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Extrapyramidal disorder
Incidence male: female- 3:2
Age of onset : above 50
Parkinsonism is a neurological syndrome characterised by
tremor, hypokinesia, rigidity and postural instability. Classified into
a) Idiopathic (Parkinson·s disease)
b) Secondary ² drug induced
- infectious ( post encephalitic, HIV)
- toxic ( CO & manganese poisoning)
- post traumatic
- Miscellaneous( hydrocephalus,paraneoplastic
syndrome)
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Progressive neurodegenerative disorder a/wloss of dopaminergic nigrostriatal neurons.
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A normally pigmented substantia nigra is seen grossly in the midbrain on the
right, but the midbrain on the left from the patient with Parkinson's diseaseshows a pale substantia nigra.
Pale substantia nigra Normal
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Loss of
neuromelanin
containing
dopamine neurons
Lewy body
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Dopamine- type of
neurotransmitter. chemical
messenger that affects the
brain processes that control
movement, emotional
response, and the capacityto feel pleasure and pain.
Dopamine is vital for
performing balanced and
controlled movements. A
shortage of dopamine can
cause a lack of controlled
movements such as thoseexperienced in Parkinson
disease.
.
GABAglut
GABA
GLUT GABA
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Both the direct and indirect pathways lead to increased
inhibitory activity from GPi to the thalamus and brainstem.
Lesion to basal ganglia causes loss of inhibitory effect to
muscle tone leading to rigidity.
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Two neurotransmitters that are involved in pre-synaptic modulation in the striatus
Dopamine
ACh
With the deficiency of dopamine, the effects of
ACh is exaggerated
The overactivity of the ACh system contributes tothe symptoms of Parkinson disease ² particularly
through the indirect pathway
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Dopamine ² Facilitates the direct pathway
Inhibits the indirect pathway
1. Dopamine deficiency in striatum affects the cerebralcortex ²
Reduces direct pathway activity, resulting in akinesia (difficulty in initiating movements)
Increases indirect pathway activity, resulting in bradykinesia (decreased amplitude and velocity of
movement), by increasing antagonist muscle action tremors by increasing inappropriate movement
2. Dopamine deficiency affects the extrapyramidal nuclei ² Inhibit the brain stem nuclei, resulting in
rigidity
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Aches and pain Tremor :- coarse , distal
- 4-7 Hz
-unilaterally in the upper limbs & eventuallyspread to all the limbs
-Occur at rest, improves with movement anddisappears drg sleep, pill rolling tremor.
Rigidity ² tone- increased resistance to passivemovement. The resistance is typically uniform throughoutthe ROM at a p·cular joint and affects agonist andantagonist muscles.
Cogwheel rigidity- superimposed rachetlike interruptions inthe passive movement.
flexors muscle of neck, trunk & limb- flexed posture
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Bradykinesia- slowness or paucity of movement
- Reduced arm swing- Mask like facies- infrequent blinking and drooling
- Hypophonic, dysathria
- Dysphagia
- Reduced speed of movement
- Handwriting reduces in size- micrographia
Abnormal gait and posture
- Difficult to rise from a chair or bed
- Difficult to initiate movement (akinesia) as well as arrestthe movement & has to walk fast to prevent falling-
shuffling and festinating gait
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y Eye movements affected- loss of upward gazey Excessive sweating and greasy skiny Depression, dementiay Postural hypotensiony Impaired postural reflex- last cardinal finding- Refers to ability of the patient to right himself and to keep
himself from losing his balance when sustaining minorpostural disturbances.
- EASILY««TRAPS
Tremor (resting)
Rigidity (cogwheel)
Akinesia/bradykinesia
Postural disturbances
Speech alteration DIAGNOSIS:BRADYKINESIA
REST TREMOR RIGIDITY
POSTURAL IMBALANCE
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Hoehn & Yahr classification
Stage 1 : Unilateral disease
Stage 2 : Bilateral disease with no postural
disabilityStage 3 : Worsening bilateral disease withpostural disability
Stage 4 : Worsening of disease , patient's are
unable to live alone/independentlyStage 5 : Patients need wheel-chair assistance, bed bound .
