Part 3. A problem when there is too little, a problem when there is too much

Take Parkinson’s disease medication long enough, and you run into a strange contradiction.

When medication is too low, the body won’t move.

But taking more doesn’t make the body better, either.

Past a certain point, what appears is not the movement I want, but movement I don’t want.

Dyskinesia.

At first I thought of this simply.

OFF is a state of too little dopamine, and dyskinesia is a state of too much.

That’s not wrong.

But watching my own body over time, I came to see that this explanation alone isn’t enough.

Even taking the same dose, dyskinesia appeared some days and not others.

Stranger still, having dyskinesia didn’t always mean the body was functioning well.

The body could be swaying and walking could still be difficult.

Conversely, when I lowered the dose to get rid of dyskinesia, the body grew quiet, but OFF deepened.

In the end, the problem wasn’t whether the dose was high or low.

The problem was whether I stayed within the range of dopamine my body could actually use.

Chapter 10. Is OFF simply a state of no medication?

Explaining OFF to someone who has never experienced it isn’t easy.

It’s often explained this way.

“It’s the state where the medication has worn off.”

But the OFF a patient feels is far more complicated than that.

Walking slows. The feet won’t lift off the floor. The body grows heavy. Hand movements grow clumsy. Standing up becomes hard. Sometimes the toes curl and the muscles pull tight.

And it isn’t only motor symptoms that show up.

Anxiety can appear. Thinking can slow down. Sometimes there’s a sudden feeling of energy draining away.

That’s why it’s hard to define OFF simply as “the time without medication.”

The body may already be sensing change before the medication’s effect has fully disappeared.

OFF has depth

I stopped thinking of OFF as a single state.

Thinking in terms of output makes it much easier to understand.

Output dropping from 70 to 60 and output dropping from 20 to 10 are both declines, but what they mean to the body is completely different.

Below a certain point in particular, things change.

I could walk a moment ago, and suddenly my feet won’t lift.

The more I try to move, the more the body stiffens.

And once it drops deep, there are times when even the next dose doesn’t seem to bring it back up easily.

Experiencing states like this, I came to understand the expression Hard OFF.

What matters isn’t only whether OFF occurred.

How deep it dropped. And how long it stayed there.

Chapter 11. Why does dyskinesia happen?

When dyskinesia first appeared, I thought it simply happened because there was too much levodopa.

So the solution seemed simple too.

Just lower the dose.

In fact, levodopa exposure and dyskinesia are closely related.

But over time I learned the problem isn’t that simple.

Dyskinesia isn’t simply an “overdose warning light.”

As the disease progresses, dopamine neurons decrease, and the brain’s ability to smoothly buffer incoming dopamine stimulation declines.

In that state, when levodopa, with its short half-life, keeps arriving repeatedly, dopamine stimulation keeps rising and falling.

The brain becomes increasingly exposed to pulsatile stimulation.

As a result, the response of the basal ganglia motor circuits also changes.

So it seems more appropriate to view dyskinesia not simply as something explained by the plasma concentration at that one moment, but as a phenomenon produced jointly by disease progression and the neural circuits that repeated dopamine stimulation has changed over time.

Peak-dose dyskinesia

The easiest form to understand is dyskinesia that appears when the drug’s effect is at its highest.

You take the dose.

Output rises.

You enter a good ON.

But it climbs a little further.

The body starts to sway.

This kind of dyskinesia is called peak-dose dyskinesia.

It’s easy to picture as a curve.

OFF → rising phase → good ON → dyskinesia → declining phase → good ON → OFF

There’s an interesting part here.

Dyskinesia appearing can be a sign that the medication is working, but that doesn’t mean that stretch is when function is best.

What I want isn’t a body that moves a lot.

It’s a body that moves the way I want it to.

Diphasic dyskinesia

There’s a more complicated form too.

Dyskinesia can appear not when the drug’s effect peaks, but during the rise and during the decline.

This is called diphasic dyskinesia.

As a curve,

OFF → dyskinesia → ON → dyskinesia → OFF

it can look like this.

In this case, simply thinking “there’s dyskinesia, so the dose is too high” can lead the interpretation astray.

Because when the dyskinesia occurred matters.

You need to record whether it happened at the peak, while rising, or while declining.

Even the same word “dyskinesia” can mean something different depending on where it falls on the medication response curve.

Chapter 12. Dystonia — is this ON or OFF?

An even more confusing symptom is dystonia.

The toes curl. The sole pulls tight. The ankle turns. The muscle contracts hard.

These symptoms can appear in a low-dopamine state.

OFF dystonia, which typically shows up before the first morning dose or as the medication’s effect wears off, is the classic example.

But not every instance of dystonia should simply be labeled OFF.

It can also appear during the change in medication effect, or even in the ON state.

So recording only the fact that dystonia occurred isn’t enough.

