Predictability of Dyskinesia and OFF Episodes in Parkinson Disease

EP: 1.Defining the Patient Experience in Parkinson Disease

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EP: 2.Predictability of Dyskinesia and OFF Episodes in Parkinson Disease

EP: 3.Treatment of OFF Time in Parkinson Disease

EP: 4.Amantadine Extended Release for the Management of Dyskinesia and OFF Episodes

EP: 5.Unmet Needs and Future Considerations in Parkinson Disease

Robert Hauser, MD, MBA: There are several types of dyskinesia. The most common type is peak dose, levodopa-induced dyskinesia. So if you imagine a patient taking a dose of levodopa and think about the concentration of the blood, it gets absorbed, it peaks, and then it tapers down. Over time, many patients who have Parkinson disease and are on levodopa…develop what looks like a sensitivity to levodopa and higher levels of dopamine in the brain, such that when levodopa is peaking in blood, and dopamine is peaking in the brain, they’re experiencing chorea, or twisting, turning movements. And this is the peak-dose levodopa-induced dyskinesia. One can recognize this by the fact that if you lower the levodopa dose, these may be reduced or go away, and if you increase the levodopa doses [they] will be worse both in amplitude and duration. So this is the most common type of dyskinesia. If someone says, “Oh, this patient has dyskinesia,” that’s the kind of dyskinesia they’re talking about because it’s far and away the most common.

There are a few other types of dyskinesia. One type is called diphasic dyskinesia or DID, which stands for dyskinesia improvement dyskinesia. And these patients experience dyskinesia as levodopa is increasing. Then it goes away during this improvement or good ON phase, and then the dyskinesia recurs as levodopa is descending or tapering down. So it is diphasic, or 2 phases of the levodopa cycle in which patients experience dyskinesia. Some patients get it just while turning ON or while turning OFF, so it doesn’t have to be diphasic. But it’s during these changes in levodopa concentration. These tend to look a little bit different from peak-dose dyskinesia. They tend to occur more in the lower limbs, and they tend to be more dystonic or pulling-in type. They can be harder to treat. One thought is to try to keep the levodopa level up so that there’s less fluctuation up and down to cause these diphasic dyskinesias.

There’s one other kind of dyskinesia that I’ll mention that I think really shouldn’t be considered a dyskinesia because it’s really a horse of another color, and that is dystonia or OFF dystonia. These are often occur in the lower extremities, and particularly the foot may turn down or turn in, and these occur when levodopa is low or falling. Patients will say, “I get this at night or first thing in the morning,” because the levodopa levels and dopamine levels in the brain are quite low. Again, I think of them as being very different from the other kinds of dyskinesia I mentioned in that they occur as part of Parkinson disease, ie, with low dopamine levels in the brain, whereas the other kinds of dyskinesia I mentioned, peak-dose dyskinesia and diphasic dyskinesia, are really an effect of medication and effect of levodopa either going up and down or [a] patient developing a sensitivity, and they occur when levodopa is peaking.

I think predictability and variability are a topic that hasn’t really been explored as much as it should [be] in Parkinson disease. Initially, when patients begin to experience [a] wearing off of levodopa effect, it’s similar from patient to patient. They’ll say, “I noticed that my medication is wearing off a little bit. My symptoms returned, they’re mild, and then it takes some minutes for my next dose to kick in.” Now there is variability with regard to what symptoms occur for those patients. Some patients may notice tremor, others may notice slowness, some may notice fogginess of thinking or other nonmotor features. But there is this sort of pattern of, after 4 to 4 and a half hours, [there is a] wearing OFF of benefit, and it takes some minutes for the next dose to kick in. But over time, the duration of benefit from a given levodopa dose becomes much shorter, and that benefit duration becomes more variable, and when it occurs, [it] becomes much more variable.

