Published on June 8, 2019
1. Parkinson’s Disease & It’s Managements Dr. Rupendra K. Bharti Assist. Professor Late. BRKM GMC Jagdalpur
2. Introduction Parkinsonism is a generic term that is used to define a syndrome manifest as bradykinesia with rigidity and/or tremor. It has a differential diagnosis (Table 449-2) that reflects damage to different components. Among the different forms of parkinsonism, PD is the most common (approximately 75% of cases). Parkinsonism is a clinical syndrome characterized by motor symptoms like bradykinesia, tremor and rigidity.
3. Classification of the Parkinsonism Primary parkinsonism (Parkinson’s disease) Sporadic/Idiopathic Genetic (Mutation of alpha- synuclein, parkin, LRRK2, DJ1, and PINK1gene) Parkinsonism-plus syndromes (Atypical parkinsonism) Progressive supranuclear palsy (PSP) Multiple system atrophy(MSA) Cerebellar type (MSA-c) Parkinson's type (MSA-p) Cortical-basal ganglionic degeneration(CBGD) Frontotemporal dementia(FTD)
4. Secondary parkinsonism (environmental Aetiology) Drugs induced(Antipsychotic medications, Reserpine, Tetrabenazine) Postencephalitic(infection) Toxins: MPTP, cyanide,CO, Mn, hexane Heavy metal (iron, manganese) Vascular Brain tumors Head trauma Normal-pressure hydrocephalus Liver failure
5. OTHER NEURODEGENERATIVE DISORDER Wilsons disease Huntington's disease Neurodegenaration with brain iron accumulation SCA 3 (spinocerebellar ataxia) Fragile x-associated ataxia- tremor parkinsonism. Prion disease Dystonia-parkinsonism (DYT3) Alzheimer's disease with parkinsonism
6. Clinical differentiation
7. Neurodegenerative diseases Parkinson’s Disease Alzheimer’s Disease Huntington’s Disease Amyotrophic lateral sclerosis (ALS) Spinocerebellar Ataxia
8. Epidemiology of Parkinson’s disease Prevalence Crude prevalence –India - 328 per 100,00 Incidence Crude annual incidence rates- 1.5 per 100,000 population (China) in 1986 to 14.8 (Finland) through 1968 to 1970.
9. Gender differences Slightly more common in men than in women Male to female ratio- 1.2:1 to 1.5:1 Geographic distribution Crude prevalence China - 15 per 100,000 India - 328 per 100,000 Mississippi, USA - 131 per 100,000 Argentina - 657 per 100,000
10. Ethnic distribution White people in Europe and North America have a higher prevalence, around 100 to 350 per 100,000 population. Asians in Japan & China and Africans have lower rates, around one-fifth to one-tenth of those in whites.
11. Age Distribution Less common before 50 years of age & increases steadily with age thereafter up to the ninth decade. ~1 in every 200 persons aged 60–69 had PD in the United States (US) and Western Europe. For people in their 70’s, this increased to ~1 person with PD in every 100 people. For people in their 80’s, ~1 in every 35 had PD
12. Incidence “Every four seconds, a new case of dementia occurs somewhere in the world.” Cohort longitudinal studies provide rates between 10 and 15 per thousand. Advancing age -primary risk factor Women- higher risk of developing AD particularly in the population older than 85
14. Clinical Presentation
15. Rest Tremor Tremor : Rhythmical & involuntary shaking, trembling or quivering movements of the muscles. Rest tremor ( 4 - 6 Hertz) : Maximal when the limb is at rest Disappears with voluntary movement and sleep Alternating contraction of agonist and antagonist muscles at a rapid pace Usually Unilateral at onset Involves the hands, lips, chin, jaw and legs . “ P i l l-rolling”
16. Rigidity Increased muscle tone felt during examination by passive movement Both the agonist and antagonist muscles are involved Rigidity : Cogwheel rigidity Lead-pipe rigidity
17. Postural instability Stooped Posture UNIVERSAL FLEXION : Extreme neck flexion, Extreme anterior truncal flexion (camptocormia) & Flexion of elbows and knees.
