Parkinson’s Disease

1. Parkinson’s Disease AIMGP Seminar Prepared by: Ilan Lenga and Nicolas Szecket

2. References • NEJM Review Articles • Parkinson’s Disease Part One October 8, 1998 • Parkinson’s Disease Part Two October 15, 1998 • UpToDate Vol 10.2 • Treatment Guidelines by the American Academy of Neurology. Neurology 50(3) Suppl3. 1998. • Principles of Neural Science, Third edition

3. Case • Mr JP is a 63 yo male, school teacher • Gradual development of right hand resting tremor over last 6 months • Also describes “difficulty getting going”, and feeling “unsteady on my feet” • He has had no falls • His symptoms are not interfering with his job or ADL’s

4. Case • No sensory or motor symptoms • No cognitive symptoms • No bowel/bladder symptoms • No significant past medical Hx • No EtOH or other drugs

5. Case • O/E: • Vitals normal, no postural change • General physical exam unremarkable • Neuro: • asymmetrical right handed tremor 4-6 Hz • Normal CN exam • Normal bulk, strength, DTR’s • Mild increased tone, cogwheeling of R wrist • Normal sensory and cerebellar exam • Gait unremarkable • Folstein 30/30

6. Question • Does this man have Parkinson’s Disease?

7. “….Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace, the senses and intellects being uninjured.” James Parkinson, 1817

8. Features of PD T Tremor • Classic pill-rolling or pronation/supination tremor is 4 - 6 Hz, usually upper limb (75% of pts). Brought out by distraction. Decreased with movement of limbs R Rigidity • Lead-pipe or cogwheel, tone usually slightly more in flexors than extensors A Akinesia • slowness of movement (bradykinesia), poverty of movement (facial amimia, arm swing),difficulty initiating movement P Postural Instability • impaired corrective postural reflexes(early), progresses to more upper trunk instability with fall risk

9. Most Distinctive Signs of Idiopathic Parkinson’s Disease • Asymmetrical Resting Tremor • Dementia not an early feature • Normal Strength • Excellent initial response to L-dopa

10. DDx • Parkinsonism Plus • Diffuse Lewy Body Dementia • Progressive Supranuclear Palsy • Multi-System Atrophy • Shy-Drager • Striatonigral Degeneration • Olivopontocerebellar atrophy • Corticobasal Degeneration

11. DDx • Drug-induced • Vascular • Toxins • CO, methanol, manganese, MPTP • Post-infectious (Postencephalitis lethargica) • Paraneoplastic/tumour • Trauma

12. Question • His symptoms are relatively mild, what measures would you institute now? Non-Pharmacological & ?Neuroprotection?

13. Non-Pharmacological • Group Support for Patient & Family • Education • Parkinson’s Foundation of Canada; www.wemove.org • Physiotherapy • Exercise is critical to maintaining health • Occupational Therapy • Patients acquire numerous disabilities & require assistance with many ADLs • Speech-Language Pathology • Speech and swallowing difficulties develop/intensify over course of disease

14. Neuroprotection? • Selegiline • MAO-B inhibitor • Blocks formation of free radicals derived from the oxidative metabolism of Dopamine • Able to protect mice from the effects of MPTP (drug-induced PD) • RCT’s have shown that selegiline delays disability and appears to slow the progression of symptoms in previously untreated PD. • Whether this means it is truly “neuroprotective” is still being clarified

15. Case • JP and his wife join a support group, and you start him on Selegiline 5mg BID • You follow him in clinic • Over the next 6 months, his symptoms are stable, but then his akinesia and rigidity begin to progress. He has almost fallen once. • His symptoms are now interfering significantly with his job

16. Questions • Would you initiate therapy now? • What are the options?

17. Goals of Therapy • Symptomatic improvement • Maximizing quality of life • Possibly prolonging survival

18. Symptomatic Pharmacological Rx • Levodopa • Dopamine Agonists • Anticholinergics • Amantadine

19. Levodopa • The cornerstone of PD therapy • Most effective agent available • Precursor to Dopamine • Can cross blood brain barrier (dopamine can’t) • Peripheral metabolism leads to side-effects - nausea, vomiting, orthostasis • Carbidopa, a peripheral decarboxylase inhibitor, decreases peripheral metabolism

20. Levodopa • Sinemet 100/25 200/25 200/50 250/50 • Goal is lowest dose required - at start, usually 300-600mg/day, titrate up to 1g/d • Take on empty stomach, because absorption competes with amino acids Carbidopa L-Dopa

