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)