Is It Essential Tremor or a Parkinsonian Syndrome?

Diagnostic Considerations in Primary Care Faculty

Tanya Simuni, MD
Director, Parkinson's Disease and Movement Disorders Center Northwestern University Chicago, Illinois

Learning Objectives
Outline challenges to accurate and timely diagnosis of Parkinson disease (PD) in the primary care setting Compare clinical signs and symptoms of PD and other parkinsonian syndromes with those of essential tremor Recognize when neuroimaging is appropriate in the diagnostic workup of patients with suspected parkinsonian syndromes

Epidemiology of PD in the United States

1 million patients have PD Annual incidence:15-20 per 100,000
50,000-60,000 new cases per year

Prevalence increases with age (per 100,000)

40-49 years: 23 70-79 years: 525 80-89 years: 1145

More common in whites vs blacks or Asians More common in Midwest and Northeast vs other regions; more common in urban vs rural counties
Watts RL, et al[1]; Willis AW, et al. [2]

UK PDSBB Clinical Diagnostic Criteria Step 1: Diagnosis

Bradykinesia At least 1
Muscular rigidity 4-6 Hz rest tremor Postural instability
Not visual Not vestibular Not cerebellar

Not sensory

Hughes AJ, et al.[3]

UK PDSBB Clinical Diagnostic Criteria Step 2: Exclusion Criteria

History of repeated strokes, repeated head injury, or definite encephalitis Oculogyric crises Neuroleptic treatment at onset of symptoms Sustained remission Strictly unilateral after 3 years

Supranuclear gaze palsy

Cerebellar signs; early autonomic involvement Early, severe dementia; Babinski sign Cerebral tumor or hydrocephalus on CT

MPTP exposure
Poor response to levodopa
Hughes AJ, et al.[3]

UK PDSBB Clinical Diagnostic Criteria Step 3: Supportive Positive Criteria

3 or more required for definite diagnosis
Unilateral onset Rest tremor Progressive disorder Persistent asymmetry, worse on onset side 70%-100% response to levodopa Severe levodopa-induced dyskinesias Levodopa response 5 years Disease course 10 years

Hughes AJ, et al.[3]

UK PDSBB Clinical Diagnostic Criteria Diagnostic Accuracy

Initial studya:
100 cases with PD diagnosed prospectively 76% accuracy on autopsy Criteria applied retrospectively improved accuracy to 82%

Follow-up studyb:
Criteria applied prospectively in 100 cases 90% accuracy on autopsy

a. Hughes AJ, et al[3]; b. Hughes AJ, et al.[4]

Diagnostic Accuracy Improves With Disease Duration: Imaging Studies

Proportion of SWEDDs decreases with length of time since diagnosis Clinical trials:
ELLDOPA: 14% SWEDDs at 6 months REAL-PET: 12% SWEDDs at 9 months CALM-PD: 4% SWEDDs at 18 months NIL-A-CIT: 2% SWEDDs at 22 months

SWEDD=scan without evidence of dopaminergic deficit; indicates misdiagnosis of parkinsonism. Seibyl J, et al.[5]

Other Neurodegenerative Disorders With Presynaptic Dopamine Deficiency

More common
Progressive supranuclear palsy Multiple system atrophy Corticobasal ganglionic degeneration Diffuse Lewy body disease

Less common
ALS-Parkinsonism-Dementia/of Guam Alzheimer with extrapyramidal signs Rigid variant of Huntington disease

Parkinsonian Syndromes
Parkinsonian syndromes refer to neurologic disorders associated with a loss of dopamine neurons
PD (~85% of cases of parkinsonism)a MSA (< 5%)a PSP (< 5%)a

Does not include cases of clinical parkinsonism where there is not an associated loss of dopamine neurons
Drug-induced parkinsonism (7%-35% of all cases of parkinsonism)a,b,c

Vascular parkinsonism (~4%-12%)d

Psychogenic parkinsonism (0.17%-0.5%)b

a. Rajput AH, et al[6]; b. Kgi G, et al[7]; c. Thanvi B, Treadwell S[8]; d. Thanvi B, et al.[9]

What Is ET?
ET is a specific neurologic disorder Also known as familial tremor Tremor involves hands, head, voice, sometimes legs and trunk Essential means
There is no other cause for tremor There are no other neurologic signs

Familial means it can be hereditary

Other Causes of Tremor

Medication induced Electrolyte imbalance Thyroid dysfunction PD Posttraumatic tremor MS-related tremor Other neurologic conditions

Manifestations of ET
Symmetric tremor Tremor is the single manifestation (can include hand, vocal, head, trunk, leg tremors) Postural, kinetic (associated with action) tremor

How Common Is ET?

