Clinical Features and Treatment of Parkinson s Disease

Transcription

1 Clinical Features and Treatment of Parkinson s Disease Richard Camicioli, MD, FRCPC Cognitive and Movement Disorders Department of Medicine University of Alberta 1

2 Objectives To review the diagnosis and differential diagnosis of Parkinson s disease To illustrate the clinical features of atypical and typical parkinson s disease To present treatment considerations for Parkinson s disease patients To discuss the prognosis of Parkinson s disease Emphasizing risk factors and management of dementia in Parkinson s disease 2

3 Pathophysiology of PD Neurochemical changes Dopamine Noradrenaline Serotonin Acetylcholine Striatal changes Substantia nigra projections Cortical dysfunction Projections from the thalamus Widespread Lewy body changes 3

4 Clinical Features of PD Tremor Bradykinesia Rigidity Postural instability/gait disorder Diagnosis favored by: Unilateral onset Asymmetry Rest tremor Levodopa response Dyskinesias No atypical features Atypical Features: Early Dementia Hypotension Supranuclear Palsy Cerebellar Signs Pyramidal Signs Gait and Balance 4

5 Key Signs and Symptoms of PD Tremor Rigidity Akinesia/Bradykinesia Postural instability/gait imparment 5

6 Tremor 5-9 Hz rest tremor May have associated action tremor 6

7 Rigidity Cogwheel rigidity=rate independent stiffness with superimposed tremor Distinct from spasticity=rated dependent stiffness 7

8 Akinesia/Bradykinesia Akinesia=inability to initiate movement Bradykinesia=slowing of movement and decreased amplitude and velocity 8

9 Tremor and Bradykinesia 9

10 Dauer W Neuron

11 Haber SN 11

12 Haber SN 12

13 Nigro-striato-cortical Circuitry: Changes beyond the Substantia Nigra *Excitatory Output Frontal Cortex Thalamus D1 Interna Globus Pallidus Externa Putamen D2 STN Substantia Nigra PPN 13

14 Nigro-striato-cortical Circuitry: Changes beyond the Substantia Nigra *Excitatory Output Frontal Cortex Thalamus D1 Interna Globus Pallidus Externa Putamen D2 STN Substantia Nigra PPN 14

15 L-Dopa Supplementary Motor Area (SMA) and fmri 15

16 Metabolism of Levodopa 3-OMD COMT Levodopa 3-OMD COMT Levodopa Glia MAO-B 3,4 DHPA AADC Dopamine Neuron 16

17 Postural and Gait Impairment Rarely severe early in the course of disease Associated with other disorders Prominent symptom in the elderly Associated with worse prognosis Not as responsive to medications 17

18 Early Impaired Gait 18

19 Early Freezing of Gait = Atypical PD At first visit 24% of atypical PD had FoG (Corticobasal degeneration, 8%; Dementia with Lewy Bodies, 21%; Progressive supranuclear palsy, 25%; multiple system atrophy, 40%) With follow up 47% had FoG (CBD, 25%; PSP, 53%; DLB, 54%; MSA, 54%) Muller J et al Mov Disord

20 First-year Balance Impairment J Muller

21 Late PD: Complications Within 3 years up to 50% develop Wearing Off or On/Off Dyskinesia Freezing Neuropsychiatric Depression Psychosis Dementia Autonomic 21

22 Motor Complications Increase with Time % Years Old Dysk Old Fluct Young Dysk Young Fluct 22

23 Bradykinesia and Dyskinesia 23

24 Decreasing Levodopa Breakdown Increases Motor Response Dyskinesia Parkinsonism 24

25 Treatment Options: Sites of Action Entecapone Pramipexole Ropinerole Bromocriptine Pergolide Trihexyphenidyl L-DOPA L-DOPA DA Carbidopa/ Benserazide Amantadine Selegiline Rasagiline 25

26 Treatment of Wearing Off If on dopamine agonist Increase amount If on levodopa/decarboxylase inhibitor Increase dose or dosing frequency Add/Switch to controlled release (but erratic) Add COMT inhibitor (entacapone) Prolong CNS duration of action Rasagiline/selegiline 26

27 Treatment of Dyskinesias Preventive Dopamine agonists Effective in younger patients, no difference in older Once dyskinesias have developed For Peak Dose Decrease levodopa Amantadine Surgery Peak Dose End of Dose Diphasic 27

28 Agonists Reduce Dyskinesia Risk Available Agonists Bromocriptine (10) Pergolide (1) Ropinerole (6) Pramipexole (1) Dose Equivalents from C. Goetz, M. Canesi Olanow W, TINS

29 Surgery and Parkinson s Disease Tremor Thalamotomy/Thalamic DBS Motor Fluctuations/Dykinesias Pallidotomy/Pallidal DBS STN DBS Gait impairment Pedunculopontine nucleus 29

30 Nigro-striato-cortical Circuitry: Changes beyond the Substantia Nigra *Excitatory Output Frontal Cortex Thalamus Interna Globus Pallidus STN Motor Ocular Dorsolateral Orbital Medial Externa Putamen Substantia Nigra 30

31 Nigro-striato-cortical Circuitry: Post- OP Changes beyond Nigra *Excitatory Output Frontal Cortex Thalamus Interna Globus Pallidus STN Motor Ocular Dorsolateral Orbital Medial Externa Putamen Substantia Nigra 31

32 Dementia in PD Prevalence 10-40% in recent studies Incidence (DSM IIIR criteria) 4.8/100 person years, Hughes TA, /100 person years, Levy G, /100 person years, Aarsland D, % in 8 years! Dementia shortens survival in PD, Louis E,

33 Risk Factors for PDD Older age of onset Longer duration of disease Low education Decreased memory and verbal fluency Axial motor impairment Impaired response to treatment 33

34 Dementia and Parkinsonism: Older (75+) Population-based Prevalence DLB + PDD - 2nd most common cause of dementia No incidence studies of DLB ND AD DLB/PDD VD Other Rahkonen T JNNP

35 Levodopa Respoonse and Dementia in PD 35

36 Basis for Cognitive Changes Dopaminergic deficits Non-Dopaminergic deficits Noradrenergic Serotonergic Cholinergic Non-motor Circuits Cortical Pathology 36

37 Cholinergic Changes in PDD ChAT 50 0 DLB PD LBV AD NC Tiraboschi P,

38 Cholinergic Drugs and Cognition Anti-cholinergic drugs worsen cognitive function Free-Recall and Self-Ordered Pointing (Bedard, 1998) Impaired attention and learning (Cooper, 1992) Cholinergic medications Duvoisin showed worse motor function in PD Nicotinergic medications Minimal effects in untreated patients (PSG, 1999) Improvement in advanced patients (Newhouse, 2000) 38

39 Anti-Cholinergics, Alzheimer Pathology and Parkinson s Disease Plaques Tangles None Short-term Long-term Perry EK Ann Neurol

40 Rivastigmine in PDD: Improved ADAS-cog Score Rivastigmine Weeks F/U Rivastigmine Placebo Emre M et al NEJM

41 Treatment in DLB and PDD Parkinsonism Sinemet Psychosis Look for underlying cause Decrease unnecessary medications Clozapine for psychosis Cognitive Deficits Cholinesterase inhibitors TYPICAL NEURLEPTICS 41