Is It Essential Tremor or a Parkinsonian Syndrome?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

• 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 ObjectivesLearning Objectives

Epidemiology of PD in the United StatesEpidemiology 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

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

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]

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 CriteriaUK PDSBB Clinical Diagnostic Criteria Step 3: Supportive Positive Criteria

Hughes AJ, et al.[3]

UK PDSBB Clinical Diagnostic Criteria Diagnostic AccuracyUK 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 StudiesDiagnostic 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 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 SyndromesParkinsonian 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]

What Is ET?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 TremorOther Causes of Tremor

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

Manifestations of ETManifestations 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?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?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 UncertaintyAreas 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 SymptomsPD 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]

Misdiagnosis of ET and PD Is CommonMisdiagnosis 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]

• 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 PresentationCase Presentation

Case Presentation (cont)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 LigandsSPECT 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

Dopamine System ImagingDopamine System Imaging

Presynaptic radioligandsDOPA decarboxylase(measures dopamine synthesis)

DAT(provides measure of functioning dopaminergic terminals)

VMAT-2(marker for dopaminergic terminals)

Postsynaptic radioligandsD2 receptor

Amino Acid Transporter

Mitochondrion

VMAT-2Vesicle

DAT

Dopamine

D2 Receptor

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

• 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?Who Benefits From Diagnostic Imaging?

Dopaminergic Imaging vs NormalDopaminergic Imaging vs Normal

Diagnosis Findings on Dopaminergic ImagingParkinson disease Reduced striatal dopamine synthesis

Reduced dopamine storageReduced dopamine releaseReduced dopamine transporter

Dementia with Lewy bodies, PD with dementia, MSA, PSP, corticobasal degeneration

Reduced striatal dopamine synthesisReduced dopamine storageReduced 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.

Case ConclusionCase 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 PDSPECT Images: Normal vs PD

Normal Early PD

SummarySummary

• 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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