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. RIGIDITYB. 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 FOLLOWINGA. UNILATERAL ONSET *remains asymmetricB. REST TREMORC. PROGRESSIVE DISORDERD. PERSISTENT ASYMMETRY (first side worse)E. EXCELLENT RESPONSE to L-DOPA (70-100%)F. SEVERE L-DOPA-INDUCED CHOREA *fluctuations
not specificG. L-DOPA RESPONSE >5 YEARSH. 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 tremorsIt is the bradykinesia/ rigidity that defines
parkinsonism
ALGORITHIM forPARKINSONISM
DIAGNOSTIC ACCURACY: LOWAAN 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 SCANDopamine 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?)
MSAMULTIPLE 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 Subtypes1. 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 fallingSevere dysarthria and dysphoniaRespiratory stridorAnterocollisPyramidal signs
MSA/ PD-PATHOLOGY
Papp et al. (1989):
Neural and Filamentous -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. PDSIGNSIGN MSAMSA PDPD
AUTONOMICAUTONOMIC ++/+++++/+++ ++
CEREBELLAR/ CEREBELLAR/ PYRAMIDAL/ PYRAMIDAL/ PERIPHERALPERIPHERAL
++/+++++/+++
FALLSFALLS EARLYEARLY LATELATE
DEMENTIADEMENTIA ++ +/+++/++
LEVODOPA LEVODOPA RESPONSERESPONSE
+ + TRANSIENTTRANSIENT
+++ +++ PERSISTENTPERSISTENT
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
SIGNSIGN PSPPSP PDPDEYE MVTsEYE MVTs EYE BLINKINGEYE BLINKING FALLSFALLS +++ +++ EARLYEARLY + + LATELATE
REST TREMORREST TREMOR MAJORITYMAJORITY
AXIAL RIGIDITYAXIAL RIGIDITY ++++++ +/+++/++LEVODOPA LEVODOPA RESPONSERESPONSE
+++ +++ CONSISTENTCONSISTENT
CBSCORTICOBASAL 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. PDSIGNSIGN CBDCBD PDPD
ASYMMETRYASYMMETRY ++++++ ++
RIGIDITYRIGIDITY ++++++ ++++
APRAXIAAPRAXIA ++++++ --
LEVODOPA LEVODOPA RESPONSERESPONSE
+/-+/- ++++++
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 PARKINSONISMInfectious/ 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 incontinence2.Subcortical dementia3.“Magnetic gait”: wide-based, slow/ shuffly, freezing
CSF acqueductal flow MRIHigh-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)
Manganese Poisoning T1 Globus PallidusCarbon Monoxide ( T2
putamen)
“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 forPARKINSONISM
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
Parkinson’s Disease
EARLY DETECTION?
MEDICAL MANAGEMENT/ AVOIDING PITFALLS
SURGICAL MANAGEMENT
PRE-MOTOR PARKINSON’S
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.
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
iPD vs. PDD vs. DLBD: lumper or splitter?
PRE-MOTOR DETECTION?GENETIC TESTINGTISSUE BIOPSY for -synuclein
COLONSALIVARY GLAND
BIOMARKERSOLFACTORY TESTING (e.g. UPSIT)OCTVOICE ANALYSISSCREENING FOR REMBD, DEPRESSION, CONSTIPATION
IMAGINGDaT and other radioligandsDTI (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 (-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?
-synuclein VACCINATION?
Monoclonal Ab? (block “transmission” of misfolded -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
Dopamine receptors
DADA
Blood-BrainBarrier
L-DOPAL-DOPA
Periphery Brain
3-OMD3-OMD
DADA
DopamineDopamineagonistsagonists
*Only tolcapone inhibits COMT in brain.
Neuron
COMT COMT InhibitorsInhibitors
CarbidopaCarbidopa
MAO-BMAO-B InhibitorsInhibitors DOPACDOPAC
DA DA
3-MT3-MT
L-DOPAL-DOPA
DADA
DA DA
AADCAADC
DADA
DADACOMTCOMT
InhibitorInhibitor**
3-OMD=3-O-methyldopa
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 precursorAdministered 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)
**
*
*
*****
80
70
60
50
40
30
20
10
0
Mean % Change in Total UPDRS
0.0 0.5 1.0 3.0 4.0 5.0 6.02.0
Years
* P<0.05*** P<0.001
Hauser RA, et al. Mov Disord. 2008;24:562-571.
1.5 3.5 4.5 5.52.5(n=404) (n=324) (n=237) (n=206) (n=164)(n=272)
ITT Population (n = 404)
Overall difference between Early and Delayed Start Rasagiline groups is 16% (P=0.006)
Delayed Start
Early treatment
TEMPO: Mean Change in Total UPDRS at 6-Year Follow-Up
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
Adapted from Schapira AHV, Arch Neurol. Aug 2007;64(8): 1083-8
PD Treatment: Continuum of Interventions
Modified from Giroux, ML and Farris, SF. Cleveland Clinic Foundation 2005Cleveland Clinic Foundation, Center for Neurological Restoration
Signs of levodopa“wearing-off”
Dyskinesia, “On-Off” Motor
Fluctuations
Postural Instability, Freezing, Falls, Dementia
DBS
Mild Moderate Severe
Levodopa, COMT inhibitors, others
Treatment
Patient Symptoms
Disease Severity
Agonists, MAOB Inhib
How does DBS work?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.
After
Before
DBS, YES or NO?Good function on meds, but disabling motor fluctuations (wearing off, failed doses, dyskinesias) or Refractory tremor
EFFECTIVE: EFFECTIVE: ““BETTER THAN BEST MEDICAL TXBETTER THAN BEST MEDICAL TX””•5 hours/day more ON time without dyskinesia, 80-90% tremor 5 hours/day more ON time without dyskinesia, 80-90% tremor suppressionsuppression•Reduce medication doses 20-70%, side effectsReduce medication doses 20-70%, side effects•Can help some nonmotor symptoms such as sleep, bladder Can help some nonmotor symptoms such as sleep, bladder function, weight lossfunction, weight loss
WHAT IT CANNOT DOWHAT IT CANNOT DO::Does NOT slow down/ cure PD, allow patients to quit all medsDoes NOT slow down/ cure PD, allow patients to quit all medsDoes NOT make patients better than their best ON stateDoes NOT make patients better than their best ON stateDoes NOT help certain symptoms of PD that do not respond to levodopa, Does NOT help certain symptoms of PD that do not respond to levodopa, such as memory and certain types of balance, speech problemssuch as memory and certain types of balance, speech problems
QUIZ POST1. The diagnosis is idiopathic Parkinson’s Disease
a. Yesb. No (MSA)
2. The next steps should includea. 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 DBSa. Yesb. No
SUMMARYCOMMITMENTS TO CHANGEKnow 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)