Parkinsonism

parkinsonism update

1. DR RAMDHAN KR KAMAT PG (3 rd year) JLNMCH, Bhagalpur

2. History & epidemiology - Introduction and Conclusion Anatomy & physiology Pathology of Parkinsonism Clinical features & diagnosis of Parkinsonism Management of Parkinsonism Pathology of Alzheimer’s disease Clinical Feature & Diagnosis of Alzheimer’s Management Of Alzheimer’s Disease

3. 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 of the basal ganglia. Among the different forms of parkinsonism, PD is the most common (approximately 75% of cases).

4.  Parkinsonism is a clinical syndrome characterized by motor symptoms like bradykinesia,tremor and rigidity.  Classification of the Parkinsonism Primary parkinsonism (Parkinson’s disease) Sporadic / Idiopathic Genetic Parkinsonism-plus syndromes (Atypical parkinsonism) Progressive supranuclear palsy (PSP) Multiple system atrophy (MSA) Cerebellar type (MSA-c) Parkinsons type(MSA-p) Cortical-basal ganglionic degeneration (CBGD) Frontotemporal dementia(FTD)

5. Secondary parkinsonism (environmental etiology) 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

6. OTHER NEURODEGENERATIVE DISORDER Wilsons disease Huntingtons disease Neurodegenaration with brain iron accumulation SCA 3 ( spinocerebellar ataxia) Fragile x-associated ataxia-tremor parkinsonism. Prion disease Dystonia -parkinsonism (DYT3) Alzheimers disease with parkinsonism

7. Neurodegenerative diseases  Parkinson’s Disease  Alzheimer’s Disease  Huntington’s Disease  Amyotrophic lateral sclerosis (ALS)  Spinocerebellar Ataxia

8. Case Presentation

9.  Began to experience tremors and stiffness of his left arm while he walked  Changes in his posture and unusual movements of his left arm.  Sleep disturbances  Gait problems- stooped posture  Symptoms gradually worsened with time Case 1 Mr Anil chaudhry , 65 years old man, a retired university professor……

10. Case 2 Mrs Meena devi , 76 years old woman Lived alone for several years  Brought to the neurological department , by her daughter, memory impairment  General and neurological examinations- normal  Speech – highly anomic , paraphasic  Unable to provide birth month, year, current year  Cognitive domain – below average

11. HISTORY & EPIDEMIOLOGY

12. History of Parkinson’s Disease  First clear medical description: James Parkinson in An Essay on the Shaking Palsy (1817)  Jean-Martin Charcot- Influential in refining and expanding this early description & in disseminating information internationally Named the disorder as Parkinson’s disease

13.  William Gowers - Slight male predominance of the disorder, joint deformities typical of the disease.  Richer and Meige  Babinski - Babinski sign  Brissaud  Greenfield and Bosanquet- Clear delineation of the brain stem lesions

14. Epidemiology of Parkinson’s disease  Prevalence Crude prev a lence – 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.

15.  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

16.  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.

17.  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

18.  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

19. Basal Ganglia

20. GRAY MATTER (COLLECTION ) CORPOUS STRATUM AMYGDALOID CLAUSTRUM SUBTHALAMIC NUCLEI SUBSTANTIA NIGRA

21. Corpus striatum Le n tiform nucleus Globus pallidus putamen C a ud a te nucleus

22. Corpus striatum Le n tiform nucleus Globus pallidus putamen C a ud a te nucleus Neostraitum or straitum P aleostraitum

23. /striatum

24. Cognition(caudate circuit) eg:A person seeing a lion approach ???? FU N CTIO N S Executes Learned Patterns of Motor Activity eg:writing of letters of the alphabet. hammering nails, shooting a basketball through a hoop,

25. Control of movement N i gr o striat a l pathway Indirect path w ay Direct P a th w ay Planning of movement

26. PATHOLOGY OF PARKINSON’S DISEASE

27. Etiology Idiopathic Genetic Parkinson’s disease  Results due to reduction in the striatal dopamine content due to damage of nigrostriatal pathway .

28. PARKINSON’S DISEASE  Neurodegenerative disorder which a ffects the extrapyramidal system .

29. Idi o p a t h ic  Ageing Usual occurrence in late middle age, and increases in its prevalence at older ages Loss of striatal dopamine and dopamine of cells in the SN with age

30. Genetic factors  PD may be multifactorial in etiology with genetic contributions  The younger the age of symptom onset, the more likely genetic factors play a dominant role  At least ten single gene mutations identified

31.  Mutations in gene coding Alpha synuclein and LRRK2 (leucine rich repeat kinase 2) - Autosomal dominant PD  Mutations in gene coding Parkin ,DJ-1and PINK1- Autosomal recessive PD

32. Pathog e nesis  Three major mechanisms in dopaminergic neuron loss Mitochondrial dysfunction Oxidative and nitrosative stress Ubiquitin proteosome system dysfunction

33. Morphology  Macroscopic: Pallor or depigmentation of neurons in substantia nigra and locus ceruleus

34. Mic r osco p ic  Loss of pigmented ,catecholaminergic neurons  Intraneuronal Lewy bodies within the pigmented neurons of the substantia nigra.  Lewy bodies are cytoplasmic eosinophilic round to elongated inclusions that often have a dense core sourrounded by halo.  Lewy bodies are composed of Alpha –synuclein

35. NORMAL PARKINSONS DISEASE

36. Clinical Features & Diagnosis of Parkinsonism

37.  Motor symptoms  Non-motor symptoms

38. Motor symptoms  Characterized by Four cardinal features :  Bradykinesia (or Hypokinesia )  Tremor at rest  Rigidity  Postural instability

39. Bradykine s ia  Slowness of movements with a progressive loss of amplitude or speed.  Difficulty with planning , initiation and execution of movements.

