Download Morbidity & Mortality Rounds

Parkinson’s Disease
AIMGP Seminar
Prepared by: Ilan Lenga and
Nicolas Szecket
References
• NEJM Review Articles
– Parkinson’s Disease Part One October 8, 1998
– Parkinson’s Disease Part Two October 15, 1998
• UpToDate Vol 10.2
• Treatment Guidelines by the American
Academy of Neurology. Neurology 50(3)
Suppl3. 1998.
• Principles of Neural Science, Third edition
Case
• Mr JP is a 63 yo male, school teacher
• Gradual development of right hand
resting tremor over last 6 months
• Also describes “difficulty getting going”,
and feeling “unsteady on my feet”
• He has had no falls
• His symptoms are not interfering with
his job or ADL’s
Case
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No sensory or motor symptoms
No cognitive symptoms
No bowel/bladder symptoms
No significant past medical Hx
No EtOH or other drugs
Case
• O/E:
– Vitals normal, no postural change
– General physical exam unremarkable
– Neuro:
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asymmetrical right handed tremor 4-6 Hz
Normal CN exam
Normal bulk, strength, DTR’s
Mild increased tone, cogwheeling of R wrist
Normal sensory and cerebellar exam
Gait unremarkable
Folstein 30/30
Question
• Does this man have Parkinson’s
Disease?
“….Involuntary tremulous motion, with
lessened muscular power, in parts not in
action and even when supported; with a
propensity to bend the trunk forwards,
and to pass from a walking to a running
pace, the senses and intellects being
uninjured.”
James Parkinson, 1817
Features of PD
T
Tremor
• Classic pill-rolling or pronation/supination tremor is 4 - 6 Hz, usually
upper limb (75% of pts). Brought out by distraction. Decreased with
movement of limbs
R
Rigidity
• Lead-pipe or cogwheel, tone usually slightly more in flexors than
extensors
A
Akinesia
• slowness of movement (bradykinesia), poverty of movement (facial
amimia, arm swing),difficulty initiating movement
P
Postural Instability
• impaired corrective postural reflexes(early), progresses to more upper
trunk instability with fall risk
Most Distinctive Signs of
Idiopathic Parkinson’s Disease
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Asymmetrical Resting Tremor
Dementia not an early feature
Normal Strength
Excellent initial response to L-dopa
DDx
• Parkinsonism Plus
– Diffuse Lewy Body Dementia
– Progressive Supranuclear Palsy
– Multi-System Atrophy
• Shy-Drager
• Striatonigral Degeneration
• Olivopontocerebellar atrophy
– Corticobasal Degeneration
DDx
• Drug-induced
• Vascular
• Toxins
– CO, methanol, manganese, MPTP
• Post-infectious (Postencephalitis
lethargica)
• Paraneoplastic/tumour
• Trauma
Question
• His symptoms are relatively mild, what
measures would you institute now?
Non-Pharmacological
&
?Neuroprotection?
Non-Pharmacological
• Group Support for Patient & Family
• Education
• Parkinson’s Foundation of Canada; www.wemove.org
• Physiotherapy
• Exercise is critical to maintaining health
• Occupational Therapy
• Patients acquire numerous disabilities & require
assistance with many ADLs
• Speech-Language Pathology
• Speech and swallowing difficulties
develop/intensify over course of disease
Neuroprotection?
• Selegiline
• MAO-B inhibitor
• Blocks formation of free radicals derived from the
oxidative metabolism of Dopamine
• Able to protect mice from the effects of MPTP (druginduced PD)
• RCT’s have shown that selegiline delays disability
and appears to slow the progression of symptoms in
previously untreated PD.
• Whether this means it is truly “neuroprotective” is still
being clarified
Case
• JP and his wife join a support group,
and you start him on Selegiline 5mg BID
• You follow him in clinic
• Over the next 6 months, his symptoms
are stable, but then his akinesia and
rigidity begin to progress. He has
almost fallen once.
• His symptoms are now interfering
significantly with his job
Questions
• Would you initiate therapy now?
• What are the options?
