Dyskinesia: inevitable or avoidable?

Showing your work.

When I took geometry with Miss Brenny in junior high, she taught us how to use facts and reasoning to prove or disprove mathematical statements. And she emphasized that we needed to show our work.

In my first circuit analysis course with Dr. Jaggard as an engineering major in college, we were warned prior to our first exam that showing our work was a critical part of solving engineering problems. (And thankfully I recalled my experience with Miss Brenny, so I could get some partial credit even for problems I could not solve. On that exam I received a grade of 41. Yes, 41%. And while I was shocked, I learned that that was pretty good compared to many of my peers, on the border between A and B.)

Over the next few weeks or months, I'm going to work to understand dyskinesias, the uncontrollable movements affecting many with advanced Parkinson's. My goal is to understand if this problem is inevitable or avoidable. I've been asked about dyskinesias several times and I don't yet understand the problem well enough to draw any useful conclusions. By sharing with you how I tackle this matter, it will show you the analytic approach that enabled me to discover that dopamine reduction therapy is so promising for Parkinson's. And perhaps we'll also learn something useful for you!

In part, I want you to see that I will be responsive to requests - though only on an educational and not on a personal/medical level. I added a form to the website (at the bottom of the "contact us" page) for you to suggest topics for future posts. And as I can, I will tackle those that are popular requests as well as those that suggest interesting possibilities.

How will I get started? My plan is to review classic publications such as Costa, Cote and Yahr from 1966 and Barbeau and McDowell from 1970 to understand the initial clinical observations. These books reflect understanding of PD before the science enabled understanding of cell, molecule or gene functioning. Next I'll study a series of review articles about the disease by leaders in the field as edited by Olanow and Lieberman from 1992. And all the while, I'll go to the sources of the data in the peer-reviewed literature. One of the challenges is how and when to integrate genetic and molecular events with cellular behavior and clinical manifestations.

Throughout this exercise, I'll look for data supporting the established views as well as data inconsistent with these views. When statements are supported by reasoning alone and not with facts, I'll remember that they would not satisfy Miss Brenny or Dr. Jaggard. And as I dig in to understand the views and the facts better, I will show my work.

This exercise starts with my simplistic understanding of dyskinesias in Parkinson's, with recognition that these spontaneous and uncontrollable movements can differ from one person to the next, and that motor fluctuations need to be considered in parallels, as they seem related.

I was taught the problem is largely due to long-term treatment with levodopa where the levodopa is administered intermittently and the problems occur when the levels are too high. Let's look for data to show the timing lines up, which I expect it will do.

Let's also then look for evidence that long-acting versions of levodopa reduce the problem, since our technologies to make long-acting drugs generally provide lower peak levels and less dips of levels to very low amounts.

As I look at the data with questions such as these in mind, I'll try to understand whether the mechanism(s) causing dyskinesia are rooted in the pre- or postsynaptic neuron (or both). I may also look at other movement disorders (including tardive dyskinesia) to see what can be learned that is relevant to dyskinesias in Parkinson's.

The first progress report will be delivered in the next few weeks.