Overview of OFF Episodes in Parkinson’s Disease


Daniel E. Kremens, MD, JD: Hi, and thank you for joining me for this NeurologyLive® Peers & Perspectives® presentation, titled “Optimal Management of Off-Episodes in Parkinson Disease.”

Today we are going to discuss the diagnosis, management, and treatment of off-episodes in Parkinson disease.

I am Dr Dan Kremens from the Sidney Kimmel Medical College at Jefferson University in Philadelphia, Pennsylvania. Joining me today is my colleague Dr Rajeev Kumar, from the Rocky Mountain Movement Disorders Center in Englewood, Colorado. Thanks so much for joining us. Let’s begin.

Rajeev Kumar, MD: It’s a pleasure to be here.

Daniel E. Kremens, MD, JD: Rajeev, could you give me an overview of off-episodes in Parkinson disease? How do you think about them?

Rajeev Kumar, MD: When we think about off-episodes, we’re defining a time in which motor symptoms and, to some extent, nonmotor symptoms are not adequately managed. If a patient has an optimal on response, they’re functioning normally or very close to normal. They may or may not have dyskinesia if they have advanced Parkinson disease, and they typically have good relief of nonmotor symptoms. Nonmotor symptoms include such things as anxiety, sweating, and apathy. Cardinal motor symptoms, of course, are symptoms such as tremor, rigidity, bradykinesia, and gait disorder.

In somebody who has an off-episode, it could be predictable, such as end of dose wearing off. For example, if somebody is taking Sinemet [carbidopa-levodopa] 3 times a day, they may notice that the first dose of medication takes half an hour to kick in. The efficacy in terms of motor and nonmotor symptoms is 3 hours, and it wears off a half hour before their next dose if they’re taking doses every 4 hours. Surrounding each dose, they may have wearing off a half hour before, and it takes a half hour to kick in. Therefore, they’re off for an hour toward the end of a dose through the beginning of the next dose. That would be a predictable off-episode.

Off-episodes can also be characterized as a dose failure. Suppose somebody takes a dose and it doesn’t kick in at all. This may especially occur when somebody is relatively protein sensitive and may have gastroparesis. They take a dose at noon and have a lunch consisting of a heavy meal (eg, hamburger and fries). But the dose doesn’t kick in, and they’re off from noon to 4 PM, which is their next scheduled dose.

Another form of off-episode could be a delayed on response. They have their meal with their medicine, for example, and they have delay in gastric emptying because food stays in the stomach longer. Therefore, instead of their medication kicking in within a half hour, it takes an hour or an hour and a half. That would be a delayed on response.

Another form of off-episode could be unpredictable. The patient has taken their medication and seems to be doing well, but the medication doesn’t last the full 3 hours or so. For example, they took their medication at 8 AM and it kicks in, but at 10 AM it wears off and they have 2 hours till their next dose. That would be an unpredictable off-episode.

The pathogenesis of off-episodes is interesting. We think there are both pharmacokinetic and pharmacodynamic factors in play. Most of our therapies for the off-episodes revolve around treatment of the pharmacokinetic factors. We acutely apply a dopaminergic stimulus to take this person with a low amount of dopaminergic stimulus to a normal amount of dopaminergic stimulus, either by applying levodopa therapy or by applying a quick-acting dopamine agonist therapy (e.g. apomorphine).

Daniel E. Kremens, MD, JD: One of the other off-episodes that a lot of my patients complain about is morning off-episodes. They wake up in the practically defined off-episode state. They haven’t had any of their medicine since the day before, and they wake up and they’re off. They take their medicine and sometimes get dose failure. In that case, protein really isn’t an issue because they hadn’t eaten. It’s probably both a combination of the central mechanisms as well as the peripheral mechanism that you were referencing earlier (eg, gastroparesis). Another really important point that you highlighted for our colleagues who might not be movement disorder specialists is this notion that an off-episode isn’t just the classic wearing off described, and it’s not just motor symptoms. You emphasized off-episodes can definitely be nonmotor symptoms (eg, anxiety, dread, fogginess) and more than just classic wearing off. Delayed on responses, dose failures, morning off-episodes, and unpredictable off-episodes are forms of off-episodes that sometimes people don’t think as much. But the patients are certainly aware of them.

Rajeev Kumar, MD: I agree with your point, especially about the morning off-episodes. That is usually the worst off-episode of the day because they haven’t taken their levodopa for an extended period of time (maybe 8 or 12 hours). The plasma level of levodopa has really dropped, and the pharmacokinetic aspect is pretty much at its nadir, right?

Daniel E. Kremens, MD, JD: Right.

Rajeev Kumar, MD: They may require a much higher amount of dopaminergic stimulation to get them on again in that scenario. When given levodopa therapy, even orally, they may need a higher dose to kick them in than their regular dose because their plasma level is so low. When we think about plasma levels of levodopa, for those people who like to look at pharmacokinetic charts, we’re talking about trying to get the plasma level of levodopa typically above 1000 ng/mL. That’s quite a lot of levodopa. The amount of levodopa to take orally varies a lot. You can have a little thin lady needing very little. On the other hand, instead of needing 50 or 100 mg of levodopa, that same person may need 300 mg. It’s quite interesting how there’s a lot of interpatient variability. It really needs to be a customized dosing schedule. How we deal with morning off-episodes is really an interesting and important special case that I’m sure we’ll discuss du

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