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Parkinson’s disease

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A BREIF DISCRIPTION OF PARKINSON'S DISEASE..

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Parkinson’s disease

  1. 1. PARKINSON’S DISEASE DR PRASHANT DUBEY PG DEPARTMENT OF MEDICINE SN MEDICAL COLLEGE,AGRA.
  2. 2. INTRODUCTION • Parkinson’s disease is the second commonest neurodegenerative disease , exceeded only by Alzheimer’s disease. • The mean age of onset is about 60 years , but cases can be seen in patients in their 20s, and even younger. • Clinically, PD is characterised by rest tremor, rigidity, bradykinesia and gait impairment known as cardinal features of the disease
  3. 3. • Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc),reduced striatal dopamine, and intracytoplasmic proteinaceous inclusions known as Lewy bodies.
  4. 4. CLINICAL FEATURES OF PARKINSON’S DISEASE CARDINAL FEATURES OTHER MOTOR FEATURES NON MOTOR FEATURES Bradykinesia Micrographia Anosmia Rest tremor Masked facies(hypomimia) equalize Sensory disturbances (e.g pain) Rigidity Reduced eye blink Mood disorders ( e.g. depression) Gait disturbance/Postural instability Soft voice(hypomimia) Sleep disturbances Dysphagia Autonomic disturbances Orthostatic hypotension G.I disturbances Sexual dysfunction Freezing Cognitive impairment / Dementia
  5. 5. BRADYKINESIA – which means slowness rather than lack of movements . Not only is Parkinson’s patient slightly slow off the mark , but the velocity of movement, or the time from onset to completion of movement is slower than normal. Akinesia and bradykinesia can be distinguished by equating akinesia with prolonged reaction time and bradykinesia with prolonged time of execution.
  6. 6. TREMORS – may be defined as more or less involuntary and rhythmic oscillatory movement produced by alternate synchronous contraction of reciprocally innervated muscle. Its rhythmic quality distinguishes it from involuntary movements and involvement of agonist and antagonist muscle distinguish it from clonus. Tremor frequency is 4-6 hz.
  7. 7. RIGIDITY –is increased tone that is present throughout the range of motion(a lead pipe or plastic stiffness) and affects flexors and extensors equally.It sometime has a cogwheel quality that is enhanced by voluntary movement of the contralateral limb.
  8. 8. PARKINSONISM AND FESTINATING GAIT The term festination derives from the latin word ” to hasten” and appropriately describe the involuntary activation or hastening that characterizes the gait of patient with PD. Diminished or absent arm swing , turning en block, hesitation in starting to walk, shuffling or freezing briefly when encountering obstacle. Once the walking has startedthe upper part of the body advances ahead of the lower part,and the patient is impelled totake increasing short stepsas to catch up with his center of gravity.
  9. 9. DIFFERENTIAL DIAGNOSIS • Parkinsonism is a general term that is used to define a symptom complex manifest by bradykinesia with rigidity and/or tremor. • It has a wide differential diagnosis and can reflect damage to different components of basal ganglia. • Clinicopathological correlation studies determined that parkinsonism associated with rest tremor , asymmetry and a good response to levodopa was more likely to predict the correct pathological diagnosis.
  10. 10. DIFFERENTIAL DIAGNOSIS PARKINSON’S DISEASE ATYPICAL PARKINSONISM SECONDARY PARKINSONISM OTHER NEURODEGENERATIVE DISEASE Genetic Multiple system atrophy Drug induced Wilson,’s disease Sporadic Cerebellar type Tumor Huntington’s disease Dementia with Lewy bodies Parkinson type Infection Dystonia parkinsonism (DYT3) Progressive supranuclear palsy Vascular SCA-3 Normal pressure hydrocephalus Neurodegeneration with brain iron accumulation Trauma Liver failure Alzheimer’s ds with parkinsonism Toxins(Mn,CO, MPTP,Cyanide) Prion disease
  11. 11. ATYPICAL AND SECONDARY PARKINSONISM • Atypical parkinsonism refers to group of neurodegenerative conditions that usually are associated with more widespread neurodegeneration that is found in PD. • Parkinsonism in these conditions is often characterised by early speech and gait impairment, absence of rest tremor, no asymmetry, poor or no response to levodopa, and an aggressive clinical course.
