1. PARKINSON’S DISEASE June 27, 2016 Eisha Mehta PGY1, Family Medicine

2. Objectives Obtain a brief understanding of the pathophysiology of Parkinson’s disease Understand the cardinal features of the disease along with other clinical manifestations Identify the diagnostic criteria Differentiate amongst the other Parkinsonian syndromes Understand the pharmacological treatments

3. What is Parkinson’s disease Neurodegenerative disorder Degeneration of dopaminergic neurons in the basal ganglia Syndrome of bradykinesia plus at least one of rest tremor or muscular rigidity Worldwide prevalence of PD is 0.3% in general population ≥40 years M>F

4. Pathophysiology of PD

5. Nigro-striatal pathway Descending pathways SNc Brain stem VA/VL Striatum (SP, Dyn) GPi SNr Striatum (Enk) GPe Cortex D1 D2 Low tone Facilitated movements

6. Basal ganglia circuit: lack of dopamine 6 Descending pathways SNc Brain stem Cortex VA/VL Striatum (SP, Dyn) GPi SNr Striatum (Enk) GPe D1 D2 High tone Suppressed movements

7. Clinical features Classical symptoms: bradykinesia, resting tremor, rigidity, and postural instability Asymmetrical onset Tremor: resting, “pill-rolling”, and usually 3-7Hz Bradykinesia: generalized slowness of movements. Rigidity: increased resistance to passive movements. Postural instability: late sign, leads to significant risk of injury

8. Physical examination Examine gait Bradykinesia  finger tapping, heel/toe tapping In early stages, slowness and decreased amplitude is seen With disease progression, movements become less coordinated. More hesitations and/or arrests are observed https://www.youtube.com/watch?v=CH7UTwQgMm8

9. Physical Examination Tremor at rest  patient should be relaxed! Tremor can affect upper limbs, lower limbs, lips, jaw, tongue Rigidity: resistance to passive movement that is present throughout the ROM and is velocity independent https://www.youtube.com/watch?v=kDOi0m5N7Lw

10. Other motor features Craniofacial Masked facies/hypomimia Hypophonia Decreased spontaneous eye blink rate MSK Micrographia Difficulty turning in bed Reduced motor dexterity

11. Non-motor features Dementia Psychosis Mood disorders Autonomic dysfunction Pain

12. Diagnostic criteria As per the Movement Disorder Society: Diagnosis of motor Parkinsonism: bradykinesia plus tremor or rigidity In order to diagnose PD, the above is required plus: Counterbalance between supportive criteria and red flags Absence of exclusion criteria

13. Diagnostic criteria Supportive criteria: Clear and marked dramatic response to dopaminergic therapy Levodopa induced dykinesia Rest tremor of a limb Presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy Red flags: Rapid progression of gait impairment Bilateral symptoms Recurrent falls within 3 years of onset Absence of non-motor features within 5 years of disease onset Severe autonomic dysfunction in first 5 years of disease

14. Diagnostic criteria Exclusion criteria Cerebellar signs Absence of observable response to levodopa therapy Parkinsonian features isolated to lower limbs for >3 years Treatment with a dopamine receptor blocker or a dopamine- depleting agent in a dose and time-course consistent with drug- induced parkinsonism

15. Other Parkinsonian Syndromes ConditionTremorAsymmetric Movement Early Falls Early Dementia Postural Hypotension Parkinson’s disease ++--- Vascular Parkinsonism -+/- - Drug-induced Parkinsonism +/----- Lewy Body Dementia +/- + Progressive Supranuclear Palsy --++/-- Multiple system atrophy -+/- -+

16. Secondary Parkinsonian disorders ConditionTremorAsymmetric Movement Early Falls Early Dementia Postural Hypotension Parkinson’s disease ++--- Vascular Parkinsonism -+/- - Drug-induced Parkinsonism +/----- Vascular Parkinsonism: multiple lacunar infarcts in the basal ganglia Drug-induced Parkinsonism: anti-psychotics and anti- emetics are the common offenders; usually reversible

17. Parkinson-Plus Syndromes ConditionTremorAsymmetric Movement Early Falls Early Dementia Postural Hypotension Parkinson’s disease ++--- Lewy Body Dementia +/- + Progressive Supranuclear Palsy --++/-- Multiple system atrophy -+/- -+

18. Pharmacological treatments Indications: Effect on dominant hand Effect on personal and professional acitvities Patient preferences and values Levodopa typically first line However, monotherapy with dopamine agonists increasingly advocated for

19. Dopamine agonists Can initially control motor symptoms and may delay motor complications and need for Levodopa Commonly used in elderly: pramipexole and ropinirole Pramipexole: initially 0.125mg TID. Maintenance usually 0.5- 1.5mg/day Ropinirole: initially 0.25mg TID. Maintenance usually 12-16 mg/day Common SE: nausea, vomiting, orthostasis, confusion, and hallucinations

20. Dopamine Carbidopa + Levodopa  Sinemet Most effective therapy Typically start with 25/100mg tablet  half tablet BID-TID, gradually titrated over several weeks SE: Nausea, somnolence, dizziness, and HA. More serious SE include psychosis and orthostatic hypotension Motor fluctuations seen in 5-10 years of treatment

21. MAO-B inhibitors Often used as an adjunct. Enhances effect of levodopa. Has some neuroprotective properties Commonly used in the elderly: Selegiline Initial dose: 5mg qAM. Do not exceed 10mg/day SE: nausea, headaches, insomnia, confusion in older adults

22. Non-pharmacological treatment Patient education Support groups Exercise programs Diet management: high fibre, hydration, Vit D and calcium

24. References Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson's disease: a systematic review and meta- analysis. Mov Disord 2014; 29:1583 Young, R. Update on Parkinson’s disease. Am Fam Physician. 1999 Apr 15;59(8):2155-2167 Rao, S.S., Hofmann, L.A., and Shakil, A. Parkinson’s disease: Diagnosis and Treatment. Am Fam Physician. 2006 Dec 15;74(12):2046-2054. Lawes, N. “Basal ganglia”. Lecture. University of Limerick, Limerick. May 2012. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015 Oct;30(12):1591-601. Aminoff MJ. Clinical differentiation of parkinsonian syndromes: Prognostic and therapeutic relevance. Am J Med. 2004;117(6):412–419 Chou, KL. Clinical manifestations of Parkinson’s disease. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2016) Chou, KL. Diagnosis and Differential Diagnosis of Parkinson’s disease. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2016) Tolosa E, Wenning G, Poewe W. The Diagnosis of Parkinson’s disease. Lancet Neurol. 2006;5(1):75. Tarsy, D. Pharmacologic treatment of Parkinson’s disease. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on June 25, 2016)