40. Clinical Manifestations of Bradykinesia  Difficulties with tasks requiring fine motor control:  Loss of spontaneous movements and gesturing  Hypomimia (decreased facial expression) MASK LIKE FACE  Decreased spontaneous blinking  Hypophonia  Micrographia  Sialorrhoea

41. Why Bradykinesia in Parkinsonism?? “Driving while stepping on the brakes”

42. 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

43.  Involves the hands, lips, chin, jaw and legs .  “Pil l - roll i ng ” T re m or:

44. Rigidity  Increased muscle tone felt during examination by passive movement  Both the agonist and antagonist muscles are involved  Rigidity :  Cogwheel rigidity  Lead-pipe rigidity

45. Postural instability  Stooped Posture  UNIVERSAL FLEXION :  Extreme neck flexion ,  Extreme anterior truncal flexion ( camptocormia ) &  Flexion of elbows and knees.

46.  Festinating / Shuffling Gait : Difficulty to initiate walking Shortened stride Reduced arm swing Rapid small steps (shuffling)  RUNNING AFTER THE CENTRE OF GRAVITY  Freezing phenomenon

47. Non-motor symptoms  Neuropsychiatric  Depression & Anxiety disorders  Apathy  Autonomic disturbance (dysautonomia )  Urinary dysfunction  Constipation  Sensory symptoms  pain  Restless legs syndrome  Olfactory dysfunction

48.  Sleep disturbances  REM behavior disorder  excessive day time drowsiness  Cognitive impairment  Dementia : In >80% of patients after 20 years of disease

49. 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 exclude other causes.

50. 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.

51.  Rigidity : Increased resistance to passive movements  Postural stability The “Pull test” is performed in order to assess postural stability

52. 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

53.  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

54. Management of Parkinsonism

55.  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

56. Management General M e as u res Drug Therapy Surgery

57. 1.General Measures  Physiotherapy  Speech therapy  Dietary controls

58. Physio t hera p y  Helps to reduce rigidity  Corrects abnormal posture  Improves walking , turning & balance

59. Speech therapy  Helpful in patients where dysarthria and dysphonia interferes communication

60. Dietary controls  Include high-fiber diet  Choose foods low in saturated fat and cholesterol.  Avoid high protein diet

61. Drug Therapy  Does not prevent disease progression but improves quality of life Drug therapy Dopaminergic activity Cholinergic activity

62. Classification of drugs  Drugs affecting Dopaminergic system Dopamine precursors: Levodopa Peripheral decarboxylase inhibitors: Carbidopa MAO-B Inhibitors : Selegiline , rasagiline . COMT Inhibitors : Tolcapone , entacapone . Dopamine releasing drugs: Amantadine Dopamine receptor agonists:Bromocriptine , pergolide , cabergoline , ropinirole , rotigotine,pramipexole .  Drugs affecting Cholinergic system Central anticholinergic : Trihexyphenidyl , Benztropine , Biperidine , procyclidine . Antihistaminics: Promethazine

63. Levodopa  ‘ Gold-standard' treatment for Parkinson's..  Therapautic 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.

64. 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)

65. LEVODOPA + CARBIDOPA

66. Ergot derivatives: (e.g ., bromocriptine , pergolide , cabergoline ) and were associated with ergot-related side effects, including cardiac valvular damage. Second generation of nonergot dopamine agonists : ( e.g., pramipexole , ropinirole , rotigotine ) Dopamine agonist Side effect: N ausea,vomiting , and orthostatic hypotension. Hallucinations and cognitive impairment are more than levodopa so use cautiosly in age more than 70 Sedation with sudden unintended episodes of falling asleep while driving a motor vehicle have been reported.

67. MAO-B INHIBITORS Monotherapy in early disease. Reduced “off” time when used as an adjunct to levodopa in patients with motor fluctuations.

68. COMT INHIBITORS: Levodopa with a COMT inhibitor reduces “off ” time and prolongs “on” time. Two COMT inhibitors have been approved, tolcapone and entacapone .

69. Anticholinergic drugs: Their major clinical effect is on tremor, although it is not certain that this benefit is superior to what can be obtained with agents such as levodopa and dopamine agonists. Still, they can be helpful in individual patients with severe tremor. Their use is limited particularly in the elderly , due to their propensity to induce a variety of side effects including urinary dysfunction , glaucoma, and particularly cognitive impairment .

70. T reatment ap p roach e s t o newly diag n os e d PD

71. Surgery  Deep Brain Stimulation  Thalamotomy  Pallidotomy  Neural Transplantation

72. REVIEW AND CONCLUSION!

73. P ARKIN S ONISM CASE 1  Mr Poudel, 65 years old man  Difficulty in walking and speaking , tremor in left hand and leg  Sleep disturbances

74.  Rx:  Levodopa 250 mg+ carbidopa 25mg  Medication reduced his symptoms but did not stop the disease from getting worst.  His loss of mobility and speech impairment limited his social interactions.  He and his wife also have had to give up many of their retirement travel plans.

75. THANK U SIR