  12. 12. • In the early stages, they may show some modest benefit from levodopa and be difficult to distinguish from PD. • Multiple system atrophy(MSA) manifests as a combination of parkinsonism, cerebellar, and autonomic features and can be divided into a predominant parkinsonism(MSA-p) or cerebellar (MSA- c) form. • Clinically, MSA is suspected when patient presents with atypical parkinsonism in conjunction with cerebellar signs and/or early and prominent autonomic dysfunction usually orthostatic hypotension.
  13. 13. • Progressive supranuclear palsy(PSP) is a form of atypical parkinsonism that is characterised by slow ocular saccades, eyelid apraxia, and restricted eye movements with particular impairment of downward gaze.
  14. 14. ETIOLOGY AND PATHOGENESIS • Most PD occurs sporadically(85-90%) • Twin studies suggest that environmental factors likely play the more important role in patients older than 50 years, with genetic factors being more important in younger patients. • Epidemiological studies suggest increased risk with exposure to pesticides, rural living and drinking well water and reduced risk with cigarette smoking and caffeine.
  15. 15. • It has been proposed that most cases of PD are due to “double hit” involving an interaction between a gene mutation that induces susceptibility coupled with exposure to a toxic environmental factor.
  16. 16. FEATURES SUGGESTING ALTERNATE DIAGNOSIS THAN PD SYMPTOMS/SIGNS ALTERNATE DIAGNOSIS TO CONSIDER Early speech and gait impairment Atypical parkinsonism Exposure to neuroleptics Drug induced parkinsonism Onset prior to age 40 Genetic form of PD Liver disease Wilson’s disease, Non Wilson’s hepatolenticular degeneration Early hallucinations Dementia with Lewy Bodies Diplopia PSP Poor or no response to levodopa Atypical or secondary parkinsonism HISTORY
  17. 17. FEATURE DIAGNOSIS Dementia as first symptom Dementia with Lewy bodies Prominent orthostatic hypotension MSA -p Prominent cerebellar signs MSA - c Impairment of down gaze PSP High frequency(8-10 Hz) symmetric postural tremor with a prominent kinetic component Essential tremor PHYSICAL EXAMINATION
  18. 18. TREATMENT LEVODOPA – Since its introduction in late 1960s it is the mainstay of treatment. Inactive by itself, but immediate precursor of DOPAMINE. On oral administration >90% is decarboxylated in peripheral tissues 1-2%crosses brain and convertad to DA.
  19. 19. • Routinely administered with decarboxylase inhibitor (Carbidopa , Benserazide) to prevent peripheral metabolism to DA and development of nausea vomiting due to stimulation of DA receptors in area posterna not protected by BBB. • Benefits classic motor features of PD, prolongs independence and employability, improves quality of life and increases life span.
  20. 20. ADVERSE EFFECTS- AT INITATION OF THERAPY- 1. Nausea and vomiting –In almost every patient . Tolerance develops gradually. 2. Postural hypotension 3. Cardiac arrhythmias due to B adrenergic 4. Exacerbation of angina axn of DA 5. Alteration in taste sensation
  21. 21. AFTER PROLONGED THERAPY – 1.Fluctuation in motor performance – After 2-5 years control of symptomatology shows fluctuation. ”END OF DOSE” detoriation (wearing off)which is intially gradual, develops into rapid “SWITCHES” or “ON-OFF EFFECT”. With time “ALL OR NONE RESPONSE” develops. 2.Abnormal movements – Facial tics, grimacing , choreoathetosis of limbs etc. Starts appearing after few months and progress with time. No tolerance.
  22. 22. 3. Behavioural effects-Range from mild anxiety, nightmares to severe depression , mania, hallucinations, mental confusion or frank psychosis. CAUSE – Excessive DA action in limbic system. CAUTIONS – Ischemic heart disease, CVA, hepatic and renal disease, peptic ulcer , glaucoma, gout.
  23. 23. DOPAMINE AGONIST – Act directly on DA receptors. Do not require metabolism to active product like levodopa. Initial DA agonists were ergot derivatives (eg bromocriptine, pergolide, cabergoline) which were associated with ergot related side effects. Replaced by second generation non ergot DA agonists(eg pramipexole , ropinirole, rotigotine) Contd…
  24. 24. Do not have comparable efficacy to levodopa. Initially introduced as adjunct to levodopa to enhance motor function and reduce “off” time in fluctuating patients. Long acting, less prone than levodopa to induce dyskinesia. Pramipexole,ropinirole administered orally. Rotigotine as transdermal patch. APOMORPHINE –Very short half life and duration of activity.