ET is the most common movement disorder
About 5% of people age > 65 y have ET

ET frequently is not diagnosed ET usually starts age 40 y but can be seen in childhood ET symptoms start insidiously and progress slowly ET is not dangerous but can be disabling

Louis ED.[10]

Is ET Related to PD?
NO, NO, NO
ET tremor differs from PD ET patients do not feel slow or stiff ET patients do not have difficulty walking ET does not progress into PD Some patients can have both diagnoses

Areas of Uncertainty
Definite PDa Asymmetric tremor Areas of Clinical Uncertaintyb-f Mixed tremor types Definite ETg Symmetric tremor

Resting tremor
Bradykinesia

Questionable bradykinesia
Questionable response to dopaminergic therapy

Postural and kinetic (action) tremor

Voice or head tremor

Rigidity

Family history of tremor

Ambiguous/Overlapping Symptoms PD symptoms ET symptoms + postural and kinetic tremors + symmetric tremor + symmetric tremor + no bradykinesia + no rigidity + rest tremor + cogwheeling present

a. Lees AJ, et al[11]; b. Hauser RA, et al[12]; c. Pahwa R, et al[13]; d. Hauser RA, et al[14]; e. Solida A, et al[15]; f. Marshall V, et al[16]; g. Bhidayasiri R.[17]

Misdiagnosis of ET and PD Is Common

Clinical studies have found a high level of misdiagnosis of ET and PD
A previous diagnosis of PD was rejected in 15% of patients using standardized criteria and > 1 year follow-upa ~26% of patients receiving antiparkinsonian medication did not have a parkinsonian syndromeb A previous diagnosis of ET was rejected in 37% of patients using standardized criteriac

a. Schrag A, et al[18]; b. Meara J, et al[19]; c. Jain S, et al.[20]

Case Presentation
Woman age 60 y presents for evaluation of a long-standing tremor 7-year history of bilateral symmetric hand tremor that occurs with activity and is especially bothersome when she writes or holds a cup Tremor improves with wine. Her father had a similar tremor Not bothersome but has increased in past several months Recently noticed occasional right-arm tremor at rest

Case Presentation (cont)

Neurologic examination
Bilateral action tremor when she holds a cup Slight rest tremor component in the right arm Trace of increased tone in the right wrist Normal balance and gait

No other medical history

SPECT and PET Ligands

The most commonly used SPECT ligands bind to the striatal presynaptic membraneassociated dopamine active transporter protein Reduction of the dopamine transporter correlates with the loss of presynaptic dopamine Other ligands measure
Vesicular monoamine transport DOPA decarboxylase activity

Dopamine System Imaging

Presynaptic radioligands DOPA decarboxylase (measures dopamine synthesis) DAT (provides measure of functioning dopaminergic terminals) VMAT-2 (marker for dopaminergic terminals) Postsynaptic radioligands D2 receptor

VMAT-2 Vesicle DAT

Amino Acid Transporter

Dopamine D2 Receptor

Mitochondrion

Cummings JL, et al.[21] Adapted with permission.

Who Benefits From Diagnostic Imaging?

Patients with a classic presentation of PD or ET do not require additional diagnostic imaging Dopamine transporter SPECT cannot differentiate different forms of parkinsonism (eg, PD, MSA, PSP) Features that raise concerns about an alternative cause of parkinsonism that could prompt diagnostic imaging
Patients with atypical features that are beyond the scope of a classic PD presentation Patients with poor response to an appropriate trial of dopaminergic therapy

Dopaminergic Imaging vs Normal

Diagnosis Parkinson disease Findings on Dopaminergic Imaging Reduced striatal dopamine synthesis Reduced dopamine storage Reduced dopamine release Reduced dopamine transporter Reduced striatal dopamine synthesis Reduced dopamine storage Reduced dopamine transporter Possible variable reductions in dopamine function No alterations in dopamine function No alterations in dopamine function No alterations in dopamine function No alterations in dopamine function

Dementia with Lewy bodies, PD with dementia, MSA, PSP, corticobasal degeneration Vascular parkinsonism ET Drug-induced parkinsonism Psychogenic parkinsonism Alzheimer disease

Cummings JL, et al.[21] Republished with permission.

Case Conclusion
The patient had a history of long-standing ET supported by a positive family history (present in 50% of patients) and response to alcohol In addition to the bilateral action tremor typical of ET, the examination demonstrates subtle features of asymmetric rest tremor, suggestive of early PD The clinical diagnosis is ET but you are concerned that she may have early PD in addition Two possible approaches
Clinical follow-up to see if she develops clearer features of parkinsonism Obtain a dopamine transporter SPECT scan

Patient elects to have the SPECT scan

SPECT demonstrates normal dopamine uptake ET is confirmed

SPECT Images: Normal vs PD

Normal Early PD

Summary
PD and ET are clinical diagnoses, but symptoms can sometimes overlap, causing misdiagnosis Timely and accurate diagnosis of PD and ET will advance appropriate treatment and improve the patients quality of life Patients with atypical symptoms may benefit from dopamine transporter SPECT to differentiate between a parkinsonian syndrome and ET

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