Parkinsons Disease

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Parkinsons Disease

• Cathy Chuang, MD
• Jacobi Medical Center
• Department of Neurology

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Definition of parkinsonism

• Parkinsonism is a syndrome manifested by any
  combination of the following cardinal features
• 1) bradykinesia
• 2) resting tremor
• 3) rigidity
• 4) postural instability
• 5) freezing
• 6) flexed posture

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Other associated features of parkinsonism

• Other common features of parkinsonism include
  masked facies, hypophonia, micrographia,
  shuffling gait with decreased armswing, and
  increased saliva with drooling.
• Common behavioral signs include decreased
  motivation, apathy, decreased attention span,
  social withdrawal, anxiety, and depression.
• Cognitive decline can occur in 30-40 of
  patients.

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Differential diagnosis of parkinsonism

• I. Primary (idiopathic) Parkinson's disease
• II. Secondary (acquired) drugs, toxins,
  infections, vascular, trauma, hydrocephalus
• III. Parkinson's-plus syndromes or atypical
  parkinsonian syndromes PSP, MSA, DLBD, CBGD, etc
• IV. Heredodegenerative parkinsonism HD,
  Wilson's, Hallervorden-Spatz, Spinocerebellar
  ataxias, juvenile parkinsonsim (parkin gene),
  neuroacanthocystosis, X-linked dystonia-parkinsoni
  sm (Lubag), mitochondrial cytopathies with
  striatal necrosis (Leigh's disease),etc.

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Diagnostic Criteria

• Parkinsonism requires at least 2 out of 6
  cardinal features with one of them being either
  bradykinesia or rest tremor.
• Parkinsons disease-United Kingdom Parkinson's
  disease society brain bank criteria and NINDS
  diagnostic criteria
•   -Supportive features asymmetric onset,
  classical pill-rolling rest tremor, progressive
  disorder, persistent asymmetry, good response to
  levodopa, drug-induced dyskinesias, and clinical
  course gt 10 yrs lack of any atypical features
•   -Atypical features symmetric onset, early
  falls, early hallucinations, severe dementia,
  autonomic features, cerebellar signs, cortical
  signs, gaze palsy, and lack of response to high
  dose of levodopa

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Management of Early Parkinsons disease

• If very mild disease and no disability, can opt
  NOT to treat with symptomatic medications.
• May consider possibly treating with selegiline,
  rasagiline, Coenzyme Q10, or anti-oxidant
  vitamins C and E because of theoretical
  possibility of slowing disease progression.
• Physical therapy focusing on stretching exercises
  should be started as soon as the diagnosis is
  made
•  

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Medical Management Early Parkinsons disease

• Levodopa sparing strategy
• If younger patient, try to avoid using levodopa
  since they will be more prone to long-term
  complications of levodopa therapy.
• Start with dopamine agonist (Parlodel, Mirapex,
  or Requip), amantadine, or anti-cholinergic
  (Artane) for tremors.
• Selegiline (Eldepryl) or rasagiline can also
  provide some symptomatic benefit for mildly
  affected patients
• If older patient (gt65), you can start with
  levodopa

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Dopamine Agonists

• A. Ergot agonists
• 1. bromocriptine (Parlodel) oldest agent, may
  not be as effective as other agents, start with ½
  of 2.5 mg tablet bid, increasing by 2.5 mg per
  day every 14-28 days aim for dose of 30 mg per
  day
• 2. pergolide (Permax) recently taken off market
  because of valvular fibrosis

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Other Dopamine Agonists

• B. Non-ergot agonists
• 1. pramipexole (Mirapex) start with ½ of 0.25
  mg qhs and increase by ½ tabs q2-3 days until
  reach ½ tab qid then continue increasing by ½
  tab q week aiming for a dose of 1.5-4.5 mg qd
• 2. ropinirole (Requip) start with 0.25 mg 1 tab
  tid x 1 week, then 2 tabs tid x 1week, and then 3
  tabs tid for 1 week switch to 1 mg tid, and
  increase by 1 mg every week, aiming for 12-16 mg
  qd.

