Essential Tremor: Classification, Diagnosis, and Management

Paul Cullis, MD
Chief, Department of Neurology St. John Health System

Tremor Defined
An involuntary, rhythmic, oscillatory, sinusoidal movement of a part or parts of the body Produced by contractions of alternating or synchronous antagonist muscles

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Classification of Tremor
Rest tremor Action tremor
Postural tremor
Reemergent tremor

Kinetic tremor
Initial tremor Dynamic tremor Terminal tremor

Task- or position-specific tremor Isometric tremor

Internal tremor
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Clinical Classification of Tremors

NIH: Collaborative Genetic Criteria (1996) Tremor Investigation Group (TRIG) (1995) Consensus Statement of the Movement Disorder Society (MDS) (1997)
Use of such clinical classifications stimulates discussions and thus contributes to the development of tremor research.
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Clinical Classification of Tremor Based on...

Phenomenology: rest; action as in postural, kinetic (including simple kinetic or intention), or isometric Anatomic or topographic distribution Activities that activate tremor Relative frequency of tremor (cycles per second) Medical history/evaluation/current medications (primary/secondary tremor)

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Syndromic Classification of Tremor

Deuschl G, Bain P, Brin M, and an Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13 (suppl 3):2-23.

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Syndromic Classification of Tremor, (contd)

Deuschl G, Bain P, Brin M, and an Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13 (suppl 3):2-23.

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ET Anatomic Distribution (n=350)

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Classification Based on Activation Condition

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Classification of Tremor Based on Relative Frequency (Hz)

Frequency in Hz
2.4 - 4.0 4.0 - 4.5 5.5 - 7.0 7.0 - 12.0 Typical Etiology
Cerebellar, ataxic (brainstem,MS) PD (rest), rubral, neuroleptic-induced ET, PD (postural), drug (VPA), voluntary (max. 6 Hz) Physiological, exaggerated physiologic, drug-induced (e.g., epinephrine)

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NIH Collaborative Genetic Criteria Tremor Severity Scale

0 = none 1 = minimal (barely noticeable) 2 = obvious, noticeable but probably not disabling (<2 cm excursions) 3 = moderate, probably partially disabling (2 cm to 4 cm excursions) 4 = severe, coarse, and disabling ( >4 cm excursions)
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NIH Collaborative Genetic Criteria: Definite ET

2+ amplitude rating for bilateral arm tremor, Or 2+ amplitude rating in one arm and 1+ amplitude rating in other arm, Or 1+ amplitude rating in at least one arm and predominant cranial/cervical tremor with 2+ amplitude rating
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NIH Collaborative Genetic Criteria: Probable ET

1+ bilateral arm tremor Or Isolated 2+ cranial/cervical tremor Or Convincing history of ET Exclude: obvious secondary causes
(e.g., physiologic, drug-induced, CMT, etc.)
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NIH Collaborative Genetic Criteria: Possible ET

Isolated 1+ cranial/cervical tremor Or Task- or position-specific arm tremor Or Unilateral arm tremor Or Orthostatic tremor
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NIH Collaborative Genetic Criteria: Unrateable ET

Tremor is coexistent with:
Other neurologic disease Therapy with anti-tremor or tremorogenic drugs Untreated thyroid disease Coffee withdrawal or abstention, etc.

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Tremor Consensus Statement

Clinical diagnostic framework for tremor:
Nomenclature Definitions based upon phenomenology Work-up/evaluation Rating scales Differential diagnosis Supporting technical investigations

Deuschl G, Bain P, Brin M, and an Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13 (suppl 3):2-23.

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Classic ET: Inclusion Criteria

Bilateral, largely postural or kinetic tremor involving the hands and forearms Tremor is persistent and visible Or Additional or isolated tremor of the head in the absence of abnormal posturing

Deuschl G, Bain P, Brin M, and an Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13 (suppl 3):2-23.

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Classic ET: Exclusion Criteria

1. Other abnormal neurologic signs (especially dystonia) 2. Presence of known causes of enhanced physiologic tremor 3. Historical or clinical evidence of psychogenic tremor 4. Convincing evidence of sudden onset or stepwise deterioration
(Kiel, Germany; MDS Symposium, July 1997)

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Classic ET: Exclusion Criteria, (contd)

5. Primary orthostatic tremor 6. Isolated voice tremor 7. Isolated position- or task-specific tremors 8. Isolated tongue or chin tremor 9. Isolated leg tremor

(Kiel, Germany; MDS Symposium, July 1997)

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Essential Tremor: Red Flags/Epidemiology

