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 Objectives

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]

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]

UK PDSBB Clinical Diagnostic Criteria Diagnostic Accuracy Initial study a : 100 cases with PD diagnosed prospectively 76% accuracy on autopsy Criteria applied retrospectively improved accuracy to 82% Follow-up study b : 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. Kägi 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 PD a Areas of Clinical Uncertainty b-f Definite ET g Asymmetric tremorMixed tremor typesSymmetric tremor Resting tremorQuestionable 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 + 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 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-up a ~26% of patients receiving antiparkinsonian medication did not have a parkinsonian syndrome b A previous diagnosis of ET was rejected in 37% of patients using standardized criteria c 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 Presentation

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 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 Imaging Presynaptic radioligands DOPA decarboxylase (measures dopamine synthesis) DAT (provides measure of functioning dopaminergic terminals) VMAT-2 (marker for dopaminergic terminals) Postsynaptic radioligands D 2 receptor Amino Acid Transporter Mitochondrion VMAT-2 Vesicle DAT Dopamine D 2 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?

Dopaminergic Imaging vs Normal DiagnosisFindings 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 ETNo alterations in dopamine function Drug-induced parkinsonismNo alterations in dopamine function Psychogenic parkinsonismNo alterations in dopamine function Alzheimer diseaseNo alterations in dopamine function 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 NormalEarly 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 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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