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Dopamine Agonists Alternative forms of delivery

• A. SC injection apomorphine (Apokyn) used
  primarily as a rescue agent for off periods,
  needs to be given with Tigan because of nausea
• B. Transdermal patch rotigotine (Neupro),
  applied daily for 24 hours

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Side effects of dopamine agonists

• Common to all agonists nausea, vomiting,
  sedation, lightheadedness, orthostatic
  hypotension, hallucination, and confusion
• More common in ergot agonists St. Anthonys
  fire, pulmonary/retroperitoneal fibrosis, cardiac
  valvulopathy (Permax)
• Sleep attacks are controversial but may be more
  common with Mirapex and Requip

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Amantadine (Symmetrel)

• A mild indirect dopaminergic agent with several
  mechanisms of action
• 1.Augmentation of dopamine release from storage
  sites
• 2. Blocking of reuptake of dopamine into
  presynaptic terminals
• 3. Some anticholinergic properties
• 4. NMDA glutamate receptor blocking activity
• Starting dose is 100 mg qd and increase to bid or
  tid.
• Side effects include ankle edema, livedo
  reticularis, and confusion/hallucinations

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Anticholinergics

• Main anticholinergic agent used is
  trihexyphenidyl (Artane) but can also try
  benztropine (Cogentin)
• Mainly effective for treatment of tremor
• Not well tolerated in older patients because of
  confusion, memory problems, and hallucinations
• Start Artane with 1 mg (1/2 of 2 mg tab) qd and
  increase by ½ tablets every 3-4 days to 2 mg tid,
  then increase by 2mg q week aim for maximum dose
  tolerated
• Other side effects include sedation, dry mouth,
  dry eyes, and urinary retention

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Sinemet (carbidopa/levodopa)

• Begin levodopa when symptoms become disabling or
  patient is unable to tolerate other medications
  (especially in older individuals with dementia)
• Levodopa is also best Rx for intractable tremors
  but often need to increase to higher doses (1000
  mg qd or more)
• There are different formulations of Sinemet
  (25/100, 10/100, 25/250, CR 25/100, CR 50/200).
  Now also available as Parcopa which is oral
  dissolving tablet.
• It is best to start with 25/100, 1/2 tablet qd
  and increase by 1/2 tablet every week until reach
  a dose of 1 tab tid continue to increase the
  dose as needed

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Management for more advanced stages of
Parkinsons disease

• a) Begin levodopa when symptoms become more
  disabling and increase the dose gradually as
  tolerated, dividing the dose tid, qid, or more
  frequently. Switch to 25/250 strength as you
  reach higher doses, or use both low and high
  doses to titrate more gradually.
• b) Sinemet CR (25/100,50/200) formulation is best
  at bedtime when patients are having difficulty
  with sleeping secondary to being off in the
  middle of the night, but can also be added during
  the day in combination with immediate-release
  Sinemet.
•  c) Add levodopa to use in combination with a
  dopamine agonist, amantadine, or an MAO-B
  inhibitor (selegiline or rasagiline) to help keep
  the dose of levodopa low AND to smooth out motor
  fluctuations.

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Motor complications in advanced PD

• 1. Wearing off
• 2. On-off fluctuations
• 3. Delayed ons
• 4. Sudden offs
• 5. Dyskinesias

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Management of motor complications

• FIRST determine the problem! Ask these
  questions
• 1. When do you take your medications? You should
  document exactly when and what doses of
  medications are taken.
• 2. How long does it take for your medications to
  start working?
• 3. How long does the effect last for? Does the
  effect wear off before the next dose?
• 4. Do you have any involuntary movements
  (dyskinesias) secondary to your medications? How
  long do they last and when do they occur in
  relation to your dose of medicine? Do they
  interfere with you daily activities or are they
  painful?
• 5. Is there any time of day when the medication
  seems to work better or worse than other times?
• 6. How is your Parkinson's disease in the AM
  when you wake up? Do you sleep well at night?
  If no, why not?
• 7. Do you take your medications with food?
• 8. Does the levodopa ever suddenly wear off
  unpredictably?

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Wearing off

• Wearing off is when the effect of levodopa
  subsides or completely stops prior to the next
  dose.
• This can be managed with the COMT
  (catechol-O-methyl transferase) inhibitors,
  Comtan (entacapone) or Tasmar (tolcapone), which
  help to prolong the effect of Sinemet. Tasmar
  requires LFT monitoring and can only be used if
  all other drugs have been ineffective.
• Wearing off can also be managed by adding
  dopamine agonists or selegiline or rasagiline to
  levodopa, or adding CR Sinemet to immediate
  release Sinemet
• Sinemet can be dosed more frequently i.e. if
  levodopa effect only lasts for 3 hours, then give
  the Sinemet every 3 hours

