PARKINSONISM
Susie Ro, M.D.
Movement Disorders Center
Swedish Neuroscience Institute
Seattle, WA
September 13, 2014
OBJECTIVES
•
•
•
•
•
RECOGNIZE CLINICAL FEATURES of
PARKINSONISM
IDENTIFY “RED FLAGS” for ATYPICAL
PARKINSONISM
BE VIGILANT for SECONDARY
PARKINSONISM
EARLY DETECTION/ PREVENTION?
ALGORITHMIC APPROACH TO DIAGNOSIS
AND TREATMENT of PARKINSONISM
WHAT IS PARKINSONISM?
“PARKINSONISM” = Clinical syndrome of stiffness
(rigidity), slowness (bradykinesia) +/- tremor
Most commonly due to iPD, but may be due
to another degenerative process, or secondary
to another cause
“PARKINSON DISEASE” = specific disorder
(idiopathic Parkinson Disease), 2nd most
common adult onset movement disorder,
affecting >1 million Americans
PARKINSON’S DISEASE
Progressive loss of
dopamine-producing
neurons in the SNPC
causes an imbalance in
the circuits controlling
movement.
Motor symptoms are
treated by increasing
dopamine stimulation
DIAGNOSTIC CRITERIA for iPD (UK BRAIN BANK)
STEP 1: BRADYKINESIA + at least 1 of the following:
A. RIGIDITY
B. 4-6 Hz RESTING TREMOR
*1/3 of PD patients have no tremor
* PD patients may only have “action tremor”
C. POSTURAL INSTABILITY (not caused by primary visual,
vestibular, cerebellar, or proprioceptive dysfunction)
STEP 2: EXCLUDE OTHER CAUSES of PARKINSONISM
STEP 3: AT LEAST 3 OF THE FOLLOWING
A. UNILATERAL ONSET *remains asymmetric
B. REST TREMOR
C. PROGRESSIVE DISORDER
D. PERSISTENT ASYMMETRY (first side worse)
E. EXCELLENT RESPONSE to L-DOPA (70-100%)
F. SEVERE L-DOPA-INDUCED CHOREA *fluctuations not specific
G. L-DOPA RESPONSE >5 YEARS
H. CLINICAL COURSE of >10 YEARS
PARKINSONISM vs.
ESSENTIAL TREMOR (ET)
PD vs. ESSENTIAL TREMOR (ET)
-ET: Often familial (50-70%), slowly progressive (>20 yr Hx unlikely
PD) but ET and PD may coexist (shared risk factor?)
-often responsive to alcohol, worse with stress/ fatigue, smoking, and
sometimes stimulants (but not specific to ET)
-Action > distal postural tremor of the arms, but may also affect head,
trunk. Leg tremor, marked asymmetry, or rest tremor less common.
-Frequency 4-12 Hz, inverse relationship between amplitude and rate
which progresses over time, not slowed by mass loading
-Head/ vocal tremor may occur in isolation (also tongue/ chin), but
isolated head tremor with torticollis likely dystonia
Action tremor ≠ “intention tremors”
ET is not the only cause of action/ intention tremors
PD is not the only cause of resting tremors
It is the bradykinesia/ rigidity that defines parkinsonism
ALGORITHIM for
PARKINSONISM
PRIMARY
SYNUCLEINOPATHIES
TAUOPATHIES
PSP
LEWY
BODY
(iPD,
DLBD)
MSA
(SHYDRAGER,
OPCA,
SND)
SECONDARY
CBD
OTHER
FTD
DRUGINDUCED
NPH
VASCUL
AR
DIAGNOSTIC ACCURACY: LOW
AAN 2014: ProbPD (L-Dopa responsive) vs. PossPD (never treated
or not clearly responsive)
AZSAND: (Arizona Study of Aging and Neurodegenerative
Disorders, an ongoing longitudinal clinico-neuropathologic study):
PD duration <5 years, only 53% had PD at autopsy (8/15). >5 years,
often with dyskinesia, 88% (72/82)
Overall accuracy 82% (80/97) of ProbPD, 26% (9/34) of PossPD at
first visit
UK PD Society Brain Research Centre Brain Bank criteria 99%
DATATOP: 92% at 7.6 years follow up (not all pathologically
confirmed)
DaT SCAN
Dopamine Transporter SPECT
scan
-FDA approved since 2011 to
differentiate between ET
(essential tremor) and
Parkinsonian syndromes
-Cannot reliably differentiate
between different parkinsonian
syndromes (e.g. iPD, MSA, PSP)
-Can be useful to differentiate
from DIP (drug-induced
parkinsonism) and others
(?vascular? ?psychogenic?)
