parkinsonism and parkinsons disease.pptx

Parki

1. PARKINSONS DISEASE

2. PARKINSONS DISEASE (Paralysis Agitans) Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, after Alzheimer’s disease (AD) The mean age of onset of PD is about 60 years, and the lifetime risk is ~3% for men and 2% for women. It is estimated that ~5 million people around the world suffer from this disorder.

3. Etiology and Pathogenesis Most PD cases occur sporadically (~85–90%) Studies suggest that environmental factors likely play the more important role in patients older than 50 years. genetic factors being more important in younger patients increased risk of developing PD in association with exposure to pesticides, rural living, farming, and drinking well water.

4. protective factors includ e caffeine, cigarette smoking, intake of nonsteroidal anti-inflammatory drugs, and calcium channel blockers. Familial(10%) Several PD-linked genes have been identified, including SNCA, LRRK2, MAPT, GBA, and variants in the HLA region on chromosome 6

5. SNCA constitutes the major component of Lewy bodies, indicating its role in sporadic forms of PD. mutations in SNCA are associated with earlier disease onset, faster progression, and prominent nonmotor features.

6. Pathologically, the hallmark features of PD are : degeneration of dopaminergic neurons in the substantia nigra pars compacta ( SNc ), R educed striatal (caudate +putamen) dopamine, and intraneuronal proteinaceous inclusions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites, collectively as Lewy pathology)

7. BASAL GANGLIA Anatomically, it includes Putamen ,caudate nucleus ,Globus pallidus and amygdala. Caudate and Putamen collectively called neostriatum. Putamen+ globus pallidus = Nucleus lentiformis Globus pallidus divided into external and internal components.

8. Motor function is regulated by neuronal circuits involving the basal ganglia nuclei, cortical, and brainstem motor regions. Basal ganglia output provides inhibitory tone to thalamic and brainstem neurons, which connect to motor systems in the cerebral cortex and spinal cord, controlling motor function.

9. Normal dopamine innervation from SNc (substantia nigra pars compacta) neurons modulates neuronal firing and stabilizes the basal ganglia network, facilitating desired movements and suppressing unwanted ones. Pathways of Motor Loop: Direct Pathway-Overall Excitatory Indirect Pathway-Overall Inhibitory

10. Direct and Indirect motor loops

11. In PD, dopamine denervation and loss of dopaminergic tone lead to increased firing of neurons in the STN (subthalamic nucleus) and GPi, excessive thalamic inhibition, reduced cortical motor system activation, and development of parkinsonian features.

12. Microscopy

13. Clinical Features Cardinal Features: rest tremor (4-6hertz)-maximal when limb is at rest ,disappears with voluntary movement of muscles rigidity (stiffness) bradykinesia (slowing), and gait dysfunction with postural instability - A slow, shuffling,narrow -based gait is one of the most characteristic features of PD . Parkinsonism is a generic term that is used to define a syndrome manifest by bradykinesia with rigidity and/or tremor.

14. Other Motor Features Micrographia Masked facies (hypomimia) Reduced eye blinking Drooling Soft voice (hypophonia) Dysphagia Freezing consists of a sudden, transient (a few seconds) inability to move.

15. NONMOTOR FEATURES Anosmia Sensory disturbances (e.g., pain) Mood disorders (e.g., depression) Sleep disturbances (e.g., fragmented sleep, RBD) Autonomic disturbances Orthostatic hypotension Gastrointestinal disturbances Genitourinal disturbances Sexual dysfunction Cognitive impairment/dem entia

16. Diagnostic Criteria: Historically, PD was diagnosed based on the presence of two of three parkinsonian features (tremor, rigidity, bradykinesia). However, this had limitations, leading to a 24% error rate. Revised criteria, such as the U.K. Brain Bank Criteria and the MDS Clinical Diagnostic Criteria for Parkinson’s disease, incorporate additional features like rest tremor, asymmetry of motor impairment, and levodopa response to increase diagnostic accuracy.

17. Imaging Techniques: Imaging of the brain dopamine system using PET or SPECT can show reduced and asymmetric uptake of striatal dopaminergic biomarkers . Genetic Testing: While genetic testing can be helpful, monogenic forms of PD are relatively rare and likely account for no more than 10% of cases

18. Treatment No definite cure relief of cardnial signs -rigidity ,tremor,akinesia Correction of mood changes Treatment of other symptoms such as depression ,sleep disturbances .

19. Non Pharmacological manegment PHYSIOTHERAPY: Helps to reduce rigidity Corrects abnormal posture Improves walking, turning & balance Speech therapy : Helpful in patients where dysarthria and dysphonia interferes communication

20. Dietary controls: Include high-fiber diet Choose foods low insaturated fat and cholesterol. Avoid high protein diet.

21. LEVODOPA 'Gold-standard' treatment for Parkinson's..Highly effective drug Relatively rapid relief of bradykinesa, rigidity Reduces tremor in many patients Metabolic precursor of dopamine Inactive by itself , 95% of an oral dose is decarboxylated in the periphera l tissues (mainly gut and liver) and converted into DA Only about 1-2% of administered levodopa crosses to the brain

22. Always used in combination with carbidopa/benserazide(Peripheral decarboxylase inhibitor) Dosage :Carbidopa/ levodapa 10/100, 25/200, 25/250 mg 200–1000 mg levodopa/d 2–4 times/d ay

23. Adverse effects A fter the initiation of therapy:- a) CNS manifestations: Euphoria, anxiety, agitation, insomnia, psychological disturbances as confusion, delusions, hallucinations, Dyskinesia (abnormal involuntary movements which is corrected by dose reduction) b) GIT manifestations :- Anorexia, nausea, and vomiting due to stimulation of D2-receptors in CTZ Tolerance may develop to this adverse effect, but if nausea and vomiting persist, antiemetics are given; e.g. domperidone (D2 antagonist which does not cross BBB Constipation and bleeding peptic ulcer may occur.