One of the things we did in analysis was to look at a baseline database of patients who entered a clinical trial. In these clinical trials of patients with motor fluctuations, these are typically patients who are taking immediate-release carbidopa/levodopa, 5 doses per day or so, and they typically have about 6 hours of OFF time per day. But when we looked at this kind of population, what we saw was that if you look at the duration of good benefit or good ON, we call it good ON, and [for] ON without troublesome dyskinesia, the duration of that benefit was only 2.3 hours or so on average. So that’s a really short time. So, imagine living your life in these little epochs or episodes of 2.3 hours. Think about trying to, I don’t know, go out to the supermarket and buy what you need at the supermarket. You’ve got to get dressed, get out to the car, get to the supermarket and get back, presumably before you were OFF. Because for these patients, once they were OFF, they’re very slow and very stiff and may have a lot of difficulty with function. But again, it’s not just that. It’s that it’s very difficult to predict when will the 2.3 or so hours of good ON time occur. We did another analysis to look at how predictable these good ON episodes [are]. We…looked at what patients do in these studies, which is to fill out what are called diaries. So every half hour they indicate whether they’re OFF or ON [with] a troublesome dyskinesia or ON without troublesome dyskinesia. And we look to see how predictable the good times [are,] which is ON without troublesome dyskinesia also known as good ON. And we found that if you look at the same times on 2 consecutive days, only about 30% of half hours were predictable. That is the same across the 2 days for good ON time. So that just shows, even if I have that 2.3 hour episode of good ON time, I don’t know exactly when it’s going to occur, one day [at a particular time] or 10 [o’clock] another day. It may occur at 10:30. So there’s a lot of variability in response for patients on top of the fact that they’re trying to deal with these short episodes of good ON.

Both OFF and dyskinesia impact patients’ quality of life. I think in general OFF is much more obvious with regard to what can happen. Patients can become very immobile, greater kinetic tremor can return, and that’s pretty obvious to most people. On the other hand, dyskinesia, I think, is much more subtle. We ask patients in clinical trials to indicate whether their dyskinesia is nontroublesome or troublesome, and troublesome dyskinesia is an issue that interferes with function or causes meaningful discomfort. And this dyskinesia can cause sort of wild twisting, turning movements that make it impossible for patients to maintain good control, such as drinking from a glass or eating. But I think it goes [far] beyond that. There is a lot here that still needs to be explored. We know that when patients have dyskinesia, they’re more prone to falls. Also, even when patients either say that their dyskinesia is nontroublesome or they’re not having dyskinesia, it may be in part that they’re either not aware of the dyskinesia or they’re not aware of the disability from dyskinesia. In addition, like a lot of other movements, there are impacts beyond just the function, which include things like how they [are] perceived, how it affects their ability to go out and interact with other people and social interactions. So both dyskinesia and OFF can [each] play a very important role in patients’ quality of life.

I don’t think every little speck of OFF time or dyskinesia necessarily requires treatment. But I think that at every visit, the physician or health care provider should inquire about it and try to understand what’s exactly happening. One issue is, is the patient really perceiving the amount of OFF time or the [extent] of this condition, and its impact, sufficiently? Some patients may have [a] condition that they don’t even recognize, or they don’t recognize the impact. And same with OFF. A lot of patients don’t want to make changes in their medication. And it’s incumbent upon the physician or health care provider to really delve into that. At every visit, I’ve asked the patient, is their medication lasting from dose to dose? If not, how long does it last? How long does it take for the next pill to kick in? Also, what’s happening in the morning after not having taken medication overnight? Are you at your best because you have so-called sleep benefit, or are you worn [out from] OFF [time]? Do you find that it takes some time for the levodopa to kick in in the morning? Also, with regard to dyskinesia, a lot of times the patient’s partner is a lot more aware and potentially even more bothered by the dyskinesia. So it’s important to ask the partner what’s happening throughout the day with regard to OFF and dyskinesia.

These do have implications beyond just the problems that are caused by function. There are things that have to do with perception and social situations; what the patient is and is not doing. And there are also implications with regard to treatment. If a patient has both OFF and dyskinesia, the physician may not want to increase dopaminergic medication for fear of increasing dyskinesia further. So I think it’s important to try to get an accurate assessment [of] OFF and dyskinesia as soon as it occurs. A little tiny bit of dyskinesia and OFF, I’m not sure really needs to be treated, although I’m interested from a research standpoint—will there be better outcomes if we try to smooth things out right from that point forward? But surely when things begin to affect a patient’s function or cause social interactions to decline, that’s when interventions are called for.

Transcript is AI-generated and edited for clarity and readability.