Parkinson’s Disease
1. PATHOPHYSIOLOGY:
-Chronic, progressive neurodegenerative disorder characterized by pathologic intraneuronal
alpha-synuclein-positive Lewy Bodies and neuronal cell loss, classically in the substantia nigra.
-Prevalence 1-2% older than 65; 3% older than 85. 1/1000 overall
-Braak Hypothesis states that PD is the result of ascending pathology from low
brainstem/olfactory bulbs, then up to SN, then subcortex, then cortex, explaining stepwise
development of symptoms over time.
-Alpha synuclein involved in virtually all cases of Lewy Body PD, major component of Lewy
Bodies. Concern is TOO MUCH ALPHA SYNUCLEIN SPREAD/OVERFLOW OF ALPHA SYNUCLEIN.
-Alpha synuclein can cause problems from excessive amounts of the normal type, pathologic
mutations of it, as well as toxic reactions with dopamine.
-In NON- LB PD, pathogenesis seems to come from oxidative stress and mitochondrial
dysfunction.
GENETICS/PROTEINS:
-10-15% of cases of PD have a family history consistent with an AD or AR inheritance pattern.
-Risk of PD if 1st degree relative has it: 3x normal (3-7% chance).
AD:
1) PARK8 (LRRK2 gene): Later life (50-60’s), most common genetic cause (10-20% of AD cases).
Has incomplete penetrance. Most typically European, north African, ashkinazi Jews. Very rare
in Asians.
PARK1, PARK 4 (alpha-synuclein/SNCA gene): Young onset (mean age 35-45), more
malignant progression (often death in 10 years, can have seizures/psych/cognitive changes).
Pathology is likely neurotoxic collections of misfolded proteins that spread like prions.
2)
3) PARK17 (PARK-VPS35)
4) GBA: Also can cause Gaucher’s disease. Common in Ashkinazi jews.
AR:
1) PARK2 (PARKIN gene): Usual disease onset <35 (majority of cases of PD with onset <20 are
due to this gene), slowly progressive. 50% of cases of AR PD, and 15% of apparently sporadic
PD with onset <age 45. Often with early lower extremity dystonia and hyperreflexia.
Dopamine-responsive.
2) PARK6 (PINK1 gene): Young onset, slowly progressive, 1-8% of young-onset cases.
3) PARK7 (DJ1 gene): Young onset, slowly progressive, 1-2% of young-onset cases.
ENVIRONMENTAL RISKS:
-Pesticides (OR 2.4)
-Oxidative stress
-Protective factors include smoking (???), coffee, alcohol, etc.
2. CARDINAL FEATURES:
1. Bradykinesia (Slowness or smallness of movement)
-Symptoms: slowed gait, decreased volume of voice or size of handwriting, trouble with manual dexterity (buttoning
buttons/zipping zippers etc).
-Signs: hypophonia, mask-like facies, decreased blink rate, slow shuffling gait with decreased arm swing,
decrement/slowing to finger-tap or heel-stomp.
2. Rigidity:
-Symptoms: trouble getting up from soft couches/chairs, general stiffness, trouble turning in bed, MSK pain.
-Signs: cogwheeling (tremor + rigidity), increased tone. Extreme neck flexion, trunchal flexion, scoliosis, striatal limb
deformities, postural reflex loss.
3. Resting Tremor
-Symptoms/characteristics: Can be present at same times as action tremor; tends to start unilaterally, but can
spread bilaterally to involve legs and chin; classically slowly builds in frequency at rest, particularly when patient
distracted; can be brought out when walking and with stress. Can be suppressed with concentration or by using the
hand. Can be intermittent at first, but becomes constant as disease progresses. Can also have sense of “internal”
shaking” (vs. dyskinesias)
-Signs: Rhythmic, involuntary, low frequency (4-6 Hz), oscillatory, and often pill-rolling. Presenting symptom in 5070% of patients.
4. Postural instability:
-Symptoms: Unsteadiness, falls, freezing, difficulty with gait.
-Signs: Pull test/retropulsion test, narrow-based gait, festination, freezing, stooped posture.
5. Sustained and clear response to levodopa:
-Get up to total daily dose of 1000mg for at least 2 weeks).
-Exception to this rule: tremor-predominant PD is less responsive.
