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Parkinson’s Update

Learn about the history of Parkinson's disease, its clinical features, and the diagnostic process. Understand the differential diagnosis and typical progression of the disease.

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Parkinson’s Update

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  1. Parkinson’s Update Laurence Robbins, MD

  2. History of PD • “Kampa/vata” (shaking/lack of muscle movement) describes in ancient Indian medical system 4500 years ago • James Parkinson publishes his 1817 monograph, "An Essay on the Shaking Palsy“ • Frederick Lewy (1912) identifies neuronal cytoplasmic inclusions in various brain tissues • Tretiakoff (1919) describes Lewy bodies in substantia nigra in PD

  3. Prevalence of Parkinsonism (EPESE data) • Accounts for 10% of gait disorders • Community elderly >65; Gait abn & 1or more signs of parkinsonism: 15% 65-74 yo 30% 75-84 yo 50% >85 yo photo by Alan Light

  4. AES Question 1 Which patient is most likely to have Parkinson’s disease? • 70-year-old man with increased tone, bilateral symmetric action tremor and frequent falls for one year • 65-year-old woman with 3-year history of persistent right-sided rigidity, akinesia and poor response to L-dopa • 72-year-old man with a 1-year history of right-sided resting tremor and rigidity • An 80-year-old hypertensive woman with weak right grip, bilateral hyperreflexia and Babinski response on right

  5. Clinical Features • Tremor • Rigidity • Bradykinesia • Gait disorder • Blunted postural reflexes and autonomic dysfunction (usually late)

  6. Sign suggesting other diagnoses • Falls at presentation and early in disease • Poor response to levodopa • Symmetry at onset • Rapid progression • Lack of tremor • Early dysautonomia (urinary urgency/incontinence, urinary retention, fecal incontinence, diaphoresis, erectile dysfunction, symptomatic orthostasis)

  7. Predictive accuracy of dopamine challenge • Up to 30% of patients with PD might not respond to acute dopaminergic challenges • 20 to 30% of patients with a positive acute dopaminergic challenge will go on to develop another Parkinson-like syndrome • Absence of response to a levodopa dose of 1000 to 1500 mg day for > two months strongly suggests it’s not PD

  8. The practical diagnosis of Parkinson’s disease (PD) during life is based on clinical impression. There are no physiologic tests or blood tests for confirming the diagnosis, and neurodiagnostic testing with computerized imaging is almost always unrevealing. • The "gold standard" for diagnosis is neuropathologic examination.

  9. Case discussion • An 80 yo man is referred for evaluation of “possible depression; is he a Ritalin candidate?” He’s accompanied by his wife, who describes how ambulation has been much more difficulty since his esophagectomy for cancer 18 months ago. His medications include hydrochlorothiazide, lisinopril and metoclopramide.

  10. On exam, his blood pressure is 140/90. The patient has a flat affect and blinks little. He slowly rocks back and forth in his chair when asked to stand but is unable to propel himself to a standing position. When helped up to a standing position, he has trouble initiating his gait, then takes a few small steps and freezes.

  11. AES Question 2 What is your next step? A. Stop hydrochlorothiazide B. Stop metoclopramide C. Begin carbidopa/levodopa 25/100 tid D. Start ropinirole 1 mg bid

  12. Differential diagnosis • Idiopathic Parkinson’s disease 85% • Drug-induced (e.g. metoclopramide) 7-9% • Parkinson-plus syndromes 4% • Vascular parkinsonism 3%

  13. Drug-induced parkinsonism • Drug-induced parkinsonism can occur with medications not usually considered culprits (metoclopramide, valproic acid, phenytoin, prochlorperazine, calcium channel blockers, cholinomimetics, etc.) as well as with typical and atypical antipsychotic medications

  14. Central Gait Disorder vs PD • Lesions of the midline portion of the CNS may produce axial instability mimicking PD (e.g., “multi-infarct”, NPH or cerebellar disease) • Stance is wide-based vs narrow-based in PD • Stand more erect; “lower half parkinsonism”: often accompanied by dementia and frontal release signs especially if vascular etiology