  25. 25. Side effects – Nausea, vomiting, orthostatic hypotension, hallucinations, cognitive impairment . Sedation and unintended episodes of falling asleep. Impulse control disorders, hypersexuality, compulsive eating and shopping. Most alarming side effect is valvular heart disease.
  26. 26. MAO – B INIBITORS - Block central DA metabolism and increase sympathatic concentration of DA. Selegiline and Rasagiline. Provide modest benefit when used as monotherapy, and reduced off time when used as adjunct to levodopa in patients with motor fluctuations. Safe and well tolerated. Increases dyskinesia in levodopa treated patients.
  27. 27. CHEESE REACTION – Inhibition of MAO-A isoform prevents metabolism of tyramine in gut leading to fatal hypertensive reaction. Precipitated by, food rich in tyramine eg- cheese, aged meats , red wine. MPTP toxicity can be prevented by coadministration of MAO – B inhibitors that blocks its conversion to toxic pyridinium ion MPP+.
  28. 28. COMT INHIBITORS – Increases elimination half life of levodopa and increases brain availability. Combining levodopa with COMT inhibitor reduces “OFF” time and prolongs “ON” time in fluctuating patients. Tolcapone and entacapone. Side effects – Nausea, vomiting increased dyskinesia, discoloration of urine. Tolcapone – Severe diarrhoea Hepatic toxicity
  29. 29. OTHERS – CENTRAL ACTING ANTI CHOLINERGICS – Trihexyphenidyl, benztropine. Major clinical effect on tremor. Use is limited particularly in elderly. Side effects – urinary dysfunction, glaucoma, cognitive impairment.
  30. 30. AMANTADINE – Historical importance. Introduced as antiviral agent. Anti parkinsons effect due to NMDA receptor antagonism. Antidyskinesia agent in advanced PD. Side effects – Livido reticularis,weight gain, cognitive impairment. Should be discontinued slowly as patients experience withdrawl symptoms.
  31. 31. NEUROPROTECTION – Trials of promising agents as rasagiline, selegiline, coenzyme Q 10,pramipexole and ropinirole have positive results in clinical trials consistent with disease modifying effects.
  32. 32. AGENT DOSES TYPICAL DOSE LEVODOPA Carbidopa/Levodopa 10/100,25/100,25/250 200-1000mglevodopa/d Benserazide/levodopa 25/200,25/250 Carbidopa/levodopa/ent acapone 12.5/50/200,18.75/75/2 00,50/200/200 DOPAMINE AGONIST Pramipexole 0.125,0.25,0.5,1mg 0.25-1.0mg tid Ropirinirole 2,4,6,8mg 6-24mg/d Rotigotine patch 2,4,6mg patch 4-10mg/d Apomorphine SC 2-8mg
  33. 33. AGENT AVAILABLE DOSE TYPICAL DOSE COMT INHIBITORS Entacapone 200mg 200mg with each Levodopa dose Tolcapone 100,200mg 100-200mg MAO-B INHIBITORS Selegiline 5mg 5mg bid Rasagiline 0.5,1.0mg 1.0mg /d
  34. 34. SURGICAL TREATMENT- Most surgical procedures utilize deep brain stimulation. Primarily targets STN or GPI. INDICATIONS- 1.Requires a dose of levodopa which produces unacceptable dyskinesia. 3.Patient who is constantly cycling between on and off period.
  35. 35. MCQ Q 1.Which of the following is not a risk factor for Parkinsonism? a)Pesticide b)Rural living c)Drinking well water d)Cigeratte smoking
  36. 36. Q 2.Which of the following drug is not used in PD? a)Levodopa b)Ergot derivatives c)MAO – A inhibitors d)MAO – B inhibitors
  37. 37. Q 3. Which of the following is not a feature of PD? a)Rigidity b)Bradykinesia c)Intention tremor d)Gait impairment
  38. 38. • Q4 What is the characterstic inclusion body found in PD? • A) lewy body • B) lofora body • C)nicolous body • D)ashcoff body
  39. 39. • Q4.Most comman age of presentation of PD? • A)In childhood • B)40-60 • C)20-40 • D)>60
  40. 40. • Q5. A patient present with features eyelid apraxia ,restricted eye movement&history of repeated fall what is probable diagionsis? • a)multiple system atrophy • B)cortico basal ganglion degeneration • C)progressive supranuclear palsy • D)frontotemporal dementia

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