Progression of Parkinson's disease

Parkinson's disease (PD), progresses over time and is generally classified into various stages.  Diagram 1 shows the 5 stages of PD together with the common symptoms experienced in each stage.1

Motor fluctuations occur at moderate/intermediate and advanced stages of Parkinson's disease (PD). They are characterised by end of dose phenomenon or “wearing-off”, where patients have to reduce the interval between doses of oral medication.1 In addition, delays in turning "on" or delayed "on",  reflect a delay in the absorption of levodopa and a subsequent delay in crossing the blood–brain barrier. This may be a result of delayed gastric emptying (gastroparesis), presence of intestinal protein that competes with levodopa absorption, bacterial overgrowth, and/or pharmacodynamic effects.2

Diagram 2 shows initially (on the left) levodopa taken 3 times per day results in relatively smooth dopamine levels with mostly "on" time and few dyskinesias. Later in the course of PD (on the right), the reaction to levodopa is more erratic, with less time spent "on" and more time spent swinging between feeling "off" and feeling "on" but having dyskinesias.3

1. https://parkinsonsdisease.net/basics/stages. Accessed May2021

2. Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F. (2016) Apormorphine Subcutaneous Injection for the Management of Morning Akinesia in Parkinson's Disease. Movement Disorders Clinical Practice 

3. https://www.pacificneuroscienceinstitute.org/movement-disorders/treatment/deep-brain-stimulation/parkinsons-disease/. Accessed Mar2021