MSA
MULTIPLE SYSTEM ATROPHY: term first coined by
Graham and Oppenheimer (1969)
MSA = PARKINSONISM (often more rapidly progressive)
+ AUTONOMIC/ CEREBELLAR/ PYRAMIDAL
SIGNS
+ SEVERE SPEECH/ SWALLOWING/
BALANCE PROBLEMS EARLY IN COURSE
+ POOR/ TRANSIENT RESPONSE TO L-DOPA
+/- ADDITIONAL FEATURES (e.g. Peripheral neuropathy,
Abnormal eye movements)
Seen in iPD but rare in MSA: anosmia*, hallucinosis
DYSKINESIAS ARE POSSIBLE IN MSA, ESPECIALLY
CRANIOCERVICAL
MSA Subtypes
1.
MSA-A (Autonomic) Shy and Drager (1960)
a.k.a. SHY DRAGER SYNDROME
2.
MSA-C (Cerebellar) Dejerine and Thomas (1900)
a.k.a. SPORADIC OLIVOPONTOCEREBELLAR ATROPHY (OPCA)
DDx:
SCA 3, cerebellar degeneration
3.
MSA-P (Parkinsonian)
a.k.a. STRIATONIGRAL DEGENERATION (SND)
Early onset falling
Severe dysarthria and dysphonia
Respiratory stridor
Anterocollis
Pyramidal signs
MSA/ PD-PATHOLOGY
Papp et al. (1989):
Neural and Filamentous
a-synuclein containing
glial cytoplasmic
inclusions (GCIs)
Preganglionic (vs. PD
which is postganglionic)
Can have REMBD but
usually not anosmia
MSA-IMAGING
 T2 signal in putamen, “hot cross bun” sign in pons,
Pontocerebellar atrophy, T2 signal in MCP (OPCA),
?Diffusion Tensor Imaging? ?PET/ SPECT?
MSA vs. PD
SIGN
MSA
PD
AUTONOMIC
++/+++
+
CEREBELLAR/ ++/+++
PYRAMIDAL/
PERIPHERAL
FALLS
EARLY

DEMENTIA
+
+/++
LEVODOPA
RESPONSE
+
TRANSIENT
+++
PERSISTENT
LATE
PSP (Progressive Supranuclear Palsy)
Stiff, broad-based gait with slight extension of trunk/ legs armswing can be
present, marked axial rigidity, rest tremor rare
“Stunned” facial expression; “procerus sign”
EOM/ Eyelid abnormalities (wide-eyed/ eyelids closed, can’t look down)
Bulbar (dysarthria, dysphagia) and pseudobulbar palsy, Dementia (frontal
dysfunction)
PSP“Hummingbird Sign”
Olfactory sparing
No/ poor response to
sinemet; motor fluctuations
rare
PSP- “Hummingbird Sign”
PSP vs. PD
SIGN
PSP
EYE MVTs

EYE BLINKING 
FALLS
+++ EARLY
REST TREMOR 
AXIAL RIGIDITY +++
LEVODOPA

PD


+ LATE
RESPONSE
CONSISTENT
MAJORITY
+/++
+++
CBS
CORTICOBASAL GANGLIONIC SYNDROME
(a.k.a. “Parietal Pick’s Disease”)
•Markedly ASYMMETRIC Parkinsonism with mainly rigidity/
bradykinesia/ postural instability and DYSTONIA, can have
tremor and MYOCLONUS
•“Alien Hand” Syndrome (“anterior”/ motor type); spontaneous
elevation of limbs
•APRAXIA (ideomotor and ideational), the “useless hand”,
cortical sensory loss
•Frontal/ cortical dementia, language/ speech alterations
•Oculomotor findings (may be confused with PSP)
•Onset mean age, death by 8 years, M:F 3:2
CBD vs. PD
SIGN
CBD
PD
ASYMMETRY
+++
+
RIGIDITY
+++
++
APRAXIA
+++
-
LEVODOPA
RESPONSE
+/-
+++
FRONTOTEMPORAL
DEMENTIA/ FTLD
(PICK’s DISEASE)
“KNIFE-EDGE” GYRI due to
marked frontotemporal atrophy
•Prominent frontal lobe dementia
•Personality changes
(disinhibition/ inappropriate
behavior, apathy/ euphoria)
•Aphasia
• Parkinsonian features
SECONDARY PARKINSONISM
Infectious/ Postinfectious:
Viral, Syphilis, TB, Whipple’s, Prion, fungal, etc.