  15. Hallmarks of PD • Resting tremor and rigidity • Asymmetry • Response to levodopa

  16. Differential diagnosis of tremor • Resting = PD • Postural = essential • Intentional = cerebellar

  17. Differential Diagnosisof Tremor

  18. Rigidity (PD) vs Spasticity • Rigidity more uniform resistance throughout range of motion and less rate-related • Spasticity is “clasp knife”; increasing resistance with “giving way” • Spasticity worse with increased speed of passive movement

  19. Typical Progression and Course • Preclinical: 2-6 years of non-motor signs • Onset: 12 months without treatment • Honeymoon: 1-3 years of good response to medication • Motor complications: 3-8 years (wearing off, on-off, dystonia, dyskinesias) • Resistant symptoms: 8-15 years • Cognitive decline: 15-20 years (Fahn. Ann NY Acad Sci. 2003;991:1-14.)

  20. Case Discussion • The same 80 yo patient returns one week later after withdrawal of medications. He now can stand without assistance but still has difficulty initiating his gait and walks with small steps.

  21. AES Question 3 The best treatment choice now is: • Entacapone (Comtan) 200 mg qid • Pramipexole 0.5 mg tid • Selegiline 5 mg bid • Amantadine 100 mg bid • Carbidopa/levodopa 25/100 tid

  22. Treatment Principles • Most medication reduces symptoms • Very marginal evidence that disease progression may be slowed • Narrow therapeutic/toxic window • Most effective therapy aimed at dopamine

  23. Medications for PD • Carbidopa/L-dopa (Sinemet) • Dopamine agonists (pramipexole, ropinirole, rotigotine patch) • COMT inhibitors • (entacapone, tolcapone) • Anticholinergics (e.g., trihexyphenidyl) • Amantadine • MAO Inhibitor (selegiline, rasagiline)

  24. Carbidopa/Levodopa (Sinemet) • Most effective med for gait (bradykinesia, rigidity); tremor response variable • Carbidopa prevents peripheral breakdown of levodopa; >75 mg daily for max effect • Begin 25/100 bid or tid; may switch to 10/100 or 25/250 as dose increased; average patient needs @ 500 to 1000 mg L-dopa/day • Avoid taking with food

  25. Carbidopa/levodopa controlled release • Controlled release tablet has delayed onset and longer duration (25/100 or 50/200) • May reduce dosing frequency by 1/3 • Only 70% absorbed (total dose higher); taken with food improves absorption • Useful at bedtime for better overnight control

  26. Long-term levodopa complications • 75% at >5 years have motor fluctuations, especially younger age of onset and need for higher dose • Motor fluctuations: • wearing off • dyskinesias • “on/off” • Hallucinations, psychosis

  27. Management of motor fluctuation • Simplify regimen • Give carbidopa/levodopa in smaller doses more often (wearing off, “on/off”) • Consider reducing total dose of carbidopa/levodopa (to reduce dyskinesias) • Consider adding dopamine agonist

  28. Anticholinergics • Limited benefit for tremor, rigidity, and bradykinesia • Common and disabling side effects (constipation, dry mouth, urinary retention, confusion, etc.) • DON’T USE IN THE ELDERLY

  29. Amantadine • Modestly improves tremor, bradykinesia, and rigidity • Mechanism of action uncertain • Limited efficacy as disease progresses (100 to 200 mg daily) • Toxicity includes confusion, psychosis • May reduce L-dopa-induced dyskinesia

  30. MAO Inhibitors: selegiline and rasagiline • Monoamine Oxidase Inhibitor (MAOI) inhibits breakdown of dopamine • Minimal symptomatic benefit alone • Early selegiline studies suggest delayed progress of PD (5 mg bid) but benefit wanes • Risk of serotonin syndrome with SSRI

  31. MAO B Inhibitors: Rasagiline (Azilect) • FDA-approved May 2006 • Advantage over selegiline: has modest benefit for motor function when used alone • Dose 0.5 to 1 mg daily: expensive!

