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  • Key point: Lewy bodies are abnormal accumulations of neurofilament proteins in degenerating nerve cells that are a pathological hallmark of PD patients with or without dementia, and of DLB. They belong to a group of neurodegenerative disorders characterized as ‘α-synucleinopathies’.
    In healthy individuals, the brain region known as the substantia nigra in the brainstem is populated by dark brown nerve cells that produce the neurotransmitter, dopamine. In PD (as well as in dementia associated with PD and DLB), these cells degenerate and the substantia nigra appears abnormally pale and narrow.1,2 Remaining nerve cells contain lesions called ‘Lewy bodies’ – spherical accumulations of neurofilament proteins that are a pathological hallmark of both disease processes. Lewy bodies contain accumulations of α-synuclein as a major constituent, which contributes to neuronal malfunction and cell death. In dementia associated with PD and DLB, Lewy bodies are found abundantly in higher brain regions comprising subcortical and cortical areas.
    There are as yet no definite pathological criteria that separate dementia associated with PD and DLB from each other at autopsy.3
    1Esiri MM, McShane RH. In: The Neuropathology of Dementia. Esiri MM, Morris JH (eds). Cambridge University Press, Cambridge, UK, 1997; 2Gelb DJ et al. Arch Neurol 1999;56:33–9; 3McKeith I et al. Lancet Neurol 2004;3:19–28.
  • One way to illustrate how the muscle control process works is as follows: two buckets - one for the dopamine system and one for the acetylcholine system - balanced on either end of a seesaw (figure 5). This depicts the situation at rest when the dopamine and acetylcholine systems are balanced. When you decide to move, your brain understands the movement you want to make and it sends out a balance of dopamine and acetylcholine messages to keep that movement smooth.
  • methylphenyltetrahydropyridine
  • methylphenyltetrahydopyridine

    2. 2. <ul><li>Neurologic disease caused by degeneration of dopamine neurons </li></ul><ul><li>Only neurodegenerative disease whose symptoms can so readily be treated by medication </li></ul><ul><li>Third most common cause of disability. </li></ul><ul><li>In majoriy of cases it is IDIOPATHIC. </li></ul>
    3. 3. <ul><li>English physician </li></ul><ul><li>Dr James Parkinson in 1817 </li></ul><ul><li>“ An assay on the shaking palsy </li></ul><ul><li>Also k/a “ Paralysis agitans ” </li></ul><ul><li>In 1960 – pathological and </li></ul><ul><li>biochemical changes identified </li></ul>
    4. 4. <ul><ul><ul><li>Annual incidence 0.2/1000 & prevalence of 1.5/1000. </li></ul></ul></ul><ul><ul><ul><li>Prevalence rates are similar throughout the world, except lower rates in China /West Africa. </li></ul></ul></ul><ul><ul><ul><li>Affects 1% of those over 55 years, 1.5% of people 70-79 years of age </li></ul></ul></ul><ul><ul><ul><li>Generally occurs between 50-80 years </li></ul></ul></ul><ul><ul><ul><li>Sex incidence is about equal. </li></ul></ul></ul>
    5. 5. <ul><li>A viral cause: </li></ul><ul><li>In 1918 there was an outbreak of Encephalitis Lethargica and many sufferers developed postencephalitic Parkinsonism. </li></ul><ul><li>A toxic substance: </li></ul><ul><li>For instance, the illegal drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). </li></ul><ul><li>A genetic cause : </li></ul><ul><li>Research by the NHGRI (National Human Genome Research Institute) suggests that a mutated gene, which codes the alpha synuclein protein located on chromosome 4, has a role in familial parkinsonism. </li></ul><ul><li>Another mutation occurs in parkin gene.responsible for early onset of PD . </li></ul><ul><li>Other causes: </li></ul><ul><li>Head injuries. </li></ul><ul><li>Oxidative stress. </li></ul><ul><li>Heavy metal ion exposure from fillings etc. </li></ul><ul><li>It is proposed that these factors cause the neuron's mechanisms for proteolysis to go away leading to the formation of the characteristic Lewy bodies seen on autopsy of Parkinson’s patients. The cells then fail to function correctly and ultimately die. </li></ul>
