Management challenges with advancing disease
Submitted by emily.kilby on Thu, 02/18/2021 - 14:19


Management challenges with advancing disease


Stuart H. Isaacson MD, FAAN


Parkinson Disease and Movement Disorders Center of Boca Raton, Florida, USA

In patients with Parkinson’s disease (PD), the initial effect of levodopa on motor symptoms is typically robust and durable beyond each dose. However, this so-called “long duration response” invariably wanes, often beginning in the first year after initiation of levodopa therapy [1]. Then, with loss of benefit from a levodopa dose, motor symptoms return (‘OFF episodes’) [2]. 


OFF episodes can be characterized by both pathophysiology and / or timing in relation to levodopa dose. Both central (presynaptic, striatal denervation, postsynaptic, pharmacodynamic) [3] and peripheral (delayed intestinal, competitive protein, gut bacteria) [4] mechanisms have been described, which coupled with the short plasma half-life of levodopa, can lead to OFF episodes.  OFF episodes are increasingly frequent throughout the multi-decade course of PD, despite increasing pharmacotherapy.  OFF episodes may occur unexpectedly, or be predictable in relation to time of day (i.e. morning), meals (i.e. postprandial), and other external factors (e.g. exercise).  


OFF episodes may be motor, heralded by nonmotor symptoms, or can be predominantly nonmotor.   OFF symptoms will continue to increase in severity until the benefit of the next levodopa dose begins, which may be delayed in onset, suboptimal in benefit, or fail to provide symptom benefit.  OFF episodes impact daily activities, employment, quality of life, and (when balance is affected) falls [5].


Delayed ON of the first daily dose of levodopa, known as morning akinesia or early morning OFF (EMO), can significantly impact quality of life and impair daily activities [5].  In a large European, observational study it was found that EMOs occur in nearly 60% of PD subjects across all stages of disease.  Furthermore, at least 50% of patients observed who were taking prolonged-release dopamine agonists were reporting EMOs [6].  Morning akinesia can occur due to a delay in gastric emptying, impaired intestinal absorption, pharmacodynamic effects, or other mechanisms [7-10]. Alternative delivery of dopaminergic therapy by a non-oral route may therefore be useful in patients with PD and gastroparesis.  


Subcutaneous apomorphine injection is used by patients with PD in the OFF state to provide a rapid and reliable ON.   The AM-IMPAKT trial, a multicenter, open-label investigation, confirmed the efficacy and clinical utility of subcutaneous apomorphine for the reversal of EMO [11].  Patients achieved an ON state an average of 37 minutes faster with apomorphine than with oral levodopa, representing a 61% improvement in time to ON.  Apomorphine patients also had significant improvement on quality of life and global impression scales.


As our understanding develops of the mechanisms and course of the challenges presented by advancing PD – a consequence of both the disease itself and levodopa treatment, we can become better equipped to manage our patients and provide them with a more predictable daily life.



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February 2021