-Parkinson Plus syndromes will often not respond, respond poorly/inadequately, or have wearing off of benefit
quickly.
3. Other components of the disease to ask about:
Meds effective enough?
Things you are limited in doing that you want to do?
Meds wear off?
Meds side effects (nausea/GI, cognitive changes, orthostasis)
Dyskinesias?
Car seats:
Buttons/zippers:
Gait instability:
Falls:
Dysphagia
Trouble with saliva/drooling
Dysarthria
Fatigue
Pain
Depression (SIGECAPS)
Sleep problems/trouble turning over in bed
Freezing
Hallucinations
Memory problems
Personality Changes
Tremors
Smaller handwriting
Softer voice
Orthostasis/urinary retention/constipation/ED/early satiety/gastroparesis/stridor/coordination problems
Snoring/daytime somnolence/unrefreshing sleep/apnea
ADLs/IADLS/PT/exercise
Pseudobulbar affect
Weakness/numbness/vision changes
Anosmia
Antipsychotic/antiemetic
REM sleep behavior disorder
4. PARKINSON’S-SPECIFIC FINDINGS ON NEURO EXAM:
-MS: MOCA. ? apraxia
-CN: Decrease blink rate (you blink when they do, if you’re eyes hurt, they have decreased blink), mask-like facies,
obvious dystonias, limited vertical gaze, hypophonia, square wave jerks.
-Motor: Cogwheeling, lead-pipe rigidity, rest tremor, action tremor, decriments to finger tap/hand open-close/foot
tap, dyskinesias, ability to stand from chair with arms crossed.
-Sensation, reflexes: N/A
-Coordination: ? ataxia.
-Gait: shuffling, narrow based, stooped, en bloc turning, festination, decreased arm swing, rest tremor re-emerges,
freezing, short stride length, Retropulsion test.
5. DDX:
A) Drug-induced (antipsychotics and anti-emetics classically, but also reserpine or tetrabenazine, or less likely
VPA/phenytoin/lithium/verapamil/immunosuppressants)
B) Multiple systems atrophy (prominent autonomic symptoms, ataxia, and poor response to levodopa; can present
with parkinsonian-predominant or cerebellar-predominant symptoms with associated atrophy of affected areas; hot
cross buns sign on pons).
C) Lewy Body dementia (hallucinations; dementia onset preceding or within a year of Parkinsonian symptom onset)
D) Progressive supranuclear palsy ( trouble looking vertically down > up though overcome with oculocephalics, neck
dystonia with hyperextension, prominent gait problems; “hummingbird sign” due to atrophy of midbrain)
E) Corticobasilar Degeneration: (significant asymmetry, focal dystonia, cortical myoclonus, cortical sensory loss,
apraxia, alien limb, UMN signs)
F)Vascular/traumatic lesions/structural lesions/toxins (CO, manganese, cyanide, MPTP)/post-infectious (syphilis,
encephalitis)/metabolic (hypoxia, parathyroid)
G) NPH (classically “lower extremity parkinsonism”)
H) Others: ET, Wilson’s, SCA 3, PKAN (PD + iron accumulation), neuroacanthocytosis, Juvenile HD, depression/psych,
Stiff Person’s, thyroid slowness, dystonia, psychogenic, MPTP, Manganese.
6. DIAGNOSTIC CRITERIA:
7. TREATMENT:
A) Non-medicinal:
-EXERCISE is key, goal is keeping them independent as long as possible. Physical aids. Tai Chi.
-Focus on WHAT IS BOTHERING THE PATIENT THE MOST.
-Lee Silverman Voice Treatment, speech pathology
B) Medicinal:
-MAKE SURE TO ADDRESS HOW ARE THEY FUNCTIONING, AND WHAT THEIR MAJOR CONCERN
IS TODAY, AND FOCUS ON FUNCTIONALITY.
-No way to stop progression, levodopa doesn’t become “less effective” over time, it’s just the
worsening of the disease; stem cell research ongoing but no evidence yet that it works.
1. Levodopa/sinemet (carbadopa/levodopa) (dopamine + peripheral decarboxylase inhibitor):
-Pros: Basically the most effective drug at controlling most symptoms; its limitation is side effects.