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On-Off fluctuations

• On-off fluctuations can consist of delayed on's,
  sudden offs, deep offs or dose failures. They
  are very difficult to manage.
• If possible, ask patients to keep a diary to
  record fluctuations.
• 1. Add dopamine agonists, amantadine, rasagiline,
  or selegiline to smooth out or improve the
  response to Sinemet
• 2. Decrease the interval between Sinemet doses
  while decreasing individual doses
• 3. Increase the dose of Sinemet at times which
  seem to be most problematic
• 4. Liquid Sinemet to increase the intestinal
  absorption---this can be very effective for
  delayed on's. All the Sinemet tablets can be
  made in a daily batch of liquid Sinemet and a
  small amount can be taken every hour or every
  couple of hours.
• 5. Avoid taking protein during the daytime and
  take the Sinemet on an empty stomach.
• 6. Try apomorphine injections for delayed ons or
  any off symptoms

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Dyskinesias

• Dyskinesias can occur at peak doses of Sinemet or
  biphasically at beginning and end of dose levels
  of levodopa
• For peak dose dyskinesias, the best thing to do
  is decrease the dose of Sinemet. You can give
  Sinemet more frequently while decreasing each
  individual dose.
• If the patient is on CR, you should change to
  regular Sinemet which is less likely to cause
  dyskinesias.
• If Sinemet can't be decreased without
  compromising motor abilities, you should try to
  add amantadine (up to 100 mg qid) or add an
  agonist which will allow you to lower the Sinemet
  
• If diphasic dyskinesias, may need to increase
  Sinemet or add Comtan to prevent wearing off
  between doses

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Drug-induced psychosis

• Drug-induced psychosis includes vivid
  nightmares, hallucinations, paranoia, and
  delusions.
• 1. Discontinue the offending agent if possible
  amantadine, anticholinergics, and dopamine
  agonists are prone to causing cognitive side
  effects in elderly patients
• 2. If psychosis continues on Sinemet, then you
  can add Seroquel (quetiapine) or Clozaril
  (clozapine). Try Seroquel first because it does
  not require weekly CBC monitoring
• 3. If possible, decrease the dose of levodopa,
  especially at night
• 4. If psychosis is very severe, admit patient
•  

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When to consider referral for surgery

• When patients have difficult to control motor
  fluctuations
• When patients have difficult to control
  dyskinesias
• Should probably not refer patients with
  significant cognitive decline they usually do
  not do as well

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Types of surgical intervention

• Subthalamic (STN) deep brain stimulation
• Globus pallidus interna (Gpi) deep brain
  stimulation
• Pallidotomy (Gpi)
• VIM Thalamic deep brain stimulation
• VIM Thalamotomy

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Management of non-motor symptoms

• 1. Depression anti-depressants including
  SSRI's and tricyclics, ECT can also be helpful
  for intractable cases.
•  2. Anxiety benzodiazepines, Paxil
•  3. Insomnia treating this can really benefit
  PD patients because they may have sleep
  benefit. Give CR at bedtime to help relieve
  immobility in bed, or try sleeping pill at night
  such as benzodiazepine or Ambien. Or treat with
  antidepressant if necessary. Consider Klonopin
  or dopamine agonist if has RLS
•  4. Orthostatic hypotension increase fluid and
  salt intake Ted stockings treat with Florinef
  or Midodrine if very symptomatic
•  5. Apathy or sedation try stimulants such as
  caffeine, Ritalin, Provigil.

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Non-pharmacological interventions

• Physical therapy this should begin early in
  disease course to maintain flexibility,
  especially focusing on stretching exercises.
  Continue PT throughout disease especially
  focusing on gait training to prevent falls
• Speech therapy can also be helpful for some
  patients with hypophonia Swallowing evaluation
  for those with dysphagia
• Psychotherapy for patients with depression or
  anxiety. Supportive therapy to help cope with
  the illness.
•  

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Conclusion

• There are many medications available for PD
  including levodopa, dopamine agonists,
  subcutaneous apomorphine, COMT inhibitors, MAO
  inhibitors, amantadine, and anticholinergics
• Choice of medication depends on age of patient,
  side effect profile, and specific PD problem you
  are addressing
• Management of PD differs for each patient and can
  require a huge amount of trial and error
• Dont forget non-motor symptoms which can be just
  as or more disabling than motor symptoms
• Physical therapy is crucial for maintaining
  mobility and flexibility, and preventing falls
• Consider surgery only when unable to optimize
  medical therapy