Drug-induced:
NEUROLEPTICS, ANTIEMETICS, Monoamine depleters,
Amiodarone, VPA, Li+, Ca channel blockers, etc.
Metabolic:
Acquired hepatocerebral degeneration, cerebrotendinous
xanthomatosis, ceroid lipofuscinosis, hemochromatosis,
Niemann-Pick Type C, Folate deficiency, BG calcification
Toxic: CO, Manganese, MPTP, MeOH, CN, insecticides, etc.
Structural: Vascular: multi-infarct, anoxic encephalopathy
NPH: (Normal Pressure Hydrocephalus), etc.
NPH (Normal Pressure
Hydrocephalus)
3 W’s: “wet, wacky, wobbly”
1.
Frontal urinary
incontinence
2.Subcortical dementia
3.“Magnetic gait”: wide-based,
slow/ shuffly, freezing
CSF acqueductal flow MRI
High-volume LP or lumbar drain
NPH is potentially curable…but only if treated early!
SECONDARY PARKINSONISM
(IF IT DOESN’T LOOK LIKE iPD, GET AN MRI)
Carbon Monoxide ( T2 putamen)
Manganese Poisoning
 T1 Globus Pallidus
“RED FLAGS”
SUMMARY
Hx of neuroleptic use, toxic exposure, stroke, etc.
Supranuclear gaze abnormalities, spastic/ dysarthric speech
Prominent autonomic, pyramidal, cerebellar signs or other
unexplained signs (neuropathy, amyotrophy)
Early or severe falls, dementia, apraxia/ aphasia,
pseudobulbar palsy
Marked asymmetry/ lack of asymmetry
Rapid progression or stepwise clinical course
POOR OR TRANSIENT RESPONSE TO LEVODOPA
ALGORITHIM for
PARKINSONISM
PRIMARY
SYNUCLEINOPATHIES
TAUOPATHIES
PSP
LEWY
BODY
(iPD,
DLBD)
SECONDARY
CBD
OTHER
DRUGINDUCE
D
NPH
FTD
MSA
(SHYDRAGER,
OPCA,
SND)
TAKE HOME MESSAGES:
-(Nearly) everyone deserves a trial of levodopa
-If L-dopa doesn’t work, get an MRI, refer
-Do not miss DIP or NPH
VASCUL
AR
Parkinson’s Disease
EARLY DETECTION?
MEDICAL MANAGEMENT/
AVOIDING PITFALLS
SURGICAL MANAGEMENT
PRE-MOTOR PARKINSON’S
PD is not just a
motor disease….
Non-motor symptoms
appear first.
By the time the first
motor symptoms
appear, 70% of
dopaminergic activity
is gone
Braak H et al. Staging of brain pathology related to
sporadic Parkinson’s dosease/. Neurobiol Aging
2003;24:197-211.
Schapira AH et al. Perspectives on recent advances in
the understanding and treatment of Parkinson’s disease.
Eur J Neurol. 2009;16:1090-1099.
iPD vs. PDD vs. DLBD: lumper or splitter?
PRE-MOTOR DETECTION?
GENETIC TESTING
TISSUE BIOPSY for a-synuclein
COLON
SALIVARY GLAND
BIOMARKERS
OLFACTORY TESTING (e.g. UPSIT)
OCT
VOICE ANALYSIS
SCREENING FOR REMBD,
DEPRESSION, CONSTIPATION
IMAGING
DaT and other radioligands
DTI (Diffusion Tensor Imaging), 7T MRI?
MIBG SPECT (cardiac)
Transcranial U/S
“SWALLOW TAIL SIGN”
PREVENTION? DISEASE
MODIFICATION?
CAUSE(S) of iPD are still not well understood.
-Genetic studies: hints to abnormal protein
handling
-”prion-like” spread of abnormal protein
aggregation (a-synuclein -> Lewy Bodies)
NO KNOWN PREVENTION (and by motor stage, the
“horse is out of the barn”)
PREMOTOR (or PRECLINICAL?) DETECTION +
DISEASE MODIFICATION
(or halting progression?) vs. “replacement therapy” (i.e.
stem cell implantation)
PREVENTION? DISEASE
MODIFICATION?
a-synuclein VACCINATION?