-Cons: Not usually very helpful for tremor; can cause dyskinesias, nausea (usually starts early after initiation of drug,
resolves after been on drug for a little while), orthostasis, hallucinations, lightheadedness.
-Dosing: Sinemet 25/100mg 1 pill TID x 2 weeks  increase by 1 tab every 2 weeks etc to initial goal 1200mg/day
total (though can go as high as 2500mg/day in 5-6 divided doses).
-Take 1-2 hours before or after eating, as is less effective/more unpredictable if taken at mealtime. Absorbed in small
intestine, mainly duodenum.
2. Dopamine agonist( priampexole/ropinirole/bromocriptine):
-Pros: Less risk of dyskinesia
-Cons: Not as effective; more hallucinations, orthostasis, lower extremity edema, compulsive behavior/hypersexuality
(5-10%), somnolence/sleep attacks. Takes time to be effective.
-DON’T STOP SUDDENLY; TAPER SLOWLY. Otherwise get withdrawl that looks like a drug withdrawl; need to add back
in the agonist again to counteract.
-Dosing:
a) Priampexole 0.125mg TID max of 4.5mg total daily. XR form is 0.375 mg/day with max of 4.5 mg/day.
b) Ropinirole 0.25mg TID  max 24 mg total daily
c) rotigotine (patch): 1mg patch daily x 2 weeks  2mg patch x2 weeks  max of 8mg total daily
3. MAOB-I’s (selagiline/rasagaline ; delay clearance of dopamine):
-Pros: Modest effects, well tolerated ; « dopamine-lite »
-Cons: hyperarousal, hallucinations, nausea, LH, dyskinesias.
-Dosing :
a) Selegiline 5mg daily  5mg BID max.
b) Resagaline 0.5mg daily  1mg daily max
-SSRI + MAOB-I NOT cause serotonin syndrome as long as dose is <10mg, as it does not affect MAOA at that dose and
won’t cause serotonin syndrome at that low dose.
4. Entacapone or tolacapone (inhibits dopamine breakdown)
Pros: Really only useful if dopamine wearing off too quickly, keeps each dose around an extra hour or so ; has to be
given as adjunct to dopamine.
Cons: Enhances side effects of levodopa, particularly dyskinesia. Makes urine orange.
-Dosing: 200mg with each sinemet dose; max 1600mg/day
5. Anti-cholinergic (benztropine, trihexyphenidyle):
- Pros: Mild to moderate benefit for tremor and bradykinesia, but that’s about all it is good for.
-Cons: Constipation, urinary retention, dry eyes/mouth, psychosis/cognitive problems. Avoid if >60.
6. Amantadine glutamate antagonist; dopamine transport inhibitors; improves dopamine effects by keeping it around
and making more get released)
-Pros: Great for tremor, well-tolerated, decreases dyskinesias.
-Cons: Hallucinations, cognitive problems, dry mouth, myoclonus, leg edema, prolonged QTC
-Dosing: 100mg daily, increase to 100mg TID.
8. Motor Treatment Rules-of-Thumb
-Dyskinesias: Decrease dose (if tolerable; may need to increase frequency) and add another agent
vs. add amantadine to goal 100mg TID vs. CR dosing vs. consider DBS.
-Wearing off: Add another dose vs. increase given dose vs. add entacapone vs. add MAO-I vs. add
dopamine agonist vs. consider DBS (if other options not tolerated)
-Early AM dystonia: An “off” effect. Consider CR at bedtime, or taking a dose in the middle of the
night.
-Neuroprotection: Only possibly successful agent is resagaline 1mg daily (NOT 2mg
daily) >>selagaline, with mild symptomatic effect, but study design may not be rigorous enough.
NOTHING else is helpful.
-No evidence that starting with dopamine agonists is as good as starting with levodopa early in
disease.
-Risks for getting dyskinesias from levodopa: More severe disease/duration of disease, young age,
dose of levodopa. *****DYSKINESIAS ARE NOT ASSOCIATED WITH LENGTH OF TIME YOU’VE
BEEN ON LEVODOPA.
9) Non-motor symptom treatment:
-Anxiety: SSRI, benzos
-Cognitive problems/dementia: rivastigmine, mirtazapine, clozapine, avoid anti-cholinergics, secondary causes.
