Clinical Features and Treatment of Parkinson s Disease Richard Camicioli, MD, FRCPC Cognitive and Movement Disorders Department of Medicine University of Alberta 1
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
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
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
Key Signs and Symptoms of PD Tremor Rigidity Akinesia/Bradykinesia Postural instability/gait imparment 5
Tremor 5-9 Hz rest tremor May have associated action tremor 6
Rigidity Cogwheel rigidity=rate independent stiffness with superimposed tremor Distinct from spasticity=rated dependent stiffness 7
Akinesia/Bradykinesia Akinesia=inability to initiate movement Bradykinesia=slowing of movement and decreased amplitude and velocity 8
Tremor and Bradykinesia 9
Dauer W Neuron 2003 10
Haber SN 11
Haber SN 12
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
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
L-Dopa Supplementary Motor Area (SMA) and fmri 15
Metabolism of Levodopa 3-OMD COMT Levodopa 3-OMD COMT Levodopa Glia MAO-B 3,4 DHPA AADC Dopamine Neuron 16
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
Early Impaired Gait 18
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 2002 19
First-year Balance Impairment J Muller 2000 20
Late PD: Complications Within 3 years up to 50% develop Wearing Off or On/Off Dyskinesia Freezing Neuropsychiatric Depression Psychosis Dementia Autonomic 21
Motor Complications Increase with Time % 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 Years Old Dysk Old Fluct Young Dysk Young Fluct 22
Bradykinesia and Dyskinesia 23
Decreasing Levodopa Breakdown Increases Motor Response Dyskinesia Parkinsonism 24
Treatment Options: Sites of Action Entecapone Pramipexole Ropinerole Bromocriptine Pergolide Trihexyphenidyl L-DOPA L-DOPA DA Carbidopa/ Benserazide Amantadine Selegiline Rasagiline 25
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
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
Agonists Reduce Dyskinesia Risk Available Agonists Bromocriptine (10) Pergolide (1) Ropinerole (6) Pramipexole (1) Dose Equivalents from C. Goetz, M. Canesi Olanow W, TINS 2000 28
Surgery and Parkinson s Disease Tremor Thalamotomy/Thalamic DBS Motor Fluctuations/Dykinesias Pallidotomy/Pallidal DBS STN DBS Gait impairment Pedunculopontine nucleus 29
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
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
Dementia in PD Prevalence 10-40% in recent studies Incidence (DSM IIIR criteria) 4.8/100 person years, Hughes TA, 2000 6.9/100 person years, Levy G, 2002 10/100 person years, Aarsland D, 2003 78% in 8 years! Dementia shortens survival in PD, Louis E, 1997 32
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
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 2003 34
Levodopa Respoonse and Dementia in PD 35
Basis for Cognitive Changes Dopaminergic deficits Non-Dopaminergic deficits Noradrenergic Serotonergic Cholinergic Non-motor Circuits Cortical Pathology 36
Cholinergic Changes in PDD 300 250 200 150 100 ChAT 50 0 DLB PD LBV AD NC Tiraboschi P, 2002 37
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
Anti-Cholinergics, Alzheimer Pathology and Parkinson s Disease 2.5 2 1.5 1 Plaques Tangles 0.5 0 None Short-term Long-term Perry EK Ann Neurol 2003 39
Rivastigmine in PDD: Improved ADAS-cog Score 2.5 1.5 2 0.5 1-0.5 0-1 0 16 24 Rivastigmine Weeks F/U Rivastigmine Placebo Emre M et al NEJM 2004 40
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