18. Tremor & Posture
19. Festinating / Shuffling Gait: i) Difficulty to initiate walking ii) Shortened stride iii) Reduced arm swing iv) Rapid small steps (shuffling) RUNNING AFTER THE CENTRE OFGRAVITY Freezing phenomenon
20. Gait & micrography
21. Non-motor symptoms Neuropsychiatric Depression & Anxiety disorders Apathy Autonomic disturbance (dysautonomia) Urinary dysfunction Constipation Sensory symptoms pain Restless legs syndrome Olfactory dysfunction Sleep disturbances REM behaviour disorder excessive day time drowsiness Cognitive impairment Dementia : In >80% of patients after 20 years of disease
22. Clinical picture
23. Diagnosis of Parkinsonism Diagnosis is primarily clinical, based on history and examination Confirmatory diagnosis : Histological demonstration of the intraneuronal Lewy bodies on autopsy. CT scan & MRI: to exclude other causes.
24. Examination of signs Bradykinesia : Ask patient to do repetitive movements as quickly and as possible Opening and closing the hand Tapping thumb and index fingers or tapping the foot on the ground Rest tremor: Differentiate from the intentional tremor seen in cerebellar disease Best observed while the patient is focused on a particular mental task.
25. Rigidity: Increased resistance to passive movements Postural stability The “Pull test” is performed in order to assess postural stability
26. UK Parkinson’s Disease Society Brain Bank’s clinical criteria for the diagnosis of probable Parkinson’s disease Step 1 Bradykinesia At least one of the following criteria: Rigidity Rest tremor (4–6 Hz ) Postural instability (not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction) Step 2 Exclude other causes of parkinsonism
27. Step 3 At least three of the following supportive (prospective) criteria: Unilateral onset Rest tremor Progressive disorder Persistent asymmetry Severe levodopa induced chorea (dyskinesia) Clinical course of 10 years or more
28. MODIFIED HOEHN & YAHR STAGING
30. Parkinson's disease No definite cure Relief of cardinal signs- rigidity, tremor , & akinesia Correction of mood changes Treatment of other symptoms such as depression, sleep disturbance . Treatment of cause when possible
31. NON-PHARMACOLOGICAL MANAGEMENTS Physiotherapy Speech therapy Dietary controls
32. Physiotherapy Helps to reduce rigidity Corrects abnormal posture Improves walking , turning & balance
33. Speech therapy Helpful in patients where dysarthria and dysphonia interferes communication
34. Dietary controls Include high-fiber diet Choose foods low in saturated fat and cholesterol. Avoid high protein diet
36. ANTI-PARKINSONISM PHARMACOTHERAPY INCREASE DOPAMINE a)1. Dopamine precursors: Levodopa. b)2. Peripheral decarboxylase inhibitors: Carbidopa c)3. MAO-B Inhibitors: Selegiline, rasagiline. 4. COMT Inhibitors: Tolcapone, Entacapone. 5. Dopamine releasing drugs: Amantadine 6. Dopamine receptor agonists: Bromocriptine, pergolide, cabergoline, ropinirole, rotigotine, pramipexole. DECREASE ACETYLCHOLE NE 1. Central anticholinergic: Trihexyphenidyl, Benztropine, Biperidine, procyclidine. 2. Antihistaminics: Promethazine
37. Levodopa ‘Gold-standard' treatment for Parkinson's.. Therapeutic benefit is nearly complete in early stages but declines as disease advances(“Wearing-off effect”) 1-2% cross BBB Improves cardinal signs- tremor, rigidity and akinesia.
38. ACTIONS CNS: PD CVS: Hypotension, arrhythmia CTZ: N/V Endocrine: Prolactin inhibition
39. kinetics Gastric emptying: if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longer time—less is available to penetrate blood-brain barrier. Amino acids present in food compete for the same carrier for absorption: blood levels are lower when taken with meals. Levodopa undergoes high first pass metabolism in g.i. mucosa and liver. The plasma t ½ of levodopa is 1–2 hours
40. Side Effects At the initiation of therapy Nausea, vomiting, hypotension, cardiac arrhythmias, angina, taste alteration. Avoided by gradual titration Long-term complications Dyskinesias Behavioural effects: hallucination, psychosis On–off effect Wearing-off effect (“on” episodes when the drug is working and “off” episodes when parkinsonian features return)
41. interaction Pyridoxine: Abolishes the therapeutic effect of levodopa (not combined with carbidopa) by enhancing its peripheral decarboxylation. Phenothiazines, butyrophenones, metoclopramide reverse the therapeutic effect of levodopa by blocking DA receptors. Antihypertensive drugs: more prominent postural hypotension. Nonselective MAO inhibitors: may
42. LEVODOPA + Carbidopa
43. Dopamine agonist Ergot derivatives Bromocriptine, pergolide, cabergoline associated with ergot-related side effects, including cardiac valvular damage. Second generation of non ergot dopamine agonists Pramipexole, ropinirole, rotigotine, Apomorphine
44. Common Side effect cardiac valve fibrosis (Pergolide) Nausea, vomiting, and orthostatic hypotension. Hallucinations and cognitive impairment are more than levodopa so use cautiously in age more than 70 Sedation with sudden unintended episodes of falling asleep while driving a motor vehicle have been reported.