    6. 6. Lewy Body Pathology Dopamine-producing cell (brainstem) Brown pigment (Melanin) Cell Nucleus Two Lewy bodies inside nerve cell After: Esiri MM, McShane RH. Cambridge University Press 1997 Gelb DJ. Arch Neurol 1999;56:33–9
    7. 7. <ul><li>Basal Ganglia </li></ul><ul><ul><li>Controls movement </li></ul></ul><ul><li>Dopamine </li></ul><ul><ul><li>Inhibitory neurotransmitter in the basal ganglia </li></ul></ul><ul><li>Acetylcholine </li></ul><ul><ul><li>Excitatory neurotransmitter in the basal ganglia </li></ul></ul><ul><li>Without dopamine, inhibitory influences are lost and excitatory mechanisms are unopposed  </li></ul><ul><li>Neurons of basal ganglia are over stimulated  </li></ul><ul><li>Excess muscle tone, tremors & rigidity </li></ul>
    8. 8. <ul><li>Normal movement  dependent on dopamine production in the substantia nigra that innervates the striatum </li></ul><ul><li>PD is associated with massive degeneration of dopamine-producing neurons in substantia nigra </li></ul><ul><li>When 60 to 80% of these neurons are lost, symptoms of PD appear </li></ul>
    9. 9. <ul><li>Resting Tremor (70%) </li></ul><ul><li>Bradykinesia </li></ul><ul><li>Rigidity </li></ul><ul><li>Postural Instability </li></ul><ul><ul><li>Signs start in one limb, usually an arm, </li></ul></ul><ul><ul><li>And spread to the other limb on that side </li></ul></ul>
    10. 10. <ul><li>Secondary features of the disease: </li></ul><ul><ul><ul><li>Depression </li></ul></ul></ul><ul><ul><ul><li>Dementia </li></ul></ul></ul><ul><ul><ul><li>Dysphagia </li></ul></ul></ul><ul><ul><ul><li>Anxiety </li></ul></ul></ul><ul><ul><ul><li>Orthostatic hypotension </li></ul></ul></ul><ul><ul><ul><li>Constipation </li></ul></ul></ul>
    11. 11. <ul><li>Idiopathic </li></ul><ul><li>Genetic (<50 y/o) </li></ul><ul><li>Exposure to unrecognized neurotoxins </li></ul><ul><li>Oxidation reaction with generation of free radicals </li></ul><ul><li>Reduced level of dopamine in the basal ganglia </li></ul>
    12. 12. <ul><li>The main Pathological feature of Parkinson’s disease is the loss of the dopaminergic nigrostriatal pathway </li></ul><ul><li>Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the striatum are lost </li></ul><ul><li>80% of the Dopamine producing cells must be lost before symptoms begin to show </li></ul>
    13. 16. <ul><li>Pharmacologic attempt to restore dopaminergic activity with levodopa and dopamine agonists </li></ul><ul><li>Restore normal balance of cholinergic & dopaminergic influences on the basal ganglia </li></ul>
    14. 18. <ul><li>In 1967 George Cotzias invented levodopa </li></ul><ul><li>Prodrug </li></ul><ul><li>Gold standard therapy for parkinsonism </li></ul><ul><li>Chemical name is Dihydroxy Phenyl Alanine </li></ul>GEORGE COTZIAS
    15. 19. <ul><li>Rapidly absorbed from the SI </li></ul><ul><li>Food delays absorption </li></ul><ul><li>Amino acids in food compete with drug </li></ul><ul><li>Peak plasma concentration: 1-2 hrs </li></ul><ul><li>Plasma t ½ : 1-3 hrs </li></ul><ul><li>HVA, DOPAC (dihydroxyphenylacetic acid) are main metabolites </li></ul><ul><li>1-3% enters the brain </li></ul><ul><li>Resolve hypokinesia & rigidy first and tremor later </li></ul><ul><li>Plasma t½ is 1-2 hours & metabolised by MAO and COMT enzymes </li></ul>
    16. 20.
