The spectrum of “off” in Parkinson's disease: What have we learned over 40 years?

The terms “on” and “off” were used by Marsden and his contemporaries over 40 years ago to describe times when Parkinson's disease patients experienced good motor function (“on”) and immobility (“off”). Yet there remains no published consensus definition of “off”, leading clinicians and patients to develop individualized impressions of “off” determinations. In this paper, we first discuss the evolution of the terminology and understanding of “off” states since Marsden's time, which now include non-motor as well as motor symptoms. We then review pathophysiology and risk factors for the development of “off” states as well as tools to detect the “off” state, before proposing a practical definition of “off” for consideration. A common, practical definition of the “off” state could improve clinical recognition of “off” symptoms and lead to significant benefit for patients.