Goals of Therapy
• Symptomatic improvement
• Maximizing quality of life
• Possibly prolonging survival
Symptomatic Pharmacological Rx
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Levodopa
Dopamine Agonists
Anticholinergics
Amantadine
Levodopa
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The cornerstone of PD therapy
Most effective agent available
Precursor to Dopamine
Can cross blood brain barrier (dopamine
can’t)
• Peripheral metabolism leads to sideeffects - nausea, vomiting, orthostasis
• Carbidopa, a peripheral decarboxylase
inhibitor, decreases peripheral metabolism
Levodopa
• Sinemet
100/25
200/25
Carbidopa
L-Dopa
200/50
250/50
• Goal is lowest dose required - at start,
usually 300-600mg/day, titrate up to 1g/d
• Take on empty stomach, because
absorption competes with amino acids
Levodopa
• Disadvantages
– 50% of patients within 5 years of Rx develop
L-dopa induced motor complications (stay
tuned to the case)
– Neuropsychiatric problems - confusion,
psychosis
– Theoretical concerns about accelerating
disease due to oxidative damage to neurons
Dopamine Agonists
• Act directly on striatal dopamine receptors
without synaptic uptake/release or metabolic
conversion
• Used as an L-dopa sparing strategy
• Bromocriptine and Pergolide most common
• Start slowly and increase gradually
• Side effects include orthostasis, nausea,
vomiting, hallucinations, peripheral
vasoconstriction, and rarely
pleuro/retroperitoneal fibrosis
Anticholinergics
Dopamine
Dopamine
Acetylcholine
Acetylcholine
Parkinson’s
Normal
Anticholinergics
• Restores balance between Dopamine
and ACh in the brain
• Benztropine and trihexyphenidyl
(Artane) most common
• Not well tolerated due to side effects
– mydriasis, dry mouth, impaired sweating,
urinary retention, constipation, delirium
• Used primarily for refractory tremor and
sialorrhea
Amantadine
• Mechanism of action unclear
• Short term benefit, not sustained
beyond 6 - 12 months
• Side effects include ankle edema,
insomnia, nightmares, confusion,
hallucinations, and anticholinergic
effects
• Most effective for tremor, some activity
against akinesia and rigidity
Summary of Main Effects
Drug
Tremor
Rigidity/Akinesia
L-dopa
poor
excellent
Dopamine Agonist
poor
good
Anticholinergic
good
poor
Amantadine
good
poor
Case
• You elect to start him on Sinemet, on a
dose of 100/25 TID
• His symptoms markedly improve
• He is left with a mild R hand tremor, but
otherwise returns to excellent function
Case
• You follow Mr. JP over the next 4 years
• He requires gradual titration of his
Sinemet up to a current dose of 250/50
TID
• He now comes in complaining that he is
developing rigidity and “freezing” 30-60
minutes before each dose
Questions
• What’s going on?
• What can you do for him?
“Wearing Off” Effect
• As PD progresses dopaminergic nerve
terminals degenerate and cannot store
and release dopamine well
• The result is more dependence on
plasma L-dopa levels
• L-dopa has a T1/2 of 1.3hrs, thus
adequate levels are only maintained for
up to 4 hours
Treatment Options
• Shorten dosing interval
• Sinemet CR (requires 30% increase in
dose due to lower absorption)
• Add Dopamine Agonist
• Catechol-O-methyl transferase (COMT)
inhibitor
COMT Inhibitor
• Tolcapone and entacapone
• prevent metabolism of L-dopa
• increase T1/2 of L-dopa, stabilizing
plasma levels
• Side-effects: due to increased L-dopa,
diarrhea (severe in 5%), rare
hepatotoxicity
Case
• You switch Mr. JP to Sinemet CR with
only modest improvement
• Ultimately he responses to tolcapone
100mg TID
Case
• 4 months later he begins to describe
fluctuations between being “on”
(responding to meds) and “off”
(parkinsonian)
• Also he notes occasional involuntary
movements during “on” periods and
painful leg muscle “spasms” during off
periods particularly in the early morning
Questions
• What is happening?
• Can anything be done?
Complications of L-dopa Rx
• Motor Fluctuations
– wearing off effect
– on-off phenomenon, rapid/unpredictable
• Dyskinesias
– Peak dose dyskinesias (chorea, athetosis,
ballismus, myoclonus)
– Off-period dystonias
– diphasic dyskinesias (beginning & end dose)
• Psychiatric disturbances
Management
• Important to determine relationship to
time of dose
• Peak-dose effects managed by:
– smaller frequent doses of L-dopa
• risk more off periods
– lower L-dopa & add dopamine agonist
– atypical neuroleptics (esp. clozapine)
– ? Propanolol, fluoxetine, buspirone
Management
• Trough effects managed by:
– managed as per the wearing-off strategies
– Off-period dystonias managed with:
• night time or early am dosing
• baclofen, botulinum, lithium
– a “delayed on” problem may be due to poor
gastric emptying
• managed with domperidone
Management
• Psychiatric disturbances
– Depression - treated as in non-PD patients
– Psychotic symptoms
• favour atypical antipsychotics. Clozapine has
least deletirious effect on PD, but risk of
agranulocytosis
• Ondansetron may be effective
– Dementia
• no effective treatment
Management
• Manifestations of advanced Parkinson’s
and chronic levodopa therapy are
notoriously difficult to manage
• Trial-and-error strategy required
• Seek advice from a movement disorder
specialist in difficult cases
Case
• Mr. JP initially responds to lowering his
L-dopa dose and adding bromocriptine
• Eventually he develops unpredictable
“on-off” periods and diphasic
dyskinesias
• You refer him to a movement disorder
neurologist for ongoing management
The End