Why dyskinesias are a research priority in PD
As a scientist, I have always been interested in understanding how the basal ganglia produce movement sequences that are well-matched to our needs in every circumstance. This interest led me to study levodopa-induced dyskinesia (LID) as an example of what can happen when such function goes astray. By giving levodopa to rodent models of PD I have learned that there is a tipping point at which therapeutic and dyskinetic effects of treatment can no longer be dissociated. At this point, ‘moving all over the place’ may become the price to pay for an individual to move at all. In our animal models, the tipping point is reached when the denervation of critical striatal regions exceeds 90%. By investigating how this phenomenon comes about, we can discover a lot of interesting things about the brain circuits controlling movement in health and disease.
LID is not just a fascinating topic for scientific investigation. It is a concrete medical problem affecting the lives of many people with PD. It is estimated that approximately 80% of levodopa–treated PD patients develop LID within 10 years, although people with young-onset PD are affected earlier and more severely. Several studies have reported that LID significantly impairs many crucial activities of daily living and decreases the health-related quality of life. This is not surprising if one considers that dyskinesias interfere with intentional movements, they can bring stigma and social embarrassment, and they are usually associated with unpleasant non-motor effects such as accelerated breathing, sweating, mood changes, and even weight loss.
Recently, there have been many attempts at dismissing the importance of LID research. The arguments put forward are that disabling dyskinesias are less common than they used to be, that people with PD would rather be “on” with dyskinesia than “off”, and that there are worse problems in need of research resources, such as non-motor symptoms.
On one hand, it is important to reassure people with PD that dyskinesias are not dangerous per se, and that severe dyskinesias are nowadays treated with DBS, at least in individuals eligible for this type of surgical therapy. On the other hand, arguing that there are worse problems in PD does not help the large number of patients who must deal with this troublesome condition on a daily basis. Even during the last World Parkinson Congress (Kyoto, 2019), significant concerns were expressed by people with young onset PD about the prospect of developing LID, and many questions were asked about what can be done to prevent, delay, or just lessen this complication. Concerns and questions of this kind are also being posted on social media.
Clearly, people with PD (at least the younger ones) think that dyskinesia research is important and should get more attention, not less. This standpoint can definitely be endorsed using both medical and scientific arguments, for example:
In addition to the discomfort associated with the involuntary movements, LID imposes drug dose limitations that are detrimental to controlling the primary symptoms of PD;
LID is associated with an increased risk of motor disability, including falls;
LID is the only PD-related indication for which several pharmacological treatments have proven to work in both animal and ‘human experiments’, the latter being represented by proof-of-concept/Phase 2 clinical trials. For this reason, it seems warranted to hope that more effective anti-dyskinetic medications will be developed in the very near future;
LID research will not only benefit people who suffer from this particular complication, but it will also help us understand and eventually treat some related problems in PD, such as motor fluctuations, non-motor fluctuations, impulse control disorders, and graft-induced dyskinesias (which may emerge with future cell therapy interventions).
Having been active in this research area for quite a while, it is particularly encouraging for me to see how the LID field has matured over the past 15 years. We now have a pretty good sense of which paths of investigation have reached a dead-end and which instead hold promise and deserve continued efforts. We know what new questions are to be asked and poised to find the answer using a multitude of approaches. The next decade can, therefore, be a decisive time for dyskinesia research, to the benefit of the PD field at large. Let us all give this topic the attention and support that it deserves.
A viewpoint article on the importance of dyskinesia research was published in 2019 in the Movement Disorders journal.
M. Angela Cenci Nilsson was a member of the WPC 2019 Program Committee and has presented at many of the past World Parkinson Congresses. She is currently a Professor of Experimental Medical Research at Lund University (Sweden), where she heads the Basal Ganglia Pathophysiology Unit.
Ideas and opinions expressed in this post reflect that of the author solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®