Core Criteria for Identifying ET

1.Bilateral action tremor of the hands and forearms (but not rest tremor) 2.Absence of other neurologic signs, with the exception of the cogwheel phenomenon 3.May have isolated head tremor with no abnormal posture
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Secondary Criteria for Identifying ET

1.Long duration (>3 years) 2.Family history 3.Beneficial response to ethanol

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Red Flags
1.Unilateral tremor, focal tremor, leg tremor, gait disturbance, rigidity, bradykinesia, rest tremor 2.Sudden or rapid onset 3.Current drug treatment that may cause or exacerbate tremor 4.Isolated head tremor with abnormal posture (head tilt or turning)
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Epidemiology: Case Ascertainment

Patients may not seek medical evaluation if
Tremor is mild; associated with no functional disability; accepted as a part of life Improperly attributed to old age Associated social disability from tremor is not regarded as serious Patients are unaware that effective treatment options are available
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Epidemiology: Case Ascertainment, (contd) Tremor frequently misdiagnosed: If mild ==> anxiety or neurosis If severe ==> Parkinsons disease Larson: 1 in 210 individuals contacted the hospital for treatment Rautakorpi: 1 in 10 individuals sought treatment
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Challenge to determine true frequency of ET in general population due to... Variation in the clinical criteria Lack of consensus on the definition of ET Difficulty in differentiating between mild forms of ET and exaggerated physiologic tremor (EPT) Difficulties in classifying tremor when it is associated with other conditions (e.g., dystonia and parkinsonism)
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Rajput: Incidence of ET
90 80 70 60 50 40 30 20 10 0 0-19 20-39 40-59 50-59 60-69 70-79 Age at Inciden
Brin M, Koller W. Epidemiology and genetics of essential tremor. Mov Disord 1998;13 (Suppl 3):55-63.

Number pe 100,000

80+

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Rajput: ET in Rochester, MN, USA

1935 to 1979 (45-year study) Age at Dx: mean of 58 (2 to 96 years) Incidence: 23.7/100,000 (M=F) Prevalence: 305.6/100,000 Cervical dystonia in 3% Subsequent PD diagnosis in 2% Family history of tremor in 39%
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Salemi: Prevalence of ET
6000 5000 4000 Prevalence per 3000 100,000 2000 1000 0 0-19 20-39 40-59 60-69 70-79 Age at Incidenc 80-89 90+

Salemi G, Savettieri G, Rocca WA, et al. Prevalence of essential tremor: a door-to-door survey in Terrasini, Sicily. Neurology. 1994;44:61-64.

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Prevalence Studies (1)

Larson, 1960 (Sweden): 1.7%; 3.73% over age 40. (field investigations/interviews) Hornabrook, 1976 (New Guinea): 0.35%; 1.64% over age 40 (screenings/examinations) Rautakorpi, 1978/82 (Finland): 5.55% over age 40 (personal interviews/surveys. More examined if +Hx) Haerer, 1981 (Copiah County, USA): ~0.4% over age 40 (door-to-door surveys) Rajput, 1984 (USA): 0.31 (medical records)

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Prevalence Studies (2)

Osuntokun, 1987 (Nigeria): 0.01% (door-to-door surveys; exams by teachers) Bharucha, 1988 (India): 1.7%; 2.8% over age 40 (door-to-door surveys) Salemi, 1994 (Italy): 0.4%; 1.1% over age 40 (door-to-door surveys; questionnaires, exams) Louis, 1995 (NY, USA): 4.0% (M > F) (survey==>examined if +Hx; + videotape assessment) Louis, 1999 (USA): 0.4% to 3.9% (crude)
N.B. Issues related to ascertainment bias

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Age Onset Essential Tremor: New York

Brin MF, Koller W. Epidemiology and genetics of essential tremor.

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Essential Tremor: Genetics/Pathophysiology

Genetics of ET
Familial nature noted by many including:
Most (1836) Dana (1887) Critchley (1949) Louis (1998) Findley (2000)

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Genetics of ET, (contd)

Autosomal dominant pattern of inheritance FET1 and ETM Family history reported in >50% of patients

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ET versus Other Tremor Types

Historical reviews Clinical examination Evaluation of coexistent tremors

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ET as a Central Tremor
Arises from a central oscillatory activity within a central network or cell group that enters an oscillatory mode

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ET: Complex Model

Interconnected oscillatory loops in the nervous system Oscillations in the olivo-cerebello-rubral loop
release normal dampening influences allow spinal reflex loop oscillations

PET: abnormal olivo-cerebellar tracts in ET

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CNS Influences on a Limb

Hallet M. Overview of human tremor physiology. Mov Disord 1998;13 (suppl 3):43-48.

