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PD definition

slowly progressing neurodegenerative disorder with insidious onset of asymmetric resting tremor, bradykinesia, hypokinesia, and rigidity, sometimes with postural changes


pathophysiology of PD

nerve cells in the SUBSTANTIA NIGRA send out fibers to the CORPUS STRATIA, gray and white bands of tissue located in both sides of the brain (direction is important, from substantia to corpus)


next step of patho

there the cells release dopamine, an essential neurotransmitter. Loss of dopamine in the corpus stratia is the primary defect in PD.


pathological changes in PD

dark "moustache" that represents the substantia nigra almost disappears
classical round proteinaceous body- known as Lewy body- considered pathological hallmark of PD**


incidence/ epidemiology of PD

1% of population worldwide
mean age of onset 65 years
equally affects men and women
5- 10% get it before age 40


the why's of PD

older age
first degree relative (most cases are sporadic but there is a genetic component)


more patho of PD

destruction of neural cells in the substantia nigra pars compacta (midbrain) that secrete dopamine = loss of dopamine and dopamine receptor sites (70- 80% of neurons must be dead for symptoms to appear)
Lewy bodies- pathologic hallmark but only found on autopsy


diagnosis of PD based on

clinical evaluation



any group of nervous system disorders with symptomts similar to PD


motor parkinsonism

is an essential criterion of PD and requires both of the following: bradykinesia & rest tremor or rigidity


the true "gold standard" for diagnosis for PD

neuropathologic examination. There are no physiologic tests of blood test for confirming diagnosis of PD


Diagnosis of PD based on clinical eval- what is the work up?

history (meds, trauma, family)
physical exam
CT, MRI (r/o other possible causes)
response to Levodopa
PD vs. Parkinsonism
consult neurology


the diagnosis of clinically established PD requires ALL of the following

the presence of parkinsonism
no absolute exclusion criteria (no way to say its not PD)
at least 2 supportive criteria
no red flags


clinically probable diagnosis of PD

the presence of parkinsonism
no absolute exclusion criteria
the presence of red flags must be counterbalanced by supportive criteria
- if one red flag is present, there must also be at least one supportive criterion
- if 2 red flags, at least 2 supportive criteria are needed
- no more than 2 red flags are allowed for this category


clinical presentation- idiopathic PD

plus tremor (most common sign)
or rigidity (2 of the 3 of bradykinesia, tremor, rigidity need to be present)
postural instability (occurs late in disease)
resting tremor
asymmetry (one side more affected than the other)
good response to Levodopa


supportive diagnosis

unilateral onset
masked face (decrease in spontaneous facial expression/ flat expression)
hypophonia, monotonous tone (quiet)
gait disorder, falls (forward tilt of trunk, shuffling gait)
flexed posture
reduced arm swinging
persistent asymmetry throughout the course of the disease with the side of onset most affected



generalized slowness of movement
may be described by pt as "weak, incoordination, tired, stiffness"- all words used to describe the decreased ability to initiate voluntary movement
**typically starts distally in arms with decreased manual dexterity of fingers**
in legs: dragging, shorter/ shuffling steps, unsteadiness
bradykinesia is eventually seen in all PD patients and is the **most common feature**
also is the most difficult symptom to describe for patients



resting tremor, usually unilateral
**most common PRESENTING symptom- most noticeable when the tremulous body part is supported by gravity and not engaged in purposeful activities
can be intermittent
side affected usually is the more affected side throughout disease course
usually starts unilateral in 1 hand
can involve legs, lips, jaw and tongue
big caution: the majority of people with tremor do NOT have PD: essential tremor (usually b/l and intention), MS (intention), cerebellar dysfunction (usually intention and with other cerebellar signs)



increased resistance to passive movement about a joint
occurs in approximately 90% of patients with PD
often begins unilaterally, typically same side as tremor


cogwheel rigidity

ratchet pattern of resistance and relaxation


leadpipe rigidity

present throughout movement


physical exam/ test- rigidity

(seen in 90% of PD) grasp the patient's elbow at the AC region and slowly flex and extend; or pronate and supinate the forearm-
rigidity may increase when another limb is engaged in voluntary active movement


physical exam/ test- bradykinesia

(seen in almost all PD) test the speed, amplitude and rhythm of finger tapping, hand gripping, toe tapping, pronation/ supination. In mild PD will show slowing and decreased amplitude


