about OFFs show up in the office ON.

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Videos

Panelists describe the motor and non-motor symptoms of Parkinson’s disease, linking symptoms to OFF episodes, and how to educate patients.

Motor and Non-Motor Symptoms in Parkinson’s Disease

 How do you evaluate your patients for OFF, and how do you evaluate patients from morning OFF? Patients don’t always come in and say that they have a morning OFF. How do you look for it, and what questions do you ask? Which patients do you ask?

 After asking about how they’re doing, typically my next question is, “Tell me the exact times you’re taking your levodopa”—7:11, 3:08, whatever. “At any point in between these doses, are your symptoms changing? Is anything worse?” I often say, “Around the time you’re taking a pill,” because some patients think that when they take the pill, in 2 seconds the pill is going to have its effect, but it’s typically at least 30 minutes.

“Is anything worse? Are there any changes through the day?” We try to ask, “Is there any pattern that you can come up with this?”

Sometimes you get these nice stories with a straightforward pattern. Other times it’s much more inconsistent. It’s like, “Usually I’m doing well, but every now and then, at 11 PM, I’m freezing up.” I keep it open-ended because OFFs can be quite a few types of symptoms. There are the obvious OFFs, where the tremor comes back or they can’t walk, but there’s this whole spectrum of nonmotor OFF symptoms. They break down into 2 groups, which are opposite in some way.

The first group of nonmotor OFF is this anxiety, sometimes palpitations, or even breaking out into a drenching sweat, called “the drenching paroxysmal sweat,” or Parkinson disease. These patients can look like they’re having an MI [myocardial infarction], and I’ve had plenty of patients with this sort of wearing OFF that have been evaluated with ECGs [electrocardiograms] and gone to the emergency department.

The other general nonmotor wearing OFF is the opposite, where people get fatigue or anhedonia. They don’t want to do anything, but they may be physically able to do that. I keep it very open-ended when I’m looking for anything that’s changing through their day, then looking for a pattern or not a pattern with these changes.

In the morning, some patients expect to take a little while for that first dose to kick in. We try to quantify that, and it largely comes down to how it impacts their life. This often comes down to whether they’re working or retired, and those sorts of things.

There is a small subgroup of people who do very well in the morning. Historically, in the literature this was called the sleep-sparing effect. I don’t think it has anything to do with sleep-sparing effect, but it’s more just natural circadian patterns. Our own natural dopamine levels peak, maybe 4:30 to 5 AM, or maybe 6:37 AM, and then they start to come down. This occurs in 5% of patients who have this nice time when they first wake up. Those are the ones telling you, “I’m doing fine until I take my levodopa, and then I’m doing worse.” You especially see this if they wake up very early, but that’s a minority. In most patients, the problem is the other way around: they’re taking a little while to get going in the morning. How aggressive you are with this depends on how aggressive the patient needs to be in addressing that.

 One thing that happens is that the patients accommodate it, and that’s not necessarily a good thing. They take their medicine and lie around in bed for a long time waiting for it to kick in. They delay activities in the morning, or they change their social situation, because they’re not going to turn ON.

They accept it. I tend to be a little more aggressive with questioning about that, like how much is it really impacting their day? If they say it’s not, I push them a little and ask, “Tell me about your morning.” When they tell me, “Well, I’m lying around in bed until 10 o’clock because my levodopa takes an hour or more to kick in, so I’m not going out to walk with my friends who take their 9 o’clock walk,” or things like that. They’ve gotten used to it, and the patients don’t appreciate necessarily the impact it may be having on their lives if we don’t explore it.

What does the conversation sound like in California? How do your patients feel in the morning? Is that a problem on the West Coast?

 I start with education because I can get important information from my patient if I educate them about why I’m asking the question. It usually starts with when I look at the status of my patient, if my patient is ON or if my patient is OFF. When the patient is OFF, I tell them that I’m asking because I don’t want you to feel like this the rest of the day, and I ask them, “Are you having this condition the rest of the day?”

Also, a patient can come to the clinic ON condition, and I ask them, “Is this the way you are 24-7?” All of us get this response: “Doctor, you’re so lucky. This is the only time he’s doing that well. The majority of the time, he is not like this.” Correct? Therefore, I always bring this to the front of their face. But I say, “If you can be this good, like speaking nicely, having the body language, and you can walk well, there’s no reason I cannot extend this and you’d be continuously ON.”