I came to think it’s more important to record it this way instead.

What was the output at that moment. How many minutes after the dose. Was it during the rise, holding steady, or declining.

The moment you place a single symptom onto the curve, its meaning changes.

Chapter 13. The narrow path called the therapeutic window

Here an important concept from pharmacology comes in.

Therapeutic window.

When the drug effect is too low, OFF appears.

Rise a little, and movement improves.

Within the right range, you can maintain a good ON.

But climb further, and dyskinesia can appear.

Simplified, it looks like this.

Too little dopamine → OFF → good ON → dyskinesia → excessive dopamine stimulation

The place I want to stay all day long is the middle.

The problem is that as the disease progresses, this middle zone can narrow.

Before, taking a bit too much or a bit late wasn’t much of a problem.

But at some point, small differences start making big ones.

A little too little, and it’s OFF.

A little too much, and it’s dyskinesia.

From the patient’s side, it feels like this.

“Getting the dose right keeps getting harder.”

Chapter 14. Why does matching the medication get harder as the disease progresses?

Early in Parkinson’s disease, the remaining dopamine neural system can buffer changes in incoming levodopa to some degree.

Even if plasma levodopa concentration wobbles a little, the brain’s dopamine effect may not wobble along with it in the same way.

So even taking the medication a few times a day, you can maintain a relatively stable state.

But as dopamine neurons decrease further, this buffering capacity also declines.

Then the rise and fall of plasma levodopa begins to show up more directly in clinical symptoms.

Medication rises, and it’s ON.

A little more, and it’s dyskinesia.

It falls, and it’s OFF.

The day’s curve starts to feel steeper and steeper.

I find it intuitive to understand this as the dopamine reservoir shrinking.

The actual biology is far more complex than that, but as a patient trying to understand my own variability, it’s a useful analogy.

Chapter 15. So should I just lower the dose?

When dyskinesia starts to appear, the first thought that comes to mind is this.

“Let’s bring the dopamine line down.”

If the peak really is too high, adjusting levodopa exposure to reduce dyskinesia is a strategy worth considering.

But lowering the whole curve doesn’t only bring the peak down.

The trough can come down with it.

This is the problem.

Dyskinesia may lessen, but OFF can deepen.

Especially in the evening, once you drop into a deep OFF, it can be hard to pull back up.

This is where the treatment dilemma begins.

Chapter 16. Should I allow a little dyskinesia?

In the end, the standard for choosing can differ from patient to patient.

For some people, dyskinesia may be the hardest symptom to bear.

For that person, reducing dyskinesia may matter more, even at the cost of a little OFF.

Conversely, for someone else, OFF may be far more frightening.

If the hardest part is the time when you can’t walk, the body locks up, and you can’t manage daily life, you may prefer to reduce OFF even at the cost of a little dyskinesia.

So there is no single “perfect medication combination” that exists the same way for every patient.

In the end, the important question is this.

“In what state can I actually live my life best?”

The pharmacologically optimal point and the point the patient wants aren’t necessarily the same thing.

Chapter 17. Raising the trough rather than lowering the peak

I gradually began asking a different question.

How high should I raise the peak?

Rather than that:

How much can I keep the trough from dropping?

Hitting 100 a few times during the day may matter less than never dropping below 20.

Shift the treatment goal from peak output to reducing the swing, and the way you look at medication changes too.

You stop looking only at the dose and start looking at the interval.

You start thinking differently about the roles of fast-acting and slow-acting formulations.

You start watching how much of the previous dose remains when the next one comes up.

In the end, you start thinking not about a single dose, but about the 24-hour curve.

Closing Part 3

When I first thought about Parkinson’s disease drug therapy, the goal was simple.

Dopamine is deficient, so replace it.

But in the actual body, it didn’t end there.

Too little, and you can’t move.

Too much, and movement you don’t want can appear.

And between the two lies a narrow zone where I can actually live my day.

I was searching for that zone, moving through it every day.

So now I think of the treatment goal this way.

Not creating the highest dopamine state, but maintaining the state I can use for the longest time.

Eliminating OFF completely, and reducing dyskinesia to zero no matter what, may not be achievable goals for everyone.

What matters is finding, between the dyskinesia I can tolerate and the OFF I want to avoid, the widest stretch of good ON that works for me.

And to find that, writing down only the drug name and dose isn’t enough.

When it came up.

How high it went.

At what point on the curve the dyskinesia appeared.

When the decline began.

How deep the OFF it dropped to.

That’s what needs to be recorded.

Keep recording that way, and at some point you stop looking at the medication and start looking at the curve.

And once you start looking at the curve, the question changes too.

“How much more medication should I take?”

is no longer the question.

“How can I make this curve a little flatter?”

I think that question is one of the most important questions in Parkinson’s disease drug therapy.