24. c) CVS manifestations : Postural hypotensio n—decrease central sympathetic flow Tachycardia (direct BIstimulation) Hypertension occurs with large doses or with non-selective MAO inhibitors (alstimulation)

25. Long-term complications Dyskinesia Behavioural effects: hallucination, psychosis On-off effect : ("on" episodes when the drug is working and "off episodes when parkinsonian features return) Wearing-off effect

26. Wearing off phenomenon After prolong therapy (3-5 year) Duration of beneficial effect shortens as therapy progress Disease control become poor Fluctuation in symptoms occur frequently -This may be due to the interaction of DOPAC with H202 leading to formation of toxic oxygen free radicals which destroy dopamine storage vesicles (this can be prevented by adding selective MAO-B inhibitors as seligeline)

27. 'On-off phenomenon: may be due to variable levels of dopamine in CNS In on state: - Patient enjoys normal mobility In off state:- loss of beneficial effect of drugs Fluctuation in plasma level because of short half life Treatment:- 1.Sustained released formulation of (L-dopa+carbidopa) 2. COMT-inhibitors 3. Frequent administration of levodopa

28. CARBIDOPA Decrease peripheral decarboxylation of L-dopa Don't cross BBB. Currently use fixed dose combinations:- L-dopa + carbidopa(4:1/10:1) ratio L-dopa + Benserazide (4:1) Advantage:- D ose of L-dopa can be reduced by 75% Prolongation of half life of L-dopa Systemic conc.of dopamine, decreases incidence of GI-side effect Cardiovascular complication-minimized Better patient compliance

29. Dopamine Agonists Ergot derivatives (e.g., bromocriptine, pergolide, cabergoline) and were associated with ergot-related side effects, including cardiac valvular damage. second generation of non-ergot dopamine agonists pramipexole, ropinirole, rotigotine

30. In general, dopamine agonists do not have comparable efficacy to levodopa. initially introduced as adjuncts to levodopa to enhance motor function and reduce "off" time in fluctuating patients. relatively long-acting, are less prone than levodopa to induce dyskinesia.

31. 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.

32. Monoamine oxidase Two different types of isoenzymes of MAO are found (MAO -A and MAO-B). MAO-B is responsible for most of the oxidative metabolism of dopamine in the brain. MAO-A is responsible for metabolism of NA,5-HT, tyramine

33. Selegiline Selective irreversible inhibitors of MAO-B Advantage:- Prolonging T1/2 of Endogenously produce dopamine , increases Anti-parkinsonism effect of dopamine Decreases 'On-off', 'wearing off phenomena Adverse effects: - postural hypotension, confusion, psychosis

34. RASAGILINE Newer selective MAO-B inhibitor. Advantage:- 5 time more potent than seligiline Longer acting Not metabolized to amphetamine Doesn't produce excitatory side effects

35. COMT inhibitors The principal therapeutic action of the COMT inhibitors is to block this peripheral conversion of levodopa to 3-0- methyl DOPA, increasing both the plasma 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. COMT inhibitors have been approved, tolcapone and entacapone

36. Entacapone Reversible COMT-inhibitors Only periphery action Shorter acting drug Tolcapone selective and reversible inhibitor of COMT Both action- Peripheral + Central action Longer acting drug

37. S/E Nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations An important adverse effect associated with tolcapone is hepatotoxicity, requires monitoring.

38. Amantadine:- Introduced as an antiviral agent Effective against influenza A2 virus. Mechanism of action: It acts presynaptically and postsynaptically Presynaptically:- 1. Increase release of stored catecholamine from intact dopaminergic terminals 2. Inhibits catecholamine reuptake process at the presynaptic terminal.

39. Postsynaptically:- Activation of DA receptors directly. Anticholinergic action. NDA receptor blocking effect. Side effect:- Insomnia, dizziness, confusion, nightmares

40. 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 H,antagonist

41. 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.

42. NEW DRUGS: Istrdefylline :An oral adenosine A2A receptor antagonist ,approved by FDA 2019 as an adjunctive to levadopa for treatment of wearing off symptoms . Safinamide :Approved by as an add on therapy to levadopa and carbidopa to ease motor fluctuations Opicapone : newer third generation comt inhibitor approved in april 2020

43. Prasinezumab -Monoclonal antibody that binds aggregated alpha synuclein is being investigated as a potential disease modifying therapy in early parkinsons disease

44. Most surgical procedures for PD performed today utilize deep brain stimulation (DBS). Here, an electrode is placed into the target area and connected to a stimulator inserted SC over the chest wall DBS simulates the effects of a lesion without necessitating a brain lesion.

45. The procedure has the advantage that it does not require making a lesion in the brain. Suitable for performing bilateral procedures with relative safety.

46. THANK YOU