Monoclonal Ab? (block “transmission” of misfolded
a-synuclein
EARLY MAO-B INHIBITION?
EXERCISE/ DIET? CAFFEINE?
PD-MEDICATIONS
 DOPAMINERGIC
 L-Dopa (Sinemet, Stalevo, Parcopa)
 DA Agonists (Pramipexole, Ropinirole, Rotigotine,
Apomorphine)
 MAO-B inhibitors (Selegiline, Zydis Selegiline,
Rasagiline)
 COMT inhibitors (Entacapone, Tolcapone)
 OTHER
 Anticholinergics (Trihexphenidyl, Benztropine,
Procyclidine, Profenamine, Orphenadrine)
 Amantadine
Sites of Action of Parkinson’s Disease Drugs
Periphery
Brain
Blood-Brain
Barrier
Neuron
COMT 3-OMD
Inhibitors
L-DOPA
L-DOPA
MAO-B
Inhibitors DOPAC
AADC
Carbidopa
DA
DA
DA
DA
DA
DA
Dopamine receptors
3-OMD=3-O-methyldopa
*Only tolcapone inhibits COMT in brain.
DA
COMT 3-MT
Inhibitor*
Dopamine
agonists
PD MEDS
• L-dopa- still the gold standard, most “bang for
buck” with fewest side effects, cheapest cost, but
short-acting; may lead to motor fluctuations
• DA agonists- helps reduce/ delay motor
fluctuations but higher side-effect to efficacy ratio
compared to levodopa
• COMT inhibitors- used only as adjunct to
levodopa to reduce motor fluctuations
• MAO-B inhibitors- initial or adjunctive therapy
?disease modifying? (see below)
Sinemet (carbidopa/levodopa)- the
“Gold Standard”
Dopamine precursor
Administered with carbidopa to prevent
peripheral conversion of dopamine
Several formulations- KNOW DOSES and TIMES!
IR 10/100, IR 25/100, IR 25/250, CR 25/100, CR 50/200
Stalevo 50, 75, 100, 125, 150, 200
CR (controlled release) vs. IR (regular)
CR is 30% less efficacious, less predictable absorption, does not
prolong ON time, but gentler profile
Tolosa et al. Neurology. 1998;50 (suppl 6):S2-S10; discussion S44-S48.
Olanow et al. Neurology. 2001;56 (suppl 5):S1-S88.
Jankovic and Tolosa. Parkinson’s Disease and Movement Disorders. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1998:177-190.
Sinemet (carbidopa-levodopa). Complete prescribing information. Merck & Co. Inc.; Bristol-Myers Squibb Co.; April 2002.
Barbosa et al. Psychiatr Clin North Am. 1997;20:769-790.
DOPAMINE AGONISTS
• Older (ergots cause cardiac valve fibrosis)
– Bromocriptine and Pergolide no longer used in PD
• Newer
–
–
–
–
Rotigotine (Neupro patch) back on the market
Pramipexole (Mirapex) and Mirapex XR
Ropinirole (Requip) and Requip XL
Apomorphine (Apokyn) injections (nasal spray?)
PROS: longer lasting, lessens/ postpones motor
fluctuations and need for levodopa
CONS: more dopaminergic side effects, weaker than
levodopa, more expensive
Common Side Effects of
Dopaminergic Drugs
(and what to do about them!)
• Nausea
– slow titration, small amount of non-protein food
– avoid reglan, compazine, phenergan; can use lodosyn, tigan,
zofran; ?sinemet CR?
• Drowsiness – beware “sleep attacks” and driving
– slow titration, treat any sleep disorders, use stimulants
• Dizziness - often due to low BP (orthostatic
hypotension)
– lower BP meds, stop/ decrease DA agonists, smaller more
frequent doses of sinemet
– increase fluid/ salt intake, drink water with sinemet, compression
stockings, florinef/ midodrine
Common Side Effects of
Dopaminergic Drugs
(and what to do about them!)
• Confusion/ Hallucinations
– Decrease DA agonists, anticholinergics/ amantadine +/- sinemet
– Add seroquel or memory drugs (avoid haldol, risperdal, abilify, etc.)
