Different Types of OFF Episodes in Parkinson Disease

Peter A. LeWitt, MD: In this patient, we’ve had a very particular pattern of responsiveness to levodopa. This is a wearing-off problem, but there are more types of OFF episodes that patients with advancing Parkinson disease can experience. This is 1 of the more common types, and it’s explainable by the way levodopa behaves. But there are other episodes that can also confound the issue and in fact, the same patient might have more than 1 of these episodes in their typical day. Let’s turn to a couple of these.

One type is the morning OFF episode. The patient hasn’t taken medication since the night before. Given the duration of sleep time, it’s quite understandable that there would be very low levels of levodopa medication left in that patient’s system. Upon arising in the morning, there is a delay before the next oral dose of this medication will reach therapeutic levels. This could be 15 minutes at the fastest, but sometimes, the delay can be 30 to 45 minutes. If breakfast is taken simultaneously with medication, there can perhaps be an even more prominent delay.

This is an issue that many patients have coped with by taking medication before getting out of bed and giving it a chance to absorb even before their feet hit the floor. The main problem here is delayed ON time, and this can occur at other times during the day as well. Patients whose medication starts to wear off delay taking the next dose of medication—or even take it right when they’re starting to feel off—have a 15- to 30-minute delay at the fastest.

They can have OFF symptoms as their previous dose of medication goes away and the dose they just swallowed fails to go to work. Because there’s such fluctuation in blood levels of levodopa, there can be partial ON states. The medication doesn’t really get to the desired therapeutic level within 15 to 30 minutes. And so, a patient is plagued by tremors or stumbling, something that to them sounds like they haven’t gotten the full effect of the drug. They may even feel the need to take extra medication.

But the real problem is failure of absorption, and even the next dose might fail to absorb. At worst, this could be a total dose failure if the drug were taken right on time and is sitting in the stomach. There’ve been examples of gastroscopy showing that a pill swallowed right on time with the right amount of water is nonetheless sitting there in the stomach an hour and a half later, unabsorbed. There’s delay in onset of effect. There’s wearing off.

There’s also another spectrum of problems that some patients with advancing Parkinson disease experience, and that’s the unpredictable OFF episodes. These have less clear character in terms of pharmacology. For many patients, these are triggered by episodes of stress or episodes of coming to a doorway and finding that their feet stay in place. This has been described as freezing of gait. Freezing of gait can lead to stumbling and falls but can also lead to a very stressful situation.

“Why won’t my feet follow my commands?” James Parkinson, back in 1817, had a phrase more or less explaining that the limbs failed to answer with exactness the dictates of the will. If you ever hear your patients speaking that way, you’ve got a real classic description. The main thing about these unpredictable and predictable episodes is that they can be intermingled. You want to look into the phenomenology of these as best you can by asking some pointed questions so that you can figure out what to do.

If the patient is experiencing a very short but regular duration of action from a dose of levodopa, an extender makes sense. If there’s unpredictable OFF time or marked delay, perhaps an on-demand or rescue type of therapy might be most appropriate. In fact, the combination of these options might be available, especially in the future, when we might have infusion therapies to give more continuous action. We might be bringing together immediate rescue and sustained-release therapies all in the same patient, just to give them more of their ON time back.