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.
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3. TYPES
PRIMARY (IDIOPATHIC ) PARKINSON
DISEASE
Classic Parkinsonism Disease Or Paralysis Agitans.
The disease is incurable.
SECONDARY PARKINSONISM
These disease are curable.
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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.
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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
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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
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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.
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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.
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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
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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.
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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