1. 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

2. • 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
Learning Objectives

3. 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]

4. 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]

5. 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]

6. 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
UK PDSBB Clinical Diagnostic Criteria
Step 3: Supportive Positive Criteria
Hughes AJ, et al.[3]

7. 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]

8. 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]

9. 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

10. 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. Kägi G, et al[7]
; c. Thanvi B, Treadwell S[8]
; d. Thanvi B, et al.[9]

11. 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

12. Other Causes of Tremor
• Medication induced
• Electrolyte imbalance
• Thyroid dysfunction
• PD
• Posttraumatic tremor
• MS-related tremor
• Other neurologic conditions

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

14. 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]

15. 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

16. Areas of Uncertainty
Definite PDa
Areas of Clinical
Uncertaintyb-f
Definite ETg
Asymmetric tremor Mixed tremor types Symmetric tremor
Resting tremor Questionable bradykinesia Postural and kinetic
(action) tremor
Bradykinesia Questionable response to
dopaminergic therapy
Voice or head tremor
Rigidity Family history of tremor
Ambiguous/Overlapping Symptoms
PD symptoms
+ postural and kinetic tremors
ET symptoms
+ symmetric tremor
+ symmetric tremor + rest tremor
+ no bradykinesia + cogwheeling present
+ no rigidity
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]

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]

18. • 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

19. 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

20. SPECT and PET Ligands
• The most commonly used SPECT ligands
bind to the striatal presynaptic membrane-
associated 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

21. 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
Amino Acid
Transporter
Mitochondrion
VMAT-2
Vesicle
DAT
Dopamine
D2 Receptor
Cummings JL, et al.[21]
Adapted with permission.

22. • 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
Who Benefits From Diagnostic
Imaging?

23. Dopaminergic Imaging vs Normal
Diagnosis Findings on Dopaminergic Imaging
Parkinson disease Reduced striatal dopamine synthesis
Reduced dopamine storage
Reduced dopamine release
Reduced dopamine transporter
Dementia with Lewy bodies, PD
with dementia, MSA, PSP,
corticobasal degeneration
Reduced striatal dopamine synthesis
Reduced dopamine storage
Reduced dopamine transporter
Vascular parkinsonism Possible variable reductions in
dopamine function
ET No alterations in dopamine function
Drug-induced parkinsonism No alterations in dopamine function
Psychogenic parkinsonism No alterations in dopamine function
Alzheimer disease No alterations in dopamine function
Cummings JL, et al.[21]
Republished with permission.

24. 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

25. SPECT Images: Normal vs PD
Normal Early PD

26. 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 patient’s 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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