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Parkinsonism - management

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Parkinsonism- disease, and therapy

Publié dans : Santé & Médecine
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Parkinsonism - management

  1. 1. PARKINSONISM 4/4/2018KIRSHA,1
  2. 2. DEFINITION Parkinson Disease is a slowly progressive degenerative neurological disease, affecting the basal ganglia and characterized by tremor, rigidity, bradykinesia (sluggish neuromuscular responsiveness/differing combinations of slowness of movements), and postural instability. 4/4/2018KIRSHA,2
  3. 3. TYPES  PRIMARY (IDIOPATHIC ) PARKINSON DISEASE Classic Parkinsonism Disease Or Paralysis Agitans. The disease is incurable.  SECONDARY PARKINSONISM These disease are curable. 4/4/2018KIRSHA,3
  4. 4. ETIOLOGY Primary (Idiopathic) Parkinson Disease Neuronal Loss Genetics Factors Secondary Parkinsonism Drugs Poisoning by chemicals or toxins Infectious causes Other factors- age, environmental factors 4/4/2018KIRSHA,4
  5. 5. PRIMARY PARKINSON DISEASE NEURONAL LOSS IN IDIOPATHIC PARKINSON (1) The normally high concentration in the basal ganglia of the brain is reduced in Parkinsonism. The loss of the dopaminergic neuron in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum, which causes excitatory effect on cholinergic neurons and hence symptoms like tremors. (2) There is degeneration of cells with loss of pigmented neurons in the pars compacta of substantia nigra. The degenerating pigmented neurons contain eosinophilic inclusion bodies called Lewis bodies, which are characteristics of this disease. (3) Defects of mitochondrial respiration and xenobiotic- metabolizing enzymes (eg: glutathione transferase, cytochrome P450 2D6, N-acetyl transferase) may contribute to free radical generation and oxidant stress. 4/4/2018KIRSHA,5
  6. 6. (1) Exposure to the free radicals. Hydrogen peroxide and production of free radicals—both toxic to cells— are products of catabolism. Protective reductants (eg: glutathione), enzymes, and free radical scavengers, such as vitamins E and C, protect cells from damage. It is proposed that either a decrease in these protective mechanisms or reduced dopamine concentration in the basal ganglia causes a destruction of the neurons by free radicals. GENETIC FACTORS Genes that link to Parkinson disease- such as alpha- synuclein and parkin 4/4/2018KIRSHA,6
  7. 7. SECONDARY PARKINSONISM BY DRUGS, INCLUDING DOPAMINE ANTAGONISTS  Phenothiazines (e.g., chlorpromazine, perphenazine)  Butyrophenones (e.g., haloperidol)  Reserpine POISONING BY CHEMICALS OR TOXINS  Carbon monoxide poisoning  Heavy-metal poisoning, such as that by manganese or mercury  MPTP (methyl-phenyl-tetrahydropyridine), a commercial compound used in organic synthesis and found (as a side product) in an illegal meperidine analog INFECTIOUS CAUSES  Encephalitis (viral)  Syphilis 4/4/2018KIRSHA,7
  8. 8. OTHER CAUSES  Arteriosclerosis  Degenerative diseases of the central nervous system (CNS), such as progressive Supranuclear Palsy  Metabolic disorders such as Wilson Disease Pathophysiology Absorption of highly potent neurotoxins (environmental), such as carbon monoxide, manganese, solvents, and N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), which is a product of improper synthesis of a synthetic heroin-like compound. Exposure to these agents, alone or in combination with the neuronal loss of age, may be the cause of Parkinson disease. 4/4/2018KIRSHA,8
  10. 10. 4/4/2018KIRSHA,10
  11. 11. Cardinal Features Motor Symptoms Autonomic Symptoms Mental Status Changes CLINICAL FEATURES 4/4/2018KIRSHA,11
  12. 12. CLINICAL EVALUATION 1. Clinical findings. 2. Imaging - used to rule out an origin of secondary Parkinson disease 3. Positron emission tomography (PET) scan are used to visualize dopamine uptake in the substantia nigra and basal ganglia. The PET scan measures the extent of neuronal loss in these areas. 4. Single photon emission computed tomography (SPECT) can be helpful for diagnosis of parkinsonian syndromes and non-parkinsonian syndromes, particularly essential tremor. 5. Other investigational diagnostic tools. (1) Transcranial ultrasound (2) Examine deficits in olfaction (3) Detection of oligometric alpha- synuclein in blood of patients with Parkinson disease. Other diseases that are similar to Parkinson disease are Multiple System Atrophy (Striatonigral Degeneration, Olivopontocerebellar Atrophy, Shy- Drager Syndrome), Corticobasal Ganglionic Degeneration, and Progressive Supranuclear Palsy. 4/4/2018KIRSHA,12
  13. 13. Scales for evaluating disease progression 1. Unified Parkinson Disease Rating Scale- To evaluate the clinical efficacy of antiparkinson drugs and to monitor disease progression 2. Hoehn and Yahr Scale- Evaluation based on postural instability 3. Schwab and England Activities of Daily living- Assessing the quality of life parameters in Parkinson patients 4/4/2018KIRSHA,13
