Unresolved issues relating to the shaking palsy on the celebration of James Parkinson's 250th birthday.

James Parkinson's Essay on the Shaking Palsy published in 1817 provided the first clear clinical description for the disorder now known throughout the world by his name. His primary reason for publishing his monograph shortly before his retirement from medical practice was to draw the medical profession's attention to a malady, which had not yet been defined as a nosological entity. He also hoped that the eminent anatomists of the day would be stimulated to elucidate the pathological lesion responsible for the clinical picture and that this in turn might lead to a rational cure. The concept of Parkinson's disease remains clinically based and successive generations of neurologists have refined and embellished Parkinson's seminal descriptions. Narrative accounts by affected individuals have also helped physicians understand what it is like to live with Parkinson's disease. For many years, the pathological hallmarks of Parkinson's disease were disputed and there were few clinico-pathological reports with adequate clinical description. However, most neurologists now link severe loss of nigral cells in the ventrolateral tier of the pars compacta of the substantia nigra with bradykinesia and the presence of Lewy bodies in a number of discrete brain stem and cortical regions with Parkinson's disease. There are many unanswered clinical questions relating to Parkinson's disease including the striking heterogeneity and frequent limb asymmetry. It also remains somewhat uncertain whether Parkinson's disease is ever truly unilateral by the time of clinical presentation and whether the hand rather than the foot is the most common site of onset. Hyposmia and visual hallucinations are helpful pointers in distinguishing Parkinson's disease from atypical Parkinsonism and should be specifically enquired about in the history. Simple reliable cultural-specific smell identification batteries are an urgent need and target of clinical research. It remains to be determined whether Alzheimer type dementia as opposed to a dysexecutive syndrome should be considered a part of Parkinson's disease and further detailed clinico-pathological correlative studies are needed. It is also unclear whether autosomal dominant monogenetic Parkinsonism due to synuclein or LRRK-2 mutations will prove to be identical clinically with Parkinson's disease and for the present it is wiser to regard Parkinson's disease as a sporadic disorder. Parkinson was an active political reformer and if alive today would certainly be campaigning to translate more effectively the rich seam of neuroscientific research of the last decade into therapeutic benefits for the rising number of people who are developing the shaking palsy as a result of increasing longevity in the developed world.