When they understand the importance of what I’m asking them, then I start to ask them about how they are doing from 1 dose to the other. The conversation doesn’t go the way we want, or they’re not the best historian to tell you exactly what happened during the day. I ask them chronologically, “Can you tell me how do you in the morning when you wake up? Based on what I told you what is OFF and ON, do you wake up OFF or not?” Then they tell me, step by step. I say, “If you take your first dose in 7 AM, how do you do after you take your 7 AM until your next dose?”

They walk me through that. How many times we heard from our own colleagues, “I don’t see that much unpredictable OFF time.” Patients teach us that it’s more than we expected. The first thing the patient says is, “Doctor, that’s not the way you’re asking me. It’s not the regular matter. One day my dad is doing good, the other time he’s not.” They’re telling us that these OFF times are unpredictable and not always in a regular fashion.

That’s the best way that I found to educate them about ON and OFF. Second, I emphasize that it’s important for me to know that because that’s the goal that they’re going to achieve. You’re going to achieve that if a patient is ON continuously during the day.

A discussion on how patients are evaluated for OFF episodes, by expert neurologists.

Parkinson’s Disease: Evaluating Patients for OFF Episodes

: The OFF episodes could be expected or unexpected. Patients at an FDA meeting a few years back pointed out how difficult it can be to have these unexpected disruptions during the day. What do you think about those?

: There is a little bit of a bias recall when we ask our patients about OFFs. They may be only telling us a portion of the story, and sometimes they’re not able to tell a story, and I don’t view that as a negative. I ask for patterns like, “Is it occurring after you take a dose and the dose doesn’t take effect?” That’s one pattern. “Is it occurring consistently before a dose ends? Is it occurring as a surprise to you for no rhyme or reason? Have you missed a dose, have you taken a dose close to food?” About 50% of the time, I get a typical pattern. I’m assuming that’s the most common type of OFF. I’m sure there are other lingering OFFs that they also have.

If I don’t get a clear history, I don’t view it as a negative. I use this as an opportunity for the patient to give me a journal or diary of things. I’ll give them information and a diary. Folks can download this from the internet as well. They’re available if you simply look for a Parkinson diary. I ask them to mark off 3 things: when they take their medications, when they eat food, and when they experience OFF. I ask them to keep it for 3 or 4 random days. I don’t want them to be affected by 1 day or something else going on. They bring it to our office in about 2 weeks, and with virtual visits, it’s actually even easier because I can review it while they put it up in front of the camera.

I look for a pattern. Either I’m able to identify a pattern or I am not, and we can talk about that. Many times you’ll see the pattern occurs after a meal. They take the medication, an hour later they take a meal, and then an hour later, they’re OFF and they have an extended OFF. Sometimes we look for trying to quantify how many they have. Sometimes people will say there are only 1 or 2 OFFs. But in reality, some days they will have 3 or 4 OFFs. There’s a little bit of bias recall. They might only tell me the last few days’ worth of information, but there’s more lingering underneath.

Sometimes the most interesting thing is compliance or adherence. We tell our patients to take medications on time. Now that they’re forced to mark off an X when they take the medication, many times you’ll see an X marked off at 2 o’clock with an arrow saying, “Oops, that was my 12 o’clock that I missed and I actually took it at 2.” And you can see that from 12 to 2 they had an OFF; that OFF continued till about 3. I tell them, “There are 2 types of OFFs here. One, you took your medication late, turning yourself OFF, and then it took longer to get into your system.” I say, “Look, this is self-inflicted, this is something you could have avoided with better adherence to time.” We talk about alarms.

There are a lot of different strategies, and the diaries are good as long as we use them appropriately, keeping a couple of days of diary to get a good sample size of what types of OFFs they’re having, how frequent, if there’s a pattern. If there’s a pattern, good. If there’s generally no pattern, then we work from there as well.

: You raised an interesting point that we haven’t touched on about what OFF is. Because it’s not just the wearing OFF, it’s also time to ON, and a lot of people don’t think about that when they’re talking about OFF. That really expands the OFF episode for the person. We now have therapies that can rapidly turn patients back ON, but if you just take another levodopa that has to sit in the gut and metabolize and get up to the brain, that can be awhile, and that time to turn ON is part of that full OFF episode.

: Absolutely, and you see that in diaries much more. Somebody who should have taken their dose at 12, they start to turn OFF at 10:30, and here they are still OFF at 12:30. I say, “Look, this dose never kicked in. You started to turn OFF before your next dose is due, and your next dose didn’t kick in.” You can see that and I can look at it much more neatly, whereas patients may not be able to vocalize that this was 1 combined episode from our point-of-view made up of 2 separate components.