21. Levodopa • Disadvantages • 50% of patients within 5 years of Rx develop L-dopa induced motor complications (stay tuned to the case) • Neuropsychiatric problems - confusion, psychosis • Theoretical concerns about accelerating disease due to oxidative damage to neurons

22. Dopamine Agonists • Act directly on striatal dopamine receptors without synaptic uptake/release or metabolic conversion • Used as an L-dopa sparing strategy • Bromocriptine and Pergolide most common • Start slowly and increase gradually • Side effects include orthostasis, nausea, vomiting, hallucinations, peripheral vasoconstriction, and rarely pleuro/retroperitoneal fibrosis

23. Dopamine Dopamine Acetylcholine Acetylcholine Parkinson’s Normal Anticholinergics

24. Anticholinergics • Restores balance between Dopamine and ACh in the brain • Benztropine and trihexyphenidyl (Artane) most common • Not well tolerated due to side effects • mydriasis, dry mouth, impaired sweating, urinary retention, constipation, delirium • Used primarily for refractory tremor and sialorrhea

25. Amantadine • Mechanism of action unclear • Short term benefit, not sustained beyond 6 - 12 months • Side effects include ankle edema, insomnia, nightmares, confusion, hallucinations, and anticholinergic effects • Most effective for tremor, some activity against akinesia and rigidity

26. Drug L-dopa Dopamine Agonist Anticholinergic Amantadine Tremor poor poor good good Summary of Main Effects Rigidity/Akinesia excellent good poor poor

27. A excellent, detailed, table of drugs, dosages and side effects. A recommended reference. NEJM Oct 15, 1998

28. Case • You elect to start him on Sinemet, on a dose of 100/25 TID • His symptoms markedly improve • He is left with a mild R hand tremor, but otherwise returns to excellent function

29. Case • You follow Mr. JP over the next 4 years • He requires gradual titration of his Sinemet up to a current dose of 250/50 TID • He now comes in complaining that he is developing rigidity and “freezing” 30-60 minutes before each dose

30. Questions • What’s going on? • What can you do for him?

31. “Wearing Off” Effect • As PD progresses dopaminergic nerve terminals degenerate and cannot store and release dopamine well • The result is more dependence on plasma L-dopa levels • L-dopa has a T1/2 of 1.3hrs, thus adequate levels are only maintained for up to 4 hours

32. Treatment Options • Shorten dosing interval • Sinemet CR (requires 30% increase in dose due to lower absorption) • Add Dopamine Agonist • Catechol-O-methyl transferase (COMT) inhibitor

33. COMT Inhibitor • Tolcapone and entacapone • prevent metabolism of L-dopa • increase T1/2 of L-dopa, stabilizing plasma levels • Side-effects: due to increased L-dopa, diarrhea (severe in 5%), rare hepatotoxicity

34. Case • You switch Mr. JP to Sinemet CR with only modest improvement • Ultimately he responses to tolcapone 100mg TID

35. Case • 4 months later he begins to describe fluctuations between being “on” (responding to meds) and “off” (parkinsonian) • Also he notes occasional involuntary movements during “on” periods and painful leg muscle “spasms” during off periods particularly in the early morning

36. Questions • What is happening? • Can anything be done?

37. Complications of L-dopa Rx • Motor Fluctuations • wearing off effect • on-off phenomenon, rapid/unpredictable • Dyskinesias • Peak dose dyskinesias (chorea, athetosis, ballismus, myoclonus) • Off-period dystonias • diphasic dyskinesias (beginning & end dose) • Psychiatric disturbances

38. Management • Important to determine relationship to time of dose • Peak-dose effects managed by: • smaller frequent doses of L-dopa • risk more off periods • lower L-dopa & add dopamine agonist • atypical neuroleptics (esp. clozapine) • ? Propanolol, fluoxetine, buspirone

39. Management • Trough effects managed by: • managed as per the wearing-off strategies • Off-period dystonias managed with: • night time or early am dosing • baclofen, botulinum, lithium • a “delayed on” problem may be due to poor gastric emptying • managed with domperidone

40. Management • Psychiatric disturbances • Depression - treated as in non-PD patients • Psychotic symptoms • favour atypical antipsychotics. Clozapine has least deletirious effect on PD, but risk of agranulocytosis • Ondansetron may be effective • Dementia • no effective treatment

41. Management • Manifestations of advanced Parkinson’s and chronic levodopa therapy are notoriously difficult to manage • Trial-and-error strategy required • Seek advice from a movement disorder specialist in difficult cases

42. Case • Mr. JP initially responds to lowering his L-dopa dose and adding bromocriptine • Eventually he develops unpredictable “on-off” periods and diphasic dyskinesias • You refer him to a movement disorder neurologist for ongoing management

43. The End