  14. 14. UNIFIED PARKINSON DISEASE RATING SCALE (UPDRS) The result of testing depends highly on the stage of the disease, whether the patient is being evaluated during an on or off period, and the relative distribution of the improvement across all the items evaluated. PARTS DESCRIPTION I Evaluation of mentation, behavior, and mood. II Self-reported evaluation of the activities of daily III Clinician-scored motor evaluation. Patients are evaluated for speech, rest-tremor facial expression and mobility, action or postural tremor of hands, rigidity, finger taps, hand movements, rapid alternative pronation– supination movement of hands, leg agility, ease of arising from a chair, posture, postural stability, gait, and bradykinesia. Each item is evaluated on a scale of 0 to 4. IV Hoehn and Yahr staging of severity of Parkinson disease V Schwab and England ADL scale. 4/4/2018KIRSHA,14
  15. 15. HOEHN AND YAHR STAGING OF SEVERITY OF PARKINSON DISEASE Stage Characteristics 0 No clinical signs evident I Unilateral involvement, including the major features of tremor, rigidity, or bradykinesia; minimal functional impairment II Bilateral involvement but no postural abnormalities III Mild to moderate bilateral disease, mild postural imbalance, but still ability to function independently IV Bilateral involvement with postural instability; patient requires substantial assistance V Severe disease; patient restricted to bed or wheelchair unless aided Based on postural instability 4/4/2018KIRSHA,15
  16. 16. MANAGEMENT  Parkinsonism is a long term degenerative condition without curative therapy.  Symptomatic treatment, but with no effect on progression.  Treatment on three basics: a. Initiate therapy with gradual dosage titration (start low and go slow) b. Maintain therapy at lowest effective dosage c. In case, if needed, discontinue therapy with gradual taper. 4/4/2018KIRSHA,16
  17. 17. TREATMENT PharmacologicalNon-Pharmacological • Exercise • Diet • Speech Therapy • Physical Rehabilitation • Psychological Rehabilitation • Antiparkinsonian agents • Neuroprotective agents • Drug therapy for treating associated symptom • Surgery 4/4/2018KIRSHA,17
  18. 18. Antiparkinsonian agent LEVODOPA DOSE  Initial Dose: 50 mg 8 0r 2 hourly  Total dose: 1000mg/day if necessary MOA  Decreased concentration of dopamine in the basal ganglia due to diminished number of dopamine releasing terminals in striatum. Levodopa acts as the precursor to produce more dopamine from the remaining neurons.  Levodopa, the L-isomer of the amino acid dihydroxy- phenylalanine, which is a natural precursor for all catecholamine neurotransmitters. Levodopa crosses the BBB, which is taken up by the dopaminergic neurons of the substantia nigra and converted to dopamine by the enzyme dopa decarboxylase.  Levodopa therapy is a form of neurotransmitter replacement. 4/4/2018KIRSHA,18
  19. 19. ADMINISTRATION  Combined with peripheral acting dopa decarboxylase inhibitor, in order to reduce the toxicity.  On oral administration, only 10% reaches BBB, 90% is decarboxylated peripherally in the GIT and blood vessels.  Decarboxylase inhibitor does nor crosses BBB.  Peripheral decarboxylase inhibitors, CARBIDOPA and BENSERAZIDE are available in combination with Levodopa. SIDE EFFECTS  Postural hypotension  Nausea and vomiting  Orofacial Dyskinesia  Limb and axial Dystonias  Depression  Hallucinations and delusions 4/4/2018KIRSHA,19
  20. 20. Neuroprotective treatment DOPAMINE AGONISTS It serves as scavengers of free radicals and decrease dopamine turnover, which reduces oxidative stress Direct-acting Dopamine Agonists – Bromocriptine, Apomorphine, Pergolide, Indirect-acting Dopamine Agonists It potentiates dopaminergic function by synthesis and release of dopamine, blocking reuptake or antagonism of glutamatergic cholinergic receptors. (1) Decrease Reuptake- Amantidine (2) Decrease Metabolism- Selegiline Non-ergot Dopamine Agonists- scavengers of hydrogen peroxide and enhance neurotropic activity in mesencephalic dopaminergic cultures. Pramipexol, Lisuride, Ropinirole 4/4/2018KIRSHA,20
  21. 21. MAO-Bs Selegiline , selective inhibitor of MAO-B, retards the breakdown of dopamine, prolonging the effect and decreasing the dose of Levodopa. Adjunctive therapy for patients with fluctuating or decreased response to Levodopa. Rasagiline, in preventing MPTP induced Parkinsonism. Tocopherol (vitamin E), act as a scavenger of free radicals. ANTICHOLINERGICS (For tremor and rigidity) Orphenadrine, Trihexyphenidyl, Biperiden, Procyclidine COMT(CATECHOL-O-METHYL TRANSFERASE) INHIBITORS Inhibition of dopa carboxylase cause compensatory activation of other pathways of Levodopa metabolism, especially COMT. Tolcapone, Entacapone 4/4/2018KIRSHA,21
  22. 22. Drug therapy for treating associated symptoms  Depression Tricyclic antidepressants They exhibit some dopaminergic and anticholinergic effects.  Action Tremor ß Blockers-Propranolol Benzodiazepenes Primidone  Mild Tremor Antihistamines. Diphenhydramine Hydrochloride has some mild anticholinergic effects 4/4/2018KIRSHA,22
  23. 23. Surgery  Thalamotomy /DPS of the Vim (Ventro intermediate thalamic nucleus) in patients with drug-refractory disabling tremors  Pallidotomy/ DBS of the GPi (Globus Pallidus) to improve motor disabilities  Grafting/ Transplantation of Porcine human/ embryonic mesencephalon tissue into the striatum 4/4/2018KIRSHA,23
  24. 24. Secondary effects of Parkinson disease Cardiovascular Effects Orthostatic Hypotension Arrhythmia Gastrointestinal Effects Constipation Hypersalivation Genitourinary Effects Increased Urinary Frequency Impotence Central Nervous System Effects Hallucinations Depression Psychosis 4/4/2018KIRSHA,24
  25. 25. TREATMENT ALGORITHM Motor complications Adverse events Consider Surgery Pallidotomy/ Deep brain stimulation4/4/2018KIRSHA,25
  26. 26. END 4/4/2018KIRSHA,26