Parkinson

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Parkinsons Disease

• AIMGP Seminar
• Prepared by Ilan Lenga and Nicolas Szecket

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References

• NEJM Review Articles
• Parkinsons Disease Part One October 8, 1998
• Parkinsons 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

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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
  ADLs

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Case

• No sensory or motor symptoms
• No cognitive symptoms
• No bowel/bladder symptoms
• No significant past medical Hx
• No EtOH or other drugs

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Case

• O/E
• Vitals normal, no postural change
• General physical exam unremarkable
• Neuro
• asymmetrical right handed tremor 4-6 Hz
• Normal CN exam
• Normal bulk, strength, DTRs
• Mild increased tone, cogwheeling of R wrist
• Normal sensory and cerebellar exam
• Gait unremarkable
• Folstein 30/30

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Question

• Does this man have Parkinsons Disease?

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• .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

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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

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Most Distinctive Signs of Idiopathic Parkinsons
Disease

• Asymmetrical Resting Tremor
• Dementia not an early feature
• Normal Strength
• Excellent initial response to L-dopa

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DDx

• Parkinsonism Plus
• Diffuse Lewy Body Dementia
• Progressive Supranuclear Palsy
• Multi-System Atrophy
• Shy-Drager
• Striatonigral Degeneration
• Olivopontocerebellar atrophy
• Corticobasal Degeneration

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DDx

• Drug-induced
• Vascular
• Toxins
• CO, methanol, manganese, MPTP
• Post-infectious (Postencephalitis lethargica)
• Paraneoplastic/tumour
• Trauma

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Question

• His symptoms are relatively mild, what measures
  would you institute now?

Non-Pharmacological ?Neuroprotection?
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Non-Pharmacological

• Group Support for Patient Family
• Education
• Parkinsons 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

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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
  (drug-induced PD)
• RCTs 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

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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

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Questions

• Would you initiate therapy now?
• What are the options?

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Goals of Therapy

• Symptomatic improvement
• Maximizing quality of life
• Possibly prolonging survival

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Symptomatic Pharmacological Rx

• Levodopa
• Dopamine Agonists
• Anticholinergics
• Amantadine

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Levodopa

• The cornerstone of PD therapy
• Most effective agent available
• Precursor to Dopamine
• Can cross blood brain barrier (dopamine cant)
• Peripheral metabolism leads to side-effects -
  nausea, vomiting, orthostasis
• Carbidopa, a peripheral decarboxylase inhibitor,
  decreases peripheral metabolism

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Levodopa

• Sinemet
• 100/25
• 200/25
• 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

Carbidopa
L-Dopa
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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

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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/retroperitonea
  l fibrosis

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Anticholinergics
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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

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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

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Summary of Main Effects

• Drug
• L-dopa
• Dopamine Agonist
• Anticholinergic
• Amantadine

• Tremor
• poor
• poor
• good
• good

Rigidity/Akinesia excellent good poor poor
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A excellent, detailed, table of drugs, dosages
and side effects. A recommended reference. NEJM
Oct 15, 1998
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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

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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

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Questions

• Whats going on?
• What can you do for him?

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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

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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

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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

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Case

• You switch Mr. JP to Sinemet CR with only modest
  improvement
• Ultimately he responses to tolcapone 100mg TID

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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

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Questions

• What is happening?
• Can anything be done?

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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

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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

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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

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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

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Management

• Manifestations of advanced Parkinsons and
  chronic levodopa therapy are notoriously
  difficult to manage
• Trial-and-error strategy required
• Seek advice from a movement disorder specialist
  in difficult cases

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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

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The End