Not always the usual suspect: symptom variations in Parkinson's disease beyond ON-OFF fluctuations

In addition to response fluctuations caused by the pharmacokinetics of dopamine replacement medication, temporal variation in the expression and severity of motor and non-motor symptoms, which is not or only partially attributable to the effects of the medication, are also common in Parkinson's disease (PD). The spectrum of transient changes of motor symptom expression unrelated to the classical ON-OFF fluctuations ranges from brief episodes of gait freezing or tremor breakthroughs to severe akinetic crisis and non-motor phenomena include discontinuous changes in cognition and vigilance. Disease-related factors such as dementia or orthostatic dysregulation or disturbances of the circadian rhythm may also contribute to these non-pharmacological symptom fluctuations. Additionally, external factors including infections or surgery and general anaesthesia can lead to transient changes of PD symptom severity and drug responsiveness. Accurately classifying these symptom oscillations and distinguishing them from drug-induced ON-OFF fluctuations is essential for their appropriate management.