The exact cause of Parkinson disease is unknown, but it is assumed to be the result of a combination of environmental influences superimposed on genetic predisposition or susceptibility (Table 2).14-16 There is increasing evidence that the genetic and environmental insults leading to Jankovic J. Parkinson disease commonly lead to abnormal forms of a normal protein, α-synuclein, which seems to contribute to cell death.16,23 The onset of Parkinson disease can be categorized as juvenile (age < 21 yr), early onset (21-50 yr) and late onset (generally > 60 yr).24,25 The juvenile form is rare, is often familial (in as many as 50% of cases), is most frequently associated with a parkin gene mutation and has an atypical presentation.25,26 Of patients with Parkinson disease, 10%-16% have an affected first- or second-degree relative; first-degree relatives may have double the risk of Parkinson disease compared with the general population.26-29 In early- and late-onset Parkinson disease, the frequency of a positive family history is not statistically different.24 In advanced Parkinson disease, the efficacy of levodopa can decline and fluctuate throughout the day switching between "on" and "off' medication periods.92 The motor and nonmotor fluctuations mirror those seen in levodopa plasma concentrations resulting from levodopa's short half-life.93 Providing continuous dopaminergic stimulation is the goal of treating fluctuations in patients with advanced Parkinson disease.94-96 We now have surgical options, including deep brain stimulation and levodopacarbidopa intestinal gel, to provide treatment to such patients. Currently, deep brain stimulation has the highest level of evidence with the largest number of randomized controlled trials.97 Emerging therapies currently being studied in Parkinson disease are listed in Appendix 7, available at www.cmaj.ca/lookup/suppl/doi :10.1503/cmaj.151179/-/DC1. The response to deep brain stimulation is equal to the best response on levodopa, but more effective than medical therapy in improving "on" time without troublesome dyskinesias.101,102 Deep brain stimulation typically improves levodoparesponsive symptoms (e.g., tremor, bradykinesia, rigidity) and on-off fluctuations and dyskinesias, whereas impairments in gait, balance and speech are less likely to improve. Patients should be considered for deep brain stimulation only if adequate trials of multiple medications for Parkinson disease (e.g., levodopa-carbidopa, dopamine agonists, monoamine oxidase B inhibitors and amantadine) have been unsuccessful.100 Although duration of efficacy is not clearly established, patients who undergo deep brain stimulation may have sustained benefit for at least 10 years.100 A recent study suggests that deep brain stimulation for Parkinson disease may be offered earlier for patients (mean age 52 yr, disease duration 7.5 yr) just beginning to have motor fluctuations.103 Thalamic deep brain stimulation may be considered as an option in patients who predominantly have disabling tremor where subthalamic nucleus stimulation cannot be performed.57