• Dyskinesias
– Decrease sinemet, smaller more frequent doses
– Add adjuncts such as Azilect, Comtan to lessen wearing off, or
Amantadine to lessen dyskinesia
• Compulsive behavior
– Decrease/ stop dopamine agonists
– Antidepressants, counseling
• Leg swelling
– Decrease/ stop dopamine agonists, compression stockings,
diuretics
MAO-B INHIBITORS
• Slows breakdown of both endogenous and
exogenous dopamine
• Benign side effect profile (OK with normal diet,
SSRIs, etc), but only mild symptomatic benefit
• Mainly useful as symptom stabilizer and prolonging
duration of levodopa effect (less wearing off)
• Available formulations
– Selegiline (Eldepryl)
• Amphetamine metabolites
– Zydis selegiline (Zelapar)
– Rasagiline (Azilect)
Mean % Change in Total UPDRS
TEMPO: Mean Change in Total
UPDRS at 6-Year Follow-Up
*
ITT Population (n = 404)
80
Delayed Start
70
*
Early treatment
*
60
* P<0.05
*** P<0.001
50
*
40
30
*
***
20
*
10
Years
0
0.0
0.5
(n=404)
1.0
1.5
(n=324)
2.0
2.5
(n=272)
3.0
3.5
(n=237)
4.0
4.5
(n=206)
5.0
5.5
(n=164)
Overall difference between Early and Delayed Start Rasagiline groups is 16% (P=0.006)
Hauser RA, et al. Mov Disord. 2008;24:562-571.
6.0
OTHER PD MEDS
• Amantadine– Flu drug: helps mainly rest tremor and
levodopa-induced dyskinesias,
– not great in elderly- hallucinations, leg
swelling, kidney problems?
• Anticholinergics (e.g. trihexphenidyl)
– helps mainly rest tremor, slight effect on
rigidity, no help to bradykinesia,
– high risk of side effects (memory problems,
constipation, dry mouth, blurry vision)
Initiation of Drug Tx for PD
Treat or Wait?
Very mild Sx: ?Wait
and reassess
periodically
Mild Sx: start MAO-B
inhibitor
Adapted from Schapira AHV, Arch
Neurol. Aug 2007;64(8): 1083-8
Mild-Mod Sx, no
dementia: start DA
agonist
Mod-Severe disability,
elderly or with
significant comorbidity:
start levodopa
PD Treatment:
Continuum of Interventions
Disease Severity
Mild
Moderate
Severe
Signs of levodopa Dyskinesia, “On- Postural Instability,
Freezing, Falls,
Off” Motor
“wearing-off”
Patient Symptoms
Fluctuations
Treatment
Agonists,
MAOB Inhib
Levodopa, COMT
inhibitors, others
DBS
Modified from Giroux, ML and Farris, SF. Cleveland Clinic Foundation 2005
Cleveland Clinic Foundation, Center for Neurological Restoration
Dementia
How does DBS work?
Uses an implanted electrode to deliver high-frequency electrical
stimulation to structures involved in the control of movement
This electrical stimulation helps control motor symptoms by overriding
abnormal neuronal activity within these brain regions
DBS lessens motor fluctuations
Dyskinesia
“On” Time
“Off” Time
This graph is only for illustrative purposes and
does not represent actual “on” and “off” time.
Before
After
DBS, YES or NO?
Good function on meds, but disabling motor fluctuations
(wearing off, failed doses, dyskinesias) or Refractory
tremor
EFFECTIVE: “BETTER THAN BEST MEDICAL TX”
•5 hours/day more ON time without dyskinesia, 80-90% tremor
suppression
•Reduce medication doses 20-70%, side effects
•Can help some nonmotor symptoms such as sleep, bladder function,
weight loss
WHAT IT CANNOT DO:
Does NOT slow down/ cure PD, allow patients to quit all meds
Does NOT make patients better than their best ON state
Does NOT help certain symptoms of PD that do not respond to levodopa,
such as memory and certain types of balance, speech problems
QUIZ POST
1. The diagnosis is idiopathic Parkinson’s Disease
a. Yes
b. No (MSA)
2. The next steps should include
a. Order DaT scan (does not differentiate between
PD and MSA)
b. Do ON/ OFF levodopa challenge (<40%
improvement with adequate dose is a red flag)
3. She is an appropriate candidate for DBS
a. Yes
b. No
SUMMARY
COMMITMENTS TO CHANGE
Know when MRIs, DaT scans are indicated
Try levodopa on patients with parkinsonism, avoid neuroleptics
(including anti-emetics) on patients with parkinsonism
The best medical treatment for a PD patient evolves as disease
progresses, and depends on symptoms vs. side effects.
Management of non-motor symptoms just as important.
Refer to specialist if you see “red flags” or if med management
is suboptimal (patient may be a candidate for surgery)