physical exam/ test- rest tremor

(presenting symptom in 70% PD) can be intermittent, can be seen when patient is RELAXED with hands resting quietly on the lap
- can distract patient by asking them to perform mental calculations
- or voluntary repetitive movements with the contralateral limb
- may be seen when walking


physical exam/ test- postural reflexes

"pull test" give a sudden, firm pull on the shoulders from behind the patient (be prepared to catch them). Normal postural reflex will maintain balance or take only one step; loss of reflex will take multiple steps or fall


physical exam/ test- gait disorder/ falls

observe patient walking down the hall
unilateral loss of arm swing
small step shuffling
stooped posture with flexed arm


other motor features: craniofacial (common board question)

hypomimia (masked facial expression)
*decreased spontaneous eye blink
*speech impairment (dysarthria, hypophonia)
*sialorrhea (excessive salivation)


other motor features: musculoskeletal

stopped posture
difficulty turning in bed


other motor features: visual

blurred vision
impaired contrast sensitivity


another caveat about motor features

most of these result from one or more of the cardinal features. example- decreased eye blinking, facial masking, probably a result from a combo of bradykinesia and rigidity


non motor symptoms

cognitive dysfunction and dementia
psychosis and hallucinations
mood disorders
sleep disturbances
autonomic dysfunction
olfactory dysfuntion


important snapshot

PD traditionally considered a motor system disorder.
Now recognized to be a complex disorder with diverse clinical features that include non- motor manifestations
The bottom line- PD is a chronic, progressive neurodegenerative disorder characterized by any combo of the 4 cardinal signs: bradykinesia, rest tremor, rigidity and postural instability (presents in later stages of disease)


Differentials for PD- drug induced

neuroleptics (haldol, perphenazine)
dopamine receptor antagonists
classic and atypical antipsychotic agents


other differentials for PD- neurodegenerative causes

dementia with Lewy bodies
corticobasal degeneration
frontotemporal dementia
huntingtons disease
multiple system atrophy
progressive suprnuclear palsy
spinocerebellar ataxias


other differentials for PD- symptomatic

drug- induced
metabolic (parathyroid disorders, wilsons disease)
post- traumatic
toxic (carbon monoxide, manganese)


other differentials for PD- other

essential tremor
normal pressure hydrocephalus
SWEDD (scans w/o evidence of dopaminergic deficit)


**red flags (if you see these- PD differential, but NOT as likely)

rapid progression of gait impairment (should be slow)
complete absence of progression of motor symptoms
early bulbar dysfunction
inspiratory respiratory dysfuntion
severe autonomic failure in 1st five years
recurrent falls (more than 1/ year)
disproportionate anterocollis
absence of any of the common non- motor features of PD
otherwise- unexplained pyramidal tract signs
bilateral symmetric parkinsonism (should be unilateral)


more features suggesting alternative diagnosis- see red flags

falls at presentation or early in course of disease
poor response to Levodopa
symmetric motor signs
lack of tremor
rapid progression
dysautonomia early in disease (urinary urgency/ incontinence, orthostatic hypotension, erectile failure)
h/o repeated head injury or encephalitis
h/o recurrent strokes


if in doubt of diagnosis of PD

send to neurology


dopaminergic challenge test

assessment of parkinosnian symptoms using the Unified Parkinson Disease Rating Scale (UPDRS) before and after a dose of levodopa or subq apomorphine-
positive if a clinically significant improvement in the score (15- 30% or more) 1 hour after administration of levodopa or 20 mins after apomorphine injection
- up to 30% of patients may not respond
- in patients with mild symptoms that don't interfere with ADLs, don't do the test purely for diagnostic purposes


final snapshot- 4W's

PD slowly progressive neurodegenerative disorder of asymmetric resting tremor, bradykinesia, rigidity and sometimes postural changes
d/t loss of dopamine and receptors in zone compacta of substantia nigra
there are no tests to diagnose
like with other chronic neuro disease, PE ROS A&P important
consult neuro