    17. 21. <ul><li>Early use lowers mortality rate </li></ul><ul><li>Combined with Carbidopa & Benseraside </li></ul><ul><li>Sinemet – dopa preparation containing levodopa in fixed proportion (1:10 or 1:4) </li></ul><ul><li>Sinemet 25/100 TID </li></ul><ul><li>30 -60 minutes before meals </li></ul>
    18. 22. <ul><li>Fluctuations in response </li></ul><ul><li>Misc: mydriasis, brownish discoloration of the urine, abnormal smell, transient elevations of transaminases & BUN </li></ul><ul><li>GIT effects: vomiting (CTZ) </li></ul><ul><ul><li>Reduced by carbidopa </li></ul></ul><ul><ul><li>Phenothiazenes are contraindicated </li></ul></ul><ul><ul><li>( Domperidone is the doc) </li></ul></ul><ul><li>Cardiovascular: tachycardia, ventricular extrasystoles, atrial fibrillation </li></ul>
    19. 23. <ul><li>Dyskinesias </li></ul><ul><ul><li>Common in patients receiving carbidopa </li></ul></ul><ul><li>Behavioral effects: </li></ul><ul><ul><li>Common in patients receiving levodopa </li></ul></ul><ul><ul><li>controlled by clozapine, olanzapine, resperidone </li></ul></ul>
    20. 24. <ul><li>&quot;On/off&quot; Effect Is like a Light Switch ; Without Warning, All of a Sudden, Person Goes from Full Control to Complete Reversion Back to Bradykinesia, Tremor, Etc.lasting from 30 Minutes to Several Hours and Then Get Control Again </li></ul><ul><li>&quot;On/off&quot; Effect Occurs after usually after 2 or more years on L Dopa </li></ul><ul><li>Related with continous destruction of dopaminergic neurons. </li></ul>
    21. 25. <ul><li>Treat by Giving Small Dose Regiments from 16 to 20 Hours </li></ul><ul><li>&quot;On/off&quot; Effect May Be Due to Composite of Amino Acids that use same Dopamine Transportor , causing extremely low levels of L Dopa in CNS thereby causing symptoms of Parkinsonism to reappear. </li></ul><ul><li>Changing diet (to low protein), may cause large conc of L Dopa in CNS. </li></ul>
    22. 26. <ul><li>Vitamin B6 enhance extracerebral metabolism of levodopa </li></ul><ul><ul><li>Prevented by decarboxylase inhibitors </li></ul></ul><ul><li>MAO – A inhibitors : Hypertensive crisis </li></ul><ul><li>CONTRAINDICATIONS </li></ul><ul><li>Psychoses </li></ul><ul><li>Angle closure glaucoma </li></ul><ul><li>Cardiac dysrhythmia </li></ul><ul><li>Melanoma or suspicious undiagnosed skin lesions </li></ul>
    23. 27. <ul><li>Carbidopa , Benseraside </li></ul><ul><li>Does not penetrate the BBB </li></ul><ul><li>Reduce the peripheral metabolism of levodopa </li></ul><ul><li>Increase plasma levels of levodopa </li></ul><ul><li>Prolongs the plasma half life of levodopa </li></ul><ul><li>Increase available amounts of dopa for entry into the brain </li></ul><ul><li>Reduce the daily requirement of levodopa by 75% </li></ul>
    24. 28. <ul><li>Do not require enzymatic conversion for an active metabolite </li></ul><ul><li>No potential toxic metabolites </li></ul><ul><li>Do not compete with other substances for an active transport </li></ul><ul><li>First line in parkinsonism </li></ul><ul><li>End of dose akinesia to levodopa </li></ul><ul><li>On & off phenomenon refractory to levodopa </li></ul>
