Early Parkinson Disease Treatment May Benefit Patients


Study author Luc Evers and coauthor Bastiaan R. Bloem, MD, PhD, FRCPE, offer insight into the findings of a recent study assessing early treatment in PD.

Luc Evers, a PhD student at Donders Institute for Brain, Cognition, and Behavior, at Radboud University

Luc Evers, PhD student

Recently, observational study data were published showing that the early initiation of treatment in patients with Parkinson disease may offer small improvements in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores, without worsening outcomes.

In a cohort of 302 patients with de novo Parkinson disease from the Parkinson's Progression Markers Initiative (PPMI), study author Luc Evers, a PhD student at Donders Institute for Brain, Cognition, and Behavior, at Radboud University, and colleagues observed that after 2 years there was a small improvement for those who started treatment earlier, though it was not significant. Additionally, there were similar nonsignificant improvements in subsequent years.

To inquire further about the findings, NeurologyLive reached out to Evers, as well as coauthor Bastiaan R. Bloem, MD, PhD, FRCPE, director, Radboudumc Center of Expertise for Parkinson & Movement Disorders (which is a Center of Excellence as designated by the Parkinson’s Foundation).

NeurologyLive: How do these findings translate clinically and what should the physician community take away from them?

Although dopamine replacement therapy can effectively reduce symptoms in patients with Parkinson's disease, physicians and patients sometimes choose to delay the initiation of treatment because of concerns about negative long-term effects. Using a large cohort that reflects real-life prescription behavior (the Parkinson's Progression Markers Initiative), we show that starting earlier with dopaminergic medication does not accelerate disease progression. This complements evidence from Randomized Controlled Trials (RCTs) and should further alleviate such concerns.

In addition, we want to demonstrate that large observational datasets can be a valuable source of evidence to guide treatment decisions when combined with appropriate causal analyses. By effectively controlling for time-varying confounding, we could use the remaining natural variation in the timing to start with medication (e.g., introduced by differences in physician preferences) as "virtual" RCTs. Although true RCTs remain the gold standard, such experiments are costly, and often have a relatively short follow-up period. In addition, RCTs do not always generalize well because of strict in- and exclusion criteria. The increasing availability of various sources of observational data, including digital patient records and registrations of health insurances, will make it possible to do similar causal analyses on truly real-life data without selection bias.

Were any of the findings somewhat surprising or unexpected in any way?

Our analyses demonstrate that simple adjustments are not sufficient to estimate the causal effects of treatment decisions. Instead, more sophisticated methods are needed that take into account that treatment decisions are made at different points in time, based on how the patient is doing then. We used two different methods to adjust for such time-varying confounding: the inverse probability of treatment weighting and the parametric g-formula. With this publication, we hope to increase the familiarity and acceptance of such methods in the neuroscience community, so we can "unlock" the evidence in the growing amount of observational medical data.

What challenges remain in offering effective early treatment in Parkinson disease?

One main remaining challenge remains the reluctance among many physicians and patients to initiate treatment, fearing that levodopa and possibly also other dopaminergic drugs might be toxic, thereby accelerating disease progression. Our study is now one of several that have clearly countered that fear but changing behavior in the medical world is notoriously difficult.

Another remaining challenge is the choice for a particular type of medication, once the decision has been made to initiate treatment. Levodopa is the oldest, safest and most effective drug available, but many misconceptions still cloud the use of levodopa—it is a common misconception that levodopa only works for a limited period of time (a so-called honeymoon period), and that levodopa should therefore be postponed for as long as possible. The reality is that there are various options for people with early-stage Parkinson's disease, and levodopa is definitely a very good one, alongside starting treatment with a dopamine agonist or an MAO-B inhibitor. Each of these approaches have their own pros and cons. Perhaps the greatest challenge is to share all of this knowledge in an accessible way with patients and their families, so they can become deeply involved in making these important decisions, in a shared decision-making process.

And perhaps a final word on multidisciplinary care, with the involvement of multiple professional disciplines outside the field of neurology, such as physiotherapy, occupational therapy, a Parkinson nurse, a dietician et cetera. Again, many feel that these professionals have little to add in the early stages of Parkinson's disease, but the opposite may well be true. Information provision, the timely start of exercise programs, adequate attention to early occurring issues such as constipation are all important right from the outset of the disease. Informing both professionals and patients about the value of multidisciplinary care is therefore also very important.

Transcript edited for clarity.

van den Heuvel L, Evers LJW, Meinders MJ, et al. Estimating the Effect of Early Treatment Initiation in Parkinson's Disease Using Observational Data. Movement Disord. Published October 27, 2020. doi: 10.1002/mds.28339.
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