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There are no laboratory biomakers for PD. Investigations are done mainly to
exclude other causes that may mimic PD and for evaluation of atypical
parkinsonism patients. Evaluation of patient·s medical, surgical,drug and family
hx is vital followed by complete neurological examination.
investigation rationale
Thyroid function test Exclude hypothyroidism
Toxic screening Esp in younger onset PD &
exposure to manganese and
mercury
Copper metabolism studies:
-Serum ceruloplasmin
-Serum/ urinary copper
excretion-Kayser Fleischer rings
Wilson·s disease
Genetic studies Huntington·s disease
Brain CT scan Cerebral infarcts, tumor,
hydrocephalus, subdural
hematoma
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MRI brain not considered helpful for dx of PD, MRI brain is
considered for patients with uncertainties eg: absence of tremor,
acute or stepwise progression in illness and young patients.
MRI in multiple system atrophy- putame abnormalities d/t loss of
neurons & gliosis with iron accumulation, pontine and cerebellar
atrophy may occur.
MRI in Progressive Supranuclear Palsy ² midbrain atrophy
Functional imaging with PET and SPECT is for clin. Research
though it can confirm loss of nigrostriatal dopamine neurons.
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Aims to restore the dopamine
1. Levodopa + Dopa decarboxylase inhibitor
2. Dopamine agonist
3. Enzyme inhibitors ( MAO-B & COMT)
4. Amantadine
5. Anticholinergic
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Dopami is ot s f l i tr atment of par insonism as itoes not ross lood- rain arrier
evodopa is a prodr of dopamine and it rosses t e lood- rain arrier.
est in relieving radykinesia. peak levels - rs aft oral dose, t : - rs
ombine it dopa decarboxylase inhibitor to reduce
peripheral metabolism to dopamine.
l p + car i pa = si t
l pa + benserazi e = madopar
SE :- Nausea, vomiting, hypotension
- dyskinesias (involuntary movements)- chorea,
dystonia
Dose : 300-400mg
to 600-800mg daily
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- confusion, depression
- On and off phenomena : abrupt but transient fluctuations inthe severity of parkinsonism occur at frequent intervals drgday, apparently w/o any r/ship with last dose.
- Dopamine agonist
- In early symptomatic disease in younger patients- Add on therapy in more advanced therapy.
- Increase dopamine receptor activity
- Can delay onset of levodopa induce dyskinesia
- 2 types : a) ergot
- b) non- ergot
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Ergot :-
- Bromocriptine- Pergolide
- Piribedil
- Cabergoline
Non-ergot :-
- Pramipexole
- Ropinirole
- SIDE EFFECTS : Nausea, vomiting, dyskinesias,hallucination, confusion, respi. depression
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Monoamine oxidase type B inhibitors
MOA-B: metabolize dopamine
Seligiline 5-10mg daily
Prolongs the action of levodopa and reduce
dose required
SE : anxiety, insomnia
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entacapone
Does not cross BBB
Reduces peripheral metabolism of L-Dopa (
similar to carbidopa)
Prolongs the effect of L-Dopa
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Antiviral drug
Mechanism of action: increases the release &inhibit the reuptake of dopamine
Used as as initial therapy of mild PD - Lesseffective than levodopa & more effective thananticholinergics
Adverse Effects:CNS effects: restlessness, agitation, excitement,
hallucinations, confusion, irritability, depressionAnkle edema ² Local effect on blood vesselsHeadache, CHF, postural hypotension,
gastrointestinal disturbances, urinary retention
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Trihexyphenidyl, benzatropine,
orphenadrine, procyclidine
Block central muscarinic receptors
Mostly to treat tremor, minimal effect onrigidity and bradykinesia
SE : dry mouth, constipation, urinary
retention, blurred vision, confusion
Dosage : begin with 1mg twice daily, increasing as
patient tolerates.
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Indicated when medical therapy cannot
control the symptom or when side effect of
levodopa become significant.
CI : parkinsonism plus syndrome, secondary
parkinsonism, dementia, concomitant serious
medical condition, severe depression and
psychosis not caused by the drugs.
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Globus pallidus internal-segment
pallidotomyThis procedure consists of microelectrode
destruction of a specific site in the basalganglia. It is used to relieve the dyskinesias
seen with levodopa therapy. If relief is
attained, the patient may be able to tolerate
a higher levodopa dosage and achieve
potentially better control of parkinsonian
symptoms
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Deep brain stimulation
Rather than causing destruction in the brain,
this procedure uses an implantable electrode
that is placed in the brain and attached to anexternal pacemaker for control. It is most
effective for tremor and for relieving
dyskinesias, depending on where the
electrode is placed
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