    25. 29. <ul><li>ERGOT ALKALOIDS </li></ul><ul><li>BROMOCRIPTINE </li></ul><ul><ul><li>D2 agonists </li></ul></ul><ul><ul><li>Endocrinologic disorders (hyperprolactinemia) </li></ul></ul><ul><ul><li>Peak plasma levels: 1-2 hrs </li></ul></ul><ul><ul><li>7.5 mg & 30 mg </li></ul></ul><ul><ul><li>1. 25 mg BID after meals X 2-3 months and increase 2.5 mg q 2 wks </li></ul></ul><ul><li>PERGOLIDE </li></ul><ul><ul><li>Stimulates both D1 and D2 </li></ul></ul><ul><ul><li>More effective than bromocriptine </li></ul></ul><ul><ul><li>Associated with clinical or subclinical valvular heart disease </li></ul></ul><ul><ul><li>DOSE : 3 mg daily </li></ul></ul><ul><ul><li>- 0.05 mg starter dose </li></ul></ul>
    26. 30. <ul><li>PRAMIPEXOLE </li></ul><ul><ul><li>Preferential affinity to D3 </li></ul></ul><ul><ul><li>Monotherapy is effective </li></ul></ul><ul><ul><li>Neuroprotective </li></ul></ul><ul><ul><li>Rapidly absorbed </li></ul></ul><ul><ul><li>Peak plasma concentration: 2 hrs </li></ul></ul><ul><ul><li>0.125 mg TID then doubled after 1 wk </li></ul></ul><ul><ul><li>Increments of 0.75 mg at weekly intervals </li></ul></ul><ul><li>ROPINIROLE </li></ul><ul><ul><li>Pure D2 receptor agonists </li></ul></ul><ul><ul><li>0.25 mg TID then total daily dose is increased by 0.75 mg at weekly intervals until the 4 th wk & increased by 1.5 mg thereafter </li></ul></ul>
    27. 31. <ul><li>GIT: anorexia, nausea, vomiting, bleeding PUD, reflux esophagitis </li></ul><ul><li>Cardiovascular: postural hypotension, painless digital vasospasm </li></ul><ul><li>Dyskinesias </li></ul><ul><li>Mental disturbances </li></ul><ul><li>Misc: erythromelalgia </li></ul><ul><li>Somnolence, excessive daytime sleepiness, and sleep attacks </li></ul>
    28. 32. <ul><li>Newer dopamine agonist. </li></ul><ul><li>Approved in 2007 by the FDA. </li></ul><ul><li>Non – Ergot derivative. </li></ul><ul><li>Relatively pure D2 agonist. </li></ul><ul><li>Benefits and adverse effects are similar to those of other dopamine agonists. </li></ul><ul><li>Delivered through a skin patch . </li></ul><ul><li>Local reactions may occur at the application site. </li></ul><ul><li>Crystal formation on the patches may affect the bioavailability and efficacy of the agonist. </li></ul>
    29. 33. <ul><li>Potent dopamine agonist </li></ul><ul><li>Temporary relief of off-periods of akinesia </li></ul><ul><li>Rapidly taken by blood and brain (10 minutes) and persists for 2 hours </li></ul><ul><li>Nausea – trimethobenzamide </li></ul><ul><li>Dyskinesias, drowsiness, sweating, hypotension, bruising at injection site </li></ul>
    30. 34. <ul><li>MAO – A: metabolizes NE & serotonin </li></ul><ul><li>MAO – B: metabolizes dopamine </li></ul>
    31. 35. <ul><li>Selective irreversible inhibitor of </li></ul><ul><li>MAO-B (normal doses) </li></ul><ul><li>Inhibits MAO-A (higher doses) </li></ul><ul><li>Retards breakdown of dopamine </li></ul><ul><li>Prolongs & enhances the effect of levodopa </li></ul><ul><li>Adjunct in fluctuating response to levodopa </li></ul><ul><li>5 mg with breakfast & lunch </li></ul><ul><li>Cause insomnia when taken later during the day </li></ul>
    32. 36. <ul><li>MAO-B inhibitor </li></ul><ul><li>Potent than selegiline in preventing MAO-B toxins induced parkinsonism (MPTP) </li></ul><ul><li>Combination with levodopa – HTN crisis </li></ul><ul><li>Standard dose is 1mg/day. </li></ul>
