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Parkinson’s Disease

• Definition: a progressive neurodegenerative condition resulting from the death of the

dopamine-containing cells of the substantia nigra.
o “Parkinsonism plus” syndromes: are rare disorders in which there is parkinsonism
and evidence of separate pathology
 Vascular parkinsonism
 Drug-induced parkinsonism
 Progressive supranuclear palsy
 Multiple system atrophy
 Cortical-basal ganglionic degeneration
• Epidemiology: 100-180/100,000 of the population affected, 1.5 more common in men than
in women.
• Aetiology:
o Idiopathic
o Genes:
 PARK1 gene with PD-1 mutations (in chromosomes 21-22-23), PD-1
mutations alters alpha-synuclein which is a major component of Lew bodies.
 Deletions in parkin gene (PARK2), on chromosome 6 ==> Autosomal-
recessive juvenile parkinsonism (AR-JP). In this form of Parkinson’s disease
there are no Lewy bodies in the substantia nigra.
o Drugs:
 MPTP (MethylPhenylTetrahydroPyridine): accumulates in the neuronal
mitochondria and disrupts the electron transport chain ==> cell death.
• Risk factors
o use of pesticides, living in a rural environment, consumption of well water, exposure
to herbicides, and proximity to industrial plants or quarries
o elevated total serum cholesterol in those who are younger than 55: 6-7mmol/l x1.5,
>7mmol/l x1.8 risk of PD
• Pathology
o Loss of pigmented dopaminergic neurons in the substantia nigra and the presence of
Lewy bodies. The loss of dopaminergic neurons occurs most prominently in the
ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are
lost before the motor signs of Parkinson disease emerge.
o Dopamine is released from nigrostriatal neurons to
 activate the direct pathway and
 inhibit the indirect pathway.
o In Parkinson disease, the direct pathway is inhibited ==> suppressed voluntary
movement and indirect pathway is activated ==> suppressed involuntary movement
• History & Exam
o Tremor
 4-7Hz resting tremor
 Most prominent in hands
 The tremor may appear as a pill-rolling motion of the hand or a simple
oscillation of the hand or arm
o Rigidity
 The resistance can be either smooth (lead pipe) or oscillating
 Rigidity usually is tested by flexing and extending the patient's relaxed
 Rigidity can be made more obvious with voluntary movement in the
contralateral limb.
o Bradykinesia:
 difficulty initiating movement
 Bradykinesia is defined as slowness of movement but also includes a paucity
of spontaneous movements and decreased amplitude of movement.
 Bradykinesia is also expressed as
• Micrographia (small handwriting),
• Hypomimia (decreased facial expression),
• Decreased blink rate, and
• Hypophonia (soft speech).
o Postural instability
 stooped posture
 Shuffling gait
o Insidious asymmetric onset with progressive deterioration (initially resting tremor in
one upper limb later both upper limbs).
• Investigations: the diagnosis is clinical
o Bloods:
 Serum ceruloplasmin concentration is obtained as a screening test for
Wilson disease ==> for those with parkinsonian symptoms when younger
than 40 years.
o Imaging:
 MRI/CT unremarkable in Parkinson’s disease
 Positron emission tomography (PET) and single photon emission CT (SPECT)
are useful diagnostic imaging studies; can be used as a diagnostic imaging
tools but not routinely done as the diagnosis is clinical.
• Management
o Physiotherapy & occupational therapy
o Medical therapy:
 At time of diagnosis: “start low and go slow”
• Selegiline 5 mg +/- antioxidant vitamins, still a controversial topic (L-
dopa vs Dopamine antagonist vs both)
• Delay other therapy until significant effect on quality of life
o Levodopa: still mainstay of treatment
 Immediate natural precursor of dopamine
 Converted to dopamine by amino acid decarboxylase
 Most effective treatment & benefits all Symptoms
 Long term complications
• Fluctuations
• Dyskinesias
• psychiatric
 Dopa-decarboylase Inhibition:
• Side effects due to peripheral GI dopamine receptor stimulation
• Nausea and vomiting
• Obviated by co-administration of peripheral decarboxylase
inhibitors with L-Dopa
• Carbidopa and benserazide
 COMT Inhibition (Catechol-O-methyl-transferase)
• Blocks peripheral breakdown of levodopa to 3-O-methyldopa
• Entacapone 200 mg
• Given with each dose of L-Dopa
• Generally well tolerated
• S/E: Nausea, diarrhoea
o Dopamine Agonists: D2 receptor antagonists
• Bromocriptine
• Pergolide
• Guide: “start low and go slow”
• Lower occurrence of dyskinesias
• S/E: Hypotension, confusion
• Pramipexole
• Ropinirole
• Cabergoline
• S/E: Daytime sleepiness, “Sleep attacks”
o Selective monoamine oxidase B inhibitor (Selegiline)
 Blocks central metabolism of dopamine
 Delays need for L-Dopa
 May be neuroprotective
 S/E:Nausea, confusion
o Anticholinergics:
 Central muscarinic receptor blockers; Trihexyphenidyl, benztropine,
 Helpful for tremor and rigidity, but not for bradykinesia
 Guide: start low and go slow
 Peripheral and central side effects
o Amantidine:
 Antiviral agent found to have anti-parkinsonism effects
 Promotes synthesis and release of dopamine
 Modest clinical benefit on three main symptoms
 S/E: Lower limb oedema, livedo reticularis
o Anti-oxidant vitamins: Vitamin E, Vitamin C, Co-enzyme Q10; Vitamin E is the only
one studied - low dose.
o Surgery:
 Ablative procedures
• stereotaxic thalamotomy, pallidotomy
 Deep brain stimulation (DBS)
• Thalamic stimulation
• Subthalamic stimulation for tremor and dyskinesias
 Brain implantation
• Complications
o Depression: 40% of patients.
o Pain
• Prognosis: relentless progression at linear rate, e.g. if started slowly, will develop slowly.