-Constipation: Miralax, high fiber diet, pyridostigmine.
-Depression: SSRI, tricyclics, ECT
-Drooling: 2/2 decreased swallowing. Glycopyrrolate, scopolamine patch, botox into salivary glands.
-ED: sildenafil 50mg
-Fatigue: ? OSA, depression, BP drop, medication effects. Selagaline can be used, as it is activating. Also try
methylphenidate, modafinil. Can try CR dosing of sinemet.
-Hallucinations: Quetiapine 50-75mg daily, clozapine 6.25-12.5mg QHS (with q1week CBCs looking at white count). PD
meds that can cause it are anticholinergics > amantadine >dopamine agonist > MAOI > levodopa.
-Insomnia: often responds to sinemet before bedtime. Also can try zolpidem, mirtazapine, melatonin.
- Nausea from sinemet: Decrease dose vs. switch to CR form vs. try with food vs. Zofran or donperidone; reglan or
Compazine bad.
-Orthostasis: Decrease sinemet vs. fluids/salt/wedge pillow/take time/compressions stockings/midodrine starting 5mg
daily and then going up to 10mg QID/florinef starting 0.1mg daily up to 0.4mg daily. Consider droxidopa in the future
(converts dopamine to norepinephrine, need to keep carbidopa below 100mg/day). MONITOR FOR SUPINE
HYPERTENSION.
-REM sleep behavior disorder: clonazepam 0.5mg to 1mg before bedtime; also consider melatonin 3mg or 6mg QHS
-Urinary retention: Avoid typical meds as can worsen confusion/cognition, consider anticholergics, but be careful.
Urology referral.
-RLS: Tramadol 50mg QHS (or similar opioid) vs. dopaminergic, gabapentin, pregabalin. Check ferritin (goal >50), can
consider sleep clinic referral.
-Sinemet works best for bradykinesia, but usually not helpful in non-motor symptoms, and not always helpful for tremor.
10. DEEP BRAIN STIMULATION (DBS)
-FDA approved for refractory PD and ET, and in rare cases refractory dystonia and OCD.
-Administration of chronic electrical stimulation to various deep subcortical brain nuclei; connected by wire to a battery
implanted in the chest.
Targets of surgery: ET= VIM nucleus of thalamus. PD= STN or GPi
Indications for surgery: Levodopa-responsive symptoms in non-demented patients, in patient suffering from significant
on-off fluctuations and/or tremor, with significant dyskinesias or other reasons for medical refractoriness.
Benefits: Improve tremor, rigidity, bradykinesia, postural instability; reduce on-off fluctuations and dyskinesias. As a
general rule, will provide improvement of motor symptoms equal to level of BEST prior response to levodopa. Improves
motor symptoms/ON-time by 50%, and tremor by 70-90%. Allows decrease in medications by 50% on average (but NOT
elimination of meds)
Will NOT benefit: speech, cognition, autonomic symptoms, mood/behavior, and any gait stuff that levodopa hasn’t
helped.
Risks: 3% risk of stroke, hemorrhage, or infection.
Advantages over surgically cutting out the nuclei: reversibility, programmability/adjustability, better side effect profile,
ability to perform bilateral procedures with lower risk of deficits (equivalent benefit in efficacy to pallidotomy when
unilateral).
-Getting MRI with DBS: Safe. Inform radiologist, use only head transmit coil not extend over chest, amplitude DBS set to
zero and off during MRI.
11. Disease course:
-Younger patients TEND to have slower rate of progression, more tremor predominance, more dyskinesias. Older
patients have more rapid rate of progression with more postural instability, gait disturbance, dementia.
-Complications as the disease progresses mainly involve dyskinesias (from levodopa) and “wearing off” (medication
effects don’t last as long, or not as effective).
BONUS CONTENT:
Direct pathway= pro-movement:
Stimulate caudate/putamen  inhibit GPi/SNr  stimulate thalamus  hyperkinetic
1) Indirect pathway= anti-movement: Stimulate caudate/putamen  inhibit GPe 
stimulate STN  stimulate GPi/SNr inhibit thalamus hypokinetic
-Note: whether dopamine is excitatory or inhibitory depends on receptors it is acting on.
-D1 receptors = excitatory, D2= inhibitory.
-Thalamus always is hyperkinetic