Transcript Parkinson`s disease Updated2007

Parkinson’s Disease
Cathy Chuang, MD
Jacobi Medical Center
Department of Neurology
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
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.
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, Xlinked dystonia-parkinsonism (Lubag), mitochondrial
cytopathies with striatal necrosis (Leigh's disease),etc.
Diagnostic Criteria
Parkinsonism requires at least 2 out of 6 cardinal features
with one of them being either bradykinesia or rest tremor.
Parkinson’s 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 > 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
Management of
Early Parkinson’s 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
Medical Management:
Early Parkinson’s 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 anticholinergic (Artane) for tremors.
 Selegiline (Eldepryl) or rasagiline can also
provide some symptomatic benefit for mildly
affected patients
 If older patient (>65), you can start with
levodopa
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
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.
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
Side effects of dopamine
agonists
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Common to all agonists: nausea, vomiting,
sedation, lightheadedness, orthostatic
hypotension, hallucination, and confusion
More common in ergot agonists: St.
Anthony’s fire, pulmonary/retroperitoneal
fibrosis, cardiac valvulopathy (Permax)
“Sleep attacks” are controversial but may be
more common with Mirapex and Requip
Amantadine (Symmetrel)
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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
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Starting dose is 100 mg qd and increase to
bid or tid.
Side effects include ankle edema, livedo
reticularis, and confusion/hallucinations
Anticholinergics
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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
Management for more advanced
stages of Parkinson’s 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.
Motor complications in
advanced PD
1.
2.
3.
4.
5.
Wearing off
On-off fluctuations
Delayed on’s
Sudden off’s
Dyskinesias
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?
Wearing off
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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-Omethyl 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
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 on’s or any off symptoms
Dyskinesias
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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
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
When to consider referral for
surgery
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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
Types of surgical intervention
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Subthalamic (STN) deep brain
stimulation
Globus pallidus interna (Gpi) deep brain
stimulation
Pallidotomy (Gpi)
VIM Thalamic deep brain stimulation
VIM Thalamotomy
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.
Non-pharmacological interventions
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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.
Conclusion
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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
Don’t 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