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ET: Pathophysiology
C15-labeled O2 PET demonstrated marked increased blood flow to both cerebellar hemispheres and midbrain activation in region of red nucleus No established structural lesion in ET fMRI confirmed increased activation of the cerebellum and red nucleus Abnormalities in tandem gait suggestive of cerebellar dysfunction

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Peripheral Contributors
Beta-adrenergic blockers attenuate ET and postural tremor, possibly via beta2 skeletal muscle adrenoreceptors (betablockers may also affect central pathways) Peripheral injuries may induce or precipitate tremor IV and intra-arterial epinephrine enhance PT via peripheral forearm beta-adrenoreceptors; blocked by propranolol

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Essential Tremor: Diagnosis/Differential Diagnosis

Diagnosis of ET
Clinical history/family history Physical examination (including QOL/disability, etc.) Absence of abnormal laboratory findings (normal TFT, serum ceruloplasm, etc.) Current medications Effect of ETOH Archimedes spiral; handwriting test; water test; peg board; CT scan (when warranted)

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Archimedes Spiral

Methods of Measuring Tremor

Physiologic techniques (e.g., accelerometry, EMG, digitizing tablets, or gyroscopic techniques) Subjective clinical measures (e.g., rating scales, spiral drawings, or handwriting) Objective functional performance tests (e.g., water spilled from cup, nine-hole pegboard test, maze tests) Impact of tremor on patients lives (e.g., disability, handicap, quality of life, or burden of illness)

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Functional Disability Associated with ET May Affect...

Handwriting Ability to drink liquids from a cup or glass Precise, fine manipulations of the hands Capability to feed oneself Ability to dress Speech (i.e., dysarthria as in voice tremor) Social interactions leading to embarrassment

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Accelerometry for ET
Autospectra obtained by accelerometry from a patient with ET (frequency plotted against root-mean-square [rms] acceleration [g x 10-3])

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Clinical Characteristics of ET

Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology. 1991;41(Pt 1):234-238.

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Waveforms of a Normal Subject and a Patient with ET

Differential Diagnosis
Parkinsons disease (PD) Pallidonigral degeneration Multiple system atrophy (MSA) Olivopontocerebellar atrophy (OPCA) Striatonigral degeneration Progressive pallidal atrophy Huntingtons disease (HD) Benign hereditary chorea
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Differential Diagnosis, (contd)

Fahrs disease Paroxysmal dystonic choreoathetosis (PDC) Ataxia-telangiectasia (AT) Familial intention tremor and lipofuscinosis Ramsay-Hunt syndrome
(progressive myoclonic ataxia)

Dystonia musculorum deformans DOPA-responsive dystonia

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Differential Diagnosis, (contd)

Cervical dystonia (spasmodic torticollis) Meige syndrome Task-specific tremors (writers or voice tremor) Space-occupying lesions of the brain Various metabolic diseases
(e.g., hepatic encephalopathy, etc.) (e.g., Charcot-Marie-Tooth, Guillain-Barr, etc.)
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Peripheral neuropathies

Essential Tremor and Parkinsons Disease

ET: Overlap with PD

ET and PD are among the most common movement disorders ET is considered the most prevalent movement disorder in the U.S. ET/PD: Pathophysiological relationship not established 2% to 19% of ET patients report parkinsonism
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ET: Overlap with PD

10% of ET patients have a positive family history of PD PD more common in ET and kindreds than otherwise expected: Geraghty and Jankovic (1985). Lang (1986). Koller (1994). ET patient may develop striatonigral deficiency: Lee (1999). Farrer et al. (1999).
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ET in Family Members of PD Patients

Higher Incidence:
Geraghty and Jankovic (1985) Lang et al. (1986) Jankovic et al. (1995)

Same as controls:
Duvoisin et al. (1969) Martilla and Rinne (1976) Roy et al. (1983) Cleeves et al. (1988) Martilla and Rinne (1988)

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ET and PD: Epidemiologic Investigations

No association:
Larsson and Sjgren (1960) Martilla and Rinne (1976) Martilla et al. (1984) Rajput et al. (1984) Martilla and Rinne (1988) Pahwa and Koller (1993) Bain (1994) Errea-Abad et al. (1998)
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ET and PD: Epidemiologic Investigations

Possible association:
Hornabrook and Nagurney (1976) Jankovic and Geraghty (1985) Jankovic et al. (1995)

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PD and ET

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PD and ET

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Tremor Due to PD and ET

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Essential Tremor: Additional Resources

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