  32. Dopamine Agonists • Dopamine agonists given alone may reduce PD signs; often first-line in younger patients • Probably less effective than carbidopa/L-dopa and may be more hallucinogenic • “Levodopa sparing;” delay dyskinesias • May also improve response if combined with carbidopa/L-dopa • Few comparisons between dopamine agonists; expensive

  33. Dosing Dopamine Agonists • Pramipexole (Mirapex): begin .125 tid; goal is 4.5 mg/d in divided doses • Ropinirole (Requip): begin 0.25 tid; goal is up to 24 mg/d in divided doses • Rotigotine (Neupro): begin 2 mg/24 hr patch; titrate to 6 mg/24 hr (expensive, not better)

  34. COMT Inhibitors • May smooth response to carbidopa/levodopa Entacapone (Comtan): 200 mg with each dose of carbidopa/L-dopa • Tolcapone (Tasmar) seldom used; “liver toxic” • Reduce carbidopa/L-dopa 10%-15% to avoid levodopa toxicity (dyskinesia, etc)

  35. Treatment of Tremor • All tremors: reduce caffeine, stress, fatigue • Essential tremor • propranolol 20-320 mg/d (not all beta blockers work) • Primidone (Mysoline) 25-500 mg/d • Gabapentin: one randomized trial; 1200 mg daily • Cerebellar tremor: no effective treatment

  36. Device-assisted and surgical treatment • Deep brain stimulation, Continuous levodopa-carbidopa intestinal gel (LCIG) infusion, continuous subQ apomorphine infusion (CSAI) • Indications: severe motor fluctuations despite optimal oral therapy, inconsistent response, dyskinesias or motor fluctuations that don’t respond to med adjustment, refractory severe tremor, no dementia • Require initial responsiveness to levodopa

  37. Case discussion • Three years later, your patient is now having visual delusions (example, spots on ceiling are bugs) that disturb him and frighten his wife. His medications now include carbidopa/levodopa 25/250 qid. You try to reduce his dose of carbidopa/levodopa but his motor symptoms worsen.

  38. AES Question 4 To control his delusions, you would prescribe: • Quetiapine (Seroquel) • Risperidone (Risperdal) • Haloperidol (Haldol) • Olanzapine (Zyprexa)

  39. Antipsychotics in PD • Quetiapine has the least extrapyramidal toxicity of any currently available antipsychotic medications • Clozapine in low dose is also effective in controlling delusions without worsening parkinsonism but must be monitored for bone marrow suppression

  40. Non-pharmacologic management of PD • Regular aerobic exercise may have benefit on symptoms • Twice weekly tai chi reduced self-reported falls (Li et al N Engl J Med 2012; 366:511) • 2013 Cochrane Review concludes that benefits of physical therapy is small (Cochrane Database Syst Rev 2013; 9:CD002817) • Speech therapy may improve speech volume (small studies)

  41. PD and End of life care • To date, no intervention will prevent the progression of PD • Approximately 80% of PD patients will develop dementia by the end of their lives • In US, most die in hospitals or nursing homes • Diminishing response to medications, decline in mobility and ADLs, progressive dysphagia and aspiration pneumonia, weight loss, dyspnea and reduced vital capacity may signal time to refer for hospice care

  42. Best Practice Recommendations • Carbidopa/L-dopa (Sinemet) is best; carbidopa >75 mg daily • Avoid regular carbidopa/L-dopa with food • Avoid anticholinergics and amantadine in elderly • Dopamine agonists may be added • MAOIs and COMT inhibitors expensive, modest benefit

  43. Key References • Connolly BS. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670. • Rogers G. Parkinson’s disease: summary of updated NICE guidance. BMJ 2017; 358:j1951. • Alexander N. Gait disorders in older adults. J Am Geriatr 44:434, 1996. • Nutt JG. Diagnosis and initial management of Parkinson’s disease N Engl J Med 353: 1021, 2005. LeWitt PA. Levodopa for Treatment of Parkinson’s disease. N Engl J Med 359:2468, 2008. • Langston JW. The Parkinson’s Complex Ann Neuro 59:591, 2006.

  44. Answers • C • B • E • A

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