Parkinsonism

13. Parkinsonism • Tremor – resting • Slowness – bradykinesia • Stiffness – rigidity • Loss of balance

15. Olanow. Neurology 2009

17. Dopa Dopamine Dopa

18. Cause Dopamine deficit Tremor, rigidity, bradykinesia, postural impairment Dopamine replacement

23. Golbe 1990

25. Parkinson’s – divergent causes, convergent mechanisms (Science 21 May 04)

27. Braak 2005

28. Cause Dopamine deficit Tremor, rigidity, bradykinesia, postural impairment Dopamine replacement

29. Cause Cause Cause Cause Cause Mechanism Dopamine deficit Cortical Lewy bodies Other neurotransmitters Sleep disturbance Parkinsonism Dementia Pain Depression Falls Levodopa complications Autonomic dysfunction

30. Dopaminergic Motor fluctuations and dyskinesia Parkinsonism 10 years 5 years

31. 10 years 5 years Falls autonomic failure dementia pain anosmia RBD anxiety depression Non-Dopaminergic

32. Dopaminergic Motor fluctuations and dyskinesia Parkinsonism Diagnosis and early treatment Motor complications General neurodegeneration 10 years 5 years Falls autonomic failure dementia pain anosmia RBD anxiety depression Non-Dopaminergic

33. Schwarz 2004

34. Hely 2008

35. Kempster Brain 2010

36. Kempster Brain 2010

37. Schenck et al 1986

38. REM Sleep behaviour disorder • 5 patients (4 men) • 6 years of injuring themselves or spouses during sleep • REM pathology with loss of chin atonia, increased limb activity • Reaching and searching hand gestures, punches and kicks • OPCA, GBS, SAH, atypical dementia • Excellent response to clonazepam • Replicates findings from cats with pontine tegmental lesions Schenck et al 1986

39. RBD clinical features • Male gender predilection • Mean onset 50–65 years (childhood—80 years) • Vocalizations, swearing, screaming • Simple limb jerks to complex motor behaviour, with injuries to patient or bedpartner • Dreams often involve chases or attacks by animals or humans; exhibited behaviours mirror dream content • Behaviors tend to occur in latter half of the sleep period • When associated with neurodegenerative disease, RBD often precedes dementia and/or parkinsonism by years or decades

40. “…in his right hand he held his unsheathed sword, with which he was slashing about on all sides, uttering exclamations as if he were actually fighting some giant: and the best of it was his eyes were not open, for he was fast asleep, and dreaming that he was doing battle with the giant”. Cervantes; Don Quixote 1605 Antonio Carnicero 1779

41. RBD and PD Schenck et al: • 29 patients with Idopathic-RBD – 38% developed PD 12.7 yrs post RBD onset – 65% by 7 yrs later • “Idiopathic” RBD – Olfactory deficits – Loss of striatal DA – impaired attention, executive function, and verbal memory

42. RBD and prognosis of PD • RBD more common in non-tremulous PD • Seldom occurs when PD develops <50 years • RBD is associated with visual hallucinations – ?PD psychosis may represent a narcolepsy-like REM sleep disorder • RBD is associated with worse and more rapidly developing PD – Vendette M, Gagnon J-F, Decary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007; 69:1843-1849. • RBD tends to wane with PD progression

43. The “wait and watch” option Self-reported health status deteriorated significantly over 18 months in untreated patients but not treated patients * untreated * treated n = 61 n = 114 n = 127 n = 74 modified from Grosset, D et al. J Neurol Neurosurg Psychiatry 2007;78:465-469

44. The “wait and watch” option No significant deterioration over 2 years in health status score in either group even though motor status significantly worsened in the untreated group. Change in Median UPDRS Motor Score UPDRS (Motor) Score n = 16 30 20 baseline year 2 10 0 treated untreated n = 26 “……we believe a ‘‘wait and watch’’ strategy for the treatment of newly diagnosed PD remains a credible approach……..” modified from Asimakopoulos, P et al. J Neurol Neurosurg Psychiatry 2008;79:716-718

45. In summary, it makes sense to treat patients early to improve early quality of life However, the impact of early treatment on late quality of life has not been assessed

46. Does early treatment lead to better later PD status?

47. 60 50 40 % dyskinesia <70 >70 30 20 10 0 Levodopa Ropinirole Adapted from Rascol 054 Study

48. Initial treatment • Young patients: dyskinesia – Dopamine agonists (ropinirole 3 mg tds) • Old patients: dementia – Levodopa (100 mg tds)

49. Ropinirole Adverse Events (compared to levodopa) Ropinirole Levodopa Nausea 48.6% 36.7% Somnolence 27.4 17.3 Hallucination 17.3 3.3 Edema 14.0 4.0

50. Agonists and disinhibition • Gambling • Impulsive sexual behaviour • Shopping • Eating • Punding