- pharmacological- levodopa, Dopamine Agonists, selegiline, anticholinergic agents, COMT inhibitors, amantadine, MAO B inhibitors
The decision to initiate medical therapy is based on the degree to which the patient is functionally impaired, interferes with ADLs
- surgical
- support



replaces the dopamine that is lost
precursor of dopamine agonists
Sinemet or Madopar (carbidopa- levodopa)- start low, titrate up. once stable, reassess Q 3- 6 months
- in early disease: take w/ food to avoid nausea.
- advanced disease: take on empty stomach= more effective
Adverse effects: nausea, somnolence, dizziness, headache
- most effective drug for symptom treatment of idiopathic or Lewy body PD
- most effective for akinetic sx, also tremor and rigidity, less postural instability
- combined with a peripheral decarboxylase inhibitor (carbidopa) to block its conversion to dopamine in the systemic circulation


Levodopa wearing off

most will experience fluctuations in their response to levodopa after 2- 5 years: "wearing- off phenomenon"
more common in pts with young onset
so this is the reason you delay treatment until necessary and start at lowest dose possible


dopamine agonist

synthetic agents that directly stimulate dopamine receptors
adjuncts to levodopa or monotherapy
less likely to induce dyskinesias
most beneficial in younger patients with early disease ( <60 yo)
in combo with other antiparkinsonian drugs for advanced PD
will need levodopa in a few years if used as monotherapy
AE: hypotension, caution with cardiac disease, N/V, peripheral edema
D/C gradually


dopamine agonist examples

Bromocriptine (Parlodel) 1.25mg BID
Pramipexole (Mirapex) 0.125 mg TID
Ropinirole (Requip) 0.25 mg TID
Injectable apomorphine (reserved for "rescue" when pt is having a sudden akinetic episode)


MAO B inhibitors

Selegiline or Rasagiline 5mg QAM
AE: nausea, headache, insomnia (don't take after noon), confusion in elderly, enhances levodopa adverse effects
Neuroprotective?? (unclear)
delays destruction of neurons and inhibits metabolic breakdown of DA
mild symptomatic benefits



Trihexyphenidyl (Artane) 0.5- 1mg BID
Benztropine (Cogentin) 0.5- 2mg BID
monotherapy in patients <70 with tremor as predominant problem, or advanced PD with persistent tremor despite levodopa or DA
use cautiously in elderly
D/C gradually
AE: confusion, hallucinations, dry mouth, blurred vision, constipation, urinary retention, tachycardia



(aka symmetrel, symadine) antiviral agent 200- 300 mg/ day in divided doses
advantage: low incidence of S/E
S/E: ankle edema, livedo reticularis
mechanism of action unknown
its a weak/ mild antiparkinsonian drug
useful for akinesia and rigidity
best as short term monotherapy in mild disease


COMT inhibitors (catechol- O- methyl transferase)

Entacapone (comtan) 200mg w/ each dose of Levodopa (max 8/ day)
Tolcapone (tasmar) 100mg TID- use as last resort, monitor LFT's
these are levodopa extenders, ineffective if used alone
mainly used to tx motor fluctuations, end of dose "wearing off" periods
increases plasma half- life of levodopa
may allow a reduction in the total daily levodopa dose by 30%


final thoughts on meds

Levodopa or DA initally
Levodopa is the most effective treatment, although carries higher risk of dyskinesias than DA
Initiate therapy with a DA in younger patients (<65yo) and levodopa in elderly patients (>65)
Anticholinergic drugs- for younger patients with tremor as predominant problem


to worry about- advanced PD

as many as 50% of patients on levodopa for 5 yrs experience motor fluctuations and dyskinesia
Especially common in patients with younger onset (<50yo)
motor function alterations between periods of being "on" = responding to med and being "off" = experiencing symptoms of PD
Dyskinesia- abnormal involuntary movements


more to worry about w/ advanced PD

as the disease advances, effects of levodopa begins to wear off approx 4 hours after each dose (1/2 life= 90 minutes) so patients will begin to be aware of a wearing "off" effect less than 4 hours after levodopa dose
increasing the dose is not usually effective, will increase SE w/o increasing dose duration
shorten the dose interval while administering lower doses is usually a more effective approach
add COMT inhibitor
avoid taking levodopa with high protein meals


surgery- deep brain stimulation (DBS)

surgically implanted, battery operated medical device (similar to pacemaker) that delivers electrical stimulation to targeted areas in the brain, blocking the abnormal nerve signals that cause tremor and PD symptoms.
consists of: lead (electrode) that is implanted in the brain, extension connects lead to neurostimulator, neurostimulator ("battery pack")- usually implanted under the skin near the collarbone
the most frequently performed surgical procedure for the treatment of advanced PD
factors predictive of benefit: preoperative levodopa responsiveness