    33. 37. <ul><li>Compensatory activation pathways of levodopa metabolism after dopa decarboxylase inhibition </li></ul><ul><li>Increase 3- O- methyldopa (3OMD)  poor therapeutic response to levodopa </li></ul><ul><ul><li>Competes with levodopa for an active carrier mechanism in the intestinal mucosa & BBB </li></ul></ul>
    34. 38. <ul><li>TOLCAPONE- central & peripheral metabolism. </li></ul><ul><li>Hepatotoxic : less preferred. </li></ul><ul><li>DOSE : 100 mg TDS. </li></ul><ul><li>ENTACAPONE </li></ul><ul><ul><li>peripheral metabolism </li></ul></ul><ul><ul><li>Prolongs the duration of levodopa by decreasing its peripheral metabolism </li></ul></ul><ul><ul><li>Helpful in patients receiving levodopa who have fluctuations </li></ul></ul><ul><ul><li>t ½ = 2 hrs </li></ul></ul><ul><ul><li>DOSE : 200 mg upto 5 times a day. </li></ul></ul>
    35. 39. <ul><li>Postural hypotension </li></ul><ul><li>Fatigue </li></ul><ul><li>Somnolence </li></ul><ul><li>Peripheral edema </li></ul><ul><li>Nausea </li></ul><ul><li>Constipation </li></ul><ul><li>Dyskinesias </li></ul><ul><li>Confusion </li></ul><ul><li>Orange discoloration of urine. </li></ul>
    36. 40. <ul><li>Antiviral agent </li></ul><ul><li>Potentiates dopaminergic function by influencing the synthesis, release, reuptake of dopamine </li></ul><ul><li>PHARMACOKINETICS: </li></ul><ul><li>peak plasma concentration: 1-4 hrs after oral dose </li></ul><ul><li>Plasma t ½ = 2-4 hrs </li></ul>
    37. 41. <ul><li>Less potent than levodopa and benefits are short-lived </li></ul><ul><li>100 mg BID-TID </li></ul><ul><li>ADVERSE REACTIONS: </li></ul><ul><li>Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations & confusion </li></ul><ul><li>Livedo reticularis ( cutaneous finding consisting of a mottled reticulated vascular pattern that appears like a lace-like purplish discoloration of the lower extremities )– clears within a month after drug withdrawal </li></ul>
    38. 43. <ul><li>Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia </li></ul><ul><li>Benztropine mesylate </li></ul><ul><li>Biperiden </li></ul><ul><li>Orphenadrine </li></ul><ul><li>Procyclidine </li></ul><ul><li>Trihexyphenidyl </li></ul><ul><li>DOC FOR DRUG INDUCED PARKINSONISM </li></ul>
    39. 44. <ul><li>CNS </li></ul><ul><li>Mydriasis, urinary retention, constipation, tachycardia, tachypnea, increase IOP, palpitations, cardiac arrythmias </li></ul><ul><li>Acute suppurative parotitis </li></ul><ul><li>Dryness of the mouth </li></ul><ul><li>CONTRAINDICATIONS. </li></ul><ul><li>Prostatic hyperplasia </li></ul><ul><li>Obstructive GI diseases </li></ul><ul><li>Angle closure glaucoma </li></ul>
    40. 45. <ul><li>The net result of all of these medications is the balancing out of the acetylcholine/dopamine balance and an improvement in movement </li></ul>
    41. 46. <ul><li>PARKINSONISM AND OXIDATIVE STRESS </li></ul><ul><li>In patients with Parkinson's disease, the iron content is increased in the substantia nigra, the ferritin level is decreased in the brain, and the glutathione concentration is decreased in the substantia nigra. </li></ul><ul><li>Furthermore, although 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) is not itself toxic, when oxidized by monoamine oxidase B to the methylphenylpyridium ion, it becomes a selective nigral toxin that interferes with mitochondrial respiratory mechanisms. The toxicity of MPTP may be prevented by pretreatment with a monoamine oxidase B inhibitor such as selegiline. </li></ul>