: Diaries are great, but diaries also rely on the patient to accurately fill them out, and we now have some evidence emerging with wearables. With respect to at least kinetic or motor type OFFs, the future is to use some type of wearable to more reliably correlate potentially with the diary. It’s the old “trust but verify.”

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Physicians explain expected versus unexpected OFF episodes and the use of symptom diaries in managing Parkinson’s disease.

Expected and Unexpected OFF Episodes in Parkinson’s Disease

: There’s a lot of understanding of why these motor fluctuations emerge and why they can emerge so early and continue to progress over time. It’s certainly a problem for our patients who live with Parkinson disease and rely on this cornerstone oral carbidopa/levodopa to give them benefit and improve their symptoms, but then these OFF episodes occur. How are they a problem for patients? What do patients have to contend with when these episodes are manifested?

: As we defined, OFF episodes are a reemergence of Parkinson symptoms. OFF episodes are intrusive depending on when they occur. They can occur first thing in the morning, middle of the day, or at any point. It can be predictable or they can be unpredictable. My most active patients are the ones who are the most bothered by OFFs. They value their ON time. They understand the meaning of ON time, and they understand how much they can accomplish when their medications are working. Similarly and conversely, they realize that when their medications are not working, as one of my patients said this morning, “I will do almost to anything to get rid of this OFF so that I can get back to my activity.” This is a younger, more active individual, but this logic applies to almost everybody. How bothersome are these episodes? It depends on the duration. How long are these lasting? How frequent are they? You have individuals with severe OFF episodes that are occurring multiple times a day, for 20, 30, 40 minutes, which becomes a significantly bothersome issue. People have quit jobs over this, stopped working, stopped volunteering, and stopped going to exercise classes. People have stopped doing these things because they can’t contend with these OFF episodes.

: How do they affect our patients’ quality of life? What’s the evidence that they actually impact quality of life and are not just a nuisance?

: For patients who you are leaving without managing their OFF times, you’re basically leaving them with some tremor, stiffness, and slowness of movement. The irony is that at the same time we lecture our patient that, “I want you to be physically active; I want you to do exercise.” It is completely unfair to leave the patient who does not move well, and say, “Look I want you to do 2 hours a day of exercise.” The whole OFF time is hard for our patients in their activity of daily living. It also affects them in the way we are managing the Parkinson disease as a whole.

I think morning OFF affects quality of life in 2 ways. One is the direct way, in which the patient wakes up and they have 1 symptom of tremor, bradykinesia, or a constellation of the symptoms, such as cramping plus difficulty walking. Then obviously they have a hard time getting up, they have a hard time putting their pants on or shoes, they have a hard time reaching the sink to brush their teeth. They don’t comb their hair, they have a hard time getting to the kitchen, to sit at the table and have a bowl of cereal. All of these directly affect their quality of life, and activity of daily living.

However, the other view that I have is that I look at the OFF time in the morning like a big alarm clock that you have. This alarm comes to you ear and says, “Wake up, you have Parkinson disease.” You basically wake up with this message every morning. This is in contrast to what I want for my patient. I always tell my patient that, “I want you to take control of your Parkinson, know that you are normal, because I’m managing your symptoms.”

But if the patient wakes up every morning with this message, these symptoms mean somebody is reminding you that, “You have Parkinson disease, wake up.” If I can manage the morning OFF and my patients wake up ON, they have more motivation. I want to make sure they understand that we can manage morning OFF, and there are different treatment options. We can change it in a matter of minutes that a patient can be ON and avoid all of these issues.

: Dan, there are many different types of OFF—morning OFF, overnight OFF, wearing OFF, the late ON—which ones most impact quality of life? Do they all? Do some more than others?

: They all do. It’s not just that the patient can’t move, or the patient can’t get out of a chair, it’s that the patient might have severe anxiety. The patient might have bradyphrenia. The patient might have other of these nonmotor symptoms, so it’s really important to keep in mind that these nonmotor symptoms are really important, and the impact that OFF has on people.

In terms of what are most bothersome, the EUROPAR study looked at a number of different OFFs, and they all had significant impact. But the relative incidence was that early morning OFF had a marked impact on patients and their quality of life as measured by different scales in that study. Although they all can impact patients, morning OFF clearly was rated, at least by these patients, as their most bothersome.

Key opinion leaders provide insight on how OFF episodes affect patients’ quality of life.

Stuart Isaacson, MD

Articles

Motor and Non-Motor Symptoms in Parkinson’s Disease

Parkinson’s Disease: Evaluating Patients for OFF Episodes

Expected and Unexpected OFF Episodes in Parkinson’s Disease

Impact of Parkinson’s Disease OFF Episodes on Quality of Life