Expert neurologist reviews manifestations of OFF episodes and their impact on the quality of life of patients with Parkinson’s Disease.
Stuart Isaacson, MD, FAAN: When we think about OFF episodes, we think about different characteristics that can help us explain to patients when they should be thinking about their symptom benefit: are they having an ON [episode], or are they not having benefit from that dose of levodopa and having an OFF episode? These OFF episodes can occur at different times of day. It could be a morning OFF. It could be or a postprandial OFF accompanied at mealtime by a protein effect, where protein interferes with the absorption of levodopa. It can occur at different times of day. It can occur overnight with a nocturnal OFF. Sometimes we can think about OFF episodes in relation to a dose of levodopa, occurring before the dose has a chance to work with the delayed onset. Maybe that dose doesn’t give full benefit and there’s a suboptimal ON. Maybe the duration of benefit isn’t prolonged and the end of the dose wears off. That’s another way of thinking about different types of OFF. Sometimes we think about OFF in relation to whether it’s sudden or unexpected or expected and predictable at the end of a dose. Sometimes there’s such a delay in an OFF episode being prolonged that the next dose doesn’t work at all. We call that a dose failure, or a no ON. We may talk about different types of OFF, but what we’re really talking about is recognizing when there’s no benefit from a dose of oral levodopa—the time of day in relationship to dosing, an individual dose, and other factors that might occur.
Many patients fear beginning levodopa because they think it’s going to last for only 5 years. We explain to them that the effect of levodopa goes on for decades, but each individual dose will invariably begin to last for only a few hours in everyone. We often think of risk factors—younger age, female sex, lower body weight, higher doses of levodopa—but everyone with Parkinson disease loses the long-duration response to oral levodopa within a few years. In fact, the most current clinical criteria for diagnosis by the [International Parkinson and] Movement Disorder Society [recommends revisiting the diagnosis] if a patient doesn’t experience OFF episodes within 3 to 5 years. We recently looked at a series of patients who don’t complain of having significant OFF episodes, and we found that about half of them didn’t have Parkinson disease when we did DaTscans [dopamine transporter scans] to look for the dopamine transporter and nigrostriatal dopamine degeneration. If I don’t see the emergence of OFF episodes, I’m always going to reevaluate the underlying diagnosis of Parkinson disease. It’s that common.
Once we identify the OFF episodes, it’s important to act on them because…we know our patients are always going to have OFF at some point; we just have to find it. We can find it by asking them, “If you wake up in the morning with symptoms, do they improve after your first oral dose of levodopa? How long does it take for that improvement? When do symptoms come back during the day?” In these ways, we can tease out times of the day when patients aren’t having full benefit from doses of oral levodopa. When you don’t have full benefit from doses of oral levodopa, that’s what we call an OFF episode. Patients will always get this over the years. Very rarely will we see a patient who has no OFF as time goes on.
One of the biggest issues we grapple with in managing Parkinson disease optimally is focusing not so much the number of hours ON and OFF, or what symptom is motor or nonmotor, but how this all comes together to make sure patients are living the best lives they can. How can we enhance their overall quality of life and make sure they’re getting everything they could possibly get out of the medications we have available? Luckily, we have a lot of medicines available nowadays to help our patients do better. We have to ask different types of questions and focus on how their days go. How do they wake up? Do they have symptoms when they wake up that improve with their first oral dose of levodopa? Is the benefit of improvement only a couple of hours and then there’s no longer benefit? If they’re having an OFF episode and the symptoms—motor and nonmotor—return, when do they take their next dose? How long does it take for that dose to give symptom benefit? How long does that symptom benefit last?
Then we have to understand what they do during the day. Are they working? What time do they go to work? What do they do at work? Do they have breaks during work? Can they take breaks? How does that impact when we see the tempo of when they have benefit and don’t have benefit from doses of levodopa in relation to whether they’re working? Maybe they’re retired and they play golf, or take their grandchildren to preschool. Maybe they go on family trips, volunteer, or do other activities that are important to their quality of life. How does having benefit from a dose of medication, and not having that benefit and having symptoms return in these OFF episodes, impact each patient in their own individual way? How can we personalize the treatment to make sure they enjoy all the activities they value? How can we make sure they have clinical benefit and improvement of symptoms consistently throughout the day?
What do they do when they’re not having benefit from a dose of oral levodopa? Do they stop their activities, go home, sit in a chair, go to bed, go into a car, and wait until their next dose is taken and begins to work? How long do they have to wait? How well do they know when that next dose will begin to work? How much does it disrupt how they live their days and do their activities? Sometimes OFF episodes occur very rapidly or acutely. Sometimes they come on gradually. But sometimes, once a patient has lost the benefit of an oral dose that they took a few hours ago, they don’t know when that next dose is going to work. They have to stop what they’re doing and wait. Much like someone might do if they’re driving down the road in their new car, and they hit a traffic jam and can’t get to where they’re going, and they’re going to be late and miss that activity. Patients who experience these OFF episodes— with a dose of levodopa no longer providing benefit—are in that traffic jam. They have to stop and wait until they benefit from the next dose, and then they can get on with their activities.
Transcript edited for clarity