45. Apomorphine Apomorphine is a dopaminergic agonist that can be administered by subcutaneous injection. It has high affinity for D4 receptors; moderate affinity for D2, D3, D5, and adrenergic α1D,α2B, and α2C receptors; and low affinity for D1 receptors. Apomorphine has been used as a “rescue therapy” for the acute intermittent treatment of “off” episodes in patients with a fluctuating response to dopaminergic therapy Dose: 2-6mg (depends upon tolerability of pts)
46. S/E Apomorphine is highly emetogenic and requires pre- and post-treatment anti-emetic therapy. Oral trimethobenzamide, 300 mg three times daily, should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy. Profound hypotension and loss of consciousness have occurred when apomorphine was administered with ondansetron; hence, the concomitant use of apomorphine with antiemetic drugs of the 5-HT3 antagonist class is contraindicated. Other potentially serious side effects: QT prolongation, injection-site reactions, and the development of a pattern of abuse characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behaviour.
47. MAO-B INHIBITORS Selegiline, Rasagiline Monotherapy in early disease. These agents selectively inactivate MAO-B through irreversible inhibition of the enzyme They inhibit the breakdown of DA in the striatum. Reduced “off” time when used as an adjunct to levodopa in patients with motor fluctuations.
48. Selegiline Used for symptomatic treatment for early or mild PD. Well tolerated in younger patients with PD. Also having antioxidant property. Selegiline reduces motor & cognitive effects of levodopa therapy in advance PD. S/e: anxiety, insomnia is more common selegiline therapy due to production of its active metabolites such as Amphetamine and methamphetamine.
49. Rasagiline No undesirable amphetamine effects. Rasagiline monotherapy was effective in early PD. Also significantly reduced levodopa- related “wearing off” symptoms in advanced PD.
50. Interactions Selegiline & Rasagiline can lead to the development of stupor, rigidity, agitation, and hyperthermia when administered with the analgesic meperidine. Concomitant therapy of MAO-B inhibitors with tricyclic antidepressants or with serotonin- reuptake inhibitors
51. COMT INHIBITORS Tolcapone Entacapone The principal therapeutic action of the COMT inhibitors is to block this peripheral peripheral conversion of levodopa to 3-O- methyl DOPA, increasing both the plasma t t ½ of levodopa as well as the fraction of each dose that reaches the CNS. Levodopa with a COMT inhibitor reduces “off” time and prolongs “on” time. Two COMT inhibitors have been approved, approved, tolcapone and entacapone.
52. Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. Entacapone has a short duration of action (2 hours) and usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT.
53. S/E Nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations An important adverse effect associated with tolcapone is hepatotoxicity, requires special monitoring. Entacapone has not been associated with hepatotoxicity and requires no special monitoring.
54. Anticholinergic drugs These agents helpful in patients with severe tremor. Anticholinergic drugs currently used in the treatment of PD include Trihexyphenidyl (2-4 mg three times per day), Benztropine Mesylate (1-4 mg two times per day), and Diphenhydramine hydrochloride (25-50 mg three or four times per day). Diphenhydramine also is a histamine H1 antagonist
55. These drugs have relatively modest antiparkinsonian activity and are only used in the treatment of early PD or as an adjunct to dopamimetic therapy. Adverse effects result from their anticholinergic properties. Most troublesome are sedation and mental confusion. Other side effects are constipation, urinary retention, and blurred vision through cycloplegia. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma.
56. Amantadine Amantadine, an antiviral agent used for the prophylaxis and treatment of influenza A , has antiparkinsonian activity. Amantadine appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. Its used in mild PD & L-Dopa induced motor fluctuations and abnormal movements. Fixed dose of 100 mg BD is used. S/E: Dizziness, lethargy, anticholinergic effects, and sleep disturbance
57. Treatment approaches to newly diagnosed PD
58. Surgery Deep Brain Stimulation Thalamotomy Pallidotomy Neural Transplantation