    42. 47. Copyright ©2003 Canadian Medical Association or its licensors
    43. 48. <ul><li>Thalamotomy – conspicous tremor </li></ul><ul><li>Posteroventral pallidotomy or deep-brain stimulation </li></ul>
    44. 49. <ul><li>Surgery : </li></ul><ul><li>Stereotactic surgery is another option for patients </li></ul><ul><li>with advanced   Parkinson's disease. The optimal </li></ul><ul><li>patient for surgical treatment   is someone whose: </li></ul><ul><li>disease is not adequately controlled by medication,   </li></ul><ul><li>with early onset Parkinson's disease (aged < 50 years), </li></ul><ul><li>good   response to drugs . </li></ul><ul><ul><li>Physiotherapy& rehab: </li></ul></ul><ul><ul><li>Patients at all stages of Parkinson's disease benefit from physiotherapy, which helps reduce rigidity& corrects abnormal posture. </li></ul></ul><ul><ul><li>Speech therapy may help in cases where dysarthria & dysphonia interfere with communication. </li></ul></ul>
    45. 50. <ul><li>DEEP BRAIN STIMULATION </li></ul><ul><li>Most surgical centres focus   on deep brain stimulation (DBS) of the subthalamic nuclei, globus   pallidum or thalamus depending on the clinical scenario. </li></ul><ul><li>Stimulation   of the subthalamic nuclei or globus pallidum has been associated   with improvements in bradykinesia, rigidity, drug-induced dyskinesias   and off time. </li></ul><ul><li>  Exact   mechanism of action of DBS is unknown </li></ul><ul><li>Potential benefits   of adjustable settings of stimulator frequency and intensity,   no lesion is created. </li></ul>
    46. 51. <ul><li>BRAIN GRAFTING </li></ul><ul><li>By grafting dopamine producing nerve cells into the brain. </li></ul><ul><li>Cells taken from the brains of aborted fetuses . </li></ul><ul><li>Not a successful tech. mainly because around ninety eight percent of the grafted cells die. </li></ul><ul><li>fewer than 10% of patients have shown significant improvement . </li></ul>
    47. 52. <ul><li>Recently a protein related to NGF – brain derived neurotropic factor (BDNF), was discovered. </li></ul><ul><li>Stimulates the growth of many types of neurons, including substantia nigra dopamine neurons. </li></ul><ul><li>BDNF stimulates the growth of foetal dopamine neurons in culture and may prevent progression and reversal of Parkinsonism. </li></ul><ul><li>Another factor GDNF is also under study. </li></ul><ul><li>Studies suggests that GDNF could slow the progress of Parkinson’s disease </li></ul>
    48. 53. <ul><li>MAO inhibitors: selegiline & rasagiline </li></ul><ul><li>Antiexcitotoxicity drugs: Riluzole </li></ul><ul><li>Bioenergetic antioxidant agent: coenzyme Q10 </li></ul><ul><li>GDNF </li></ul><ul><li>Anti apoptotic kinase inhibitors(eg CEP-1347) </li></ul>
    49. 54. <ul><li>Adenosine A2A receptor antagonists </li></ul><ul><li>(eg, istradefylline) </li></ul><ul><li>Gene therapy : introduction of gene into putamen coding for aromatic acid decarboxylase : it increases the metabolism L-Dopa to Dopamine. </li></ul><ul><li>Glutamic acid decarboxylase into subthalmic nucleus : increses GABA and neuronal inhibition. </li></ul><ul><li>UNDER PHASE 2 CLINICAL TRIALS </li></ul>
    50. 55. <ul><li>Thank You </li></ul>