Clinical Features, Assessment and Treatment of Essential Tremor Abstract JN Panicker*, PK Pal**

Clinical Features, Assessment and Treatment of Essential Tremor Abstract JN Panicker*, PK Pal**

Update Article
Clinical Features, Assessment and Treatment of
Essential Tremor
JN Panicker*, PK Pal**
Abstract
Essential tremor is the most common of the movement disorders, being 20 times more common than
Parkinson’s Disease. It is characterised by postural and kinetic tremor which maximally affects the hands.
It can be assessed by physiological techniques, subjective clinical methods, objective clinical methods and
handicap/disability scales. Accelerometry, spirography and handwriting assessment, volumetry and handicap/
disability questionnaires are commonly used methods. Primidone and propranolol are the first-line drugs.
Several second-line drugs have been identified. Surgical techniques include lesioning or stimulation of the
ventral lateral thalamus. Alcohol and botulinum toxin A are found to reduce tremor amplitude as well.
INTRODUCTION
T
remor is defined as an involuntary, rhythmic oscillation
of a functional body part, produced by alternating or
synchronous contractions of reciprocally innervated agonistic
and antagonistic muscles. Tremors can be classified as rest
or action, and essential tremor is the most important type of
action tremor.1,2
Essential tremor (ET) is the most common movement
disorder, being twenty times more prevalent than Parkinson’s
disease.2 The overall prevalence is 0.4-6% and increases with
age; 1-22% of elderly population suffers from ET.2,3 It is found
in all ethnic groups.4
CLINICAL FEATURES
Inspite of high prevalence of ET, accurate diagnosis has
been hampered by the lack of a consensus diagnostic criteria
and specific disease marker.3,5 It is termed ‘essential’ as there
is no underlying cause. Though it is a monosymptomatic
illness and has been considered as ‘benign’, it may produce
significant functional and social disabilities.2,6 Onset is
bimodally distributed at the 2nd and 6th decade. 2,3 Its
amplitude increases with age, but frequency may decrease
with age.2 There is no gender predilection. It has an insidious
onset with variable progression. Initially there may be a
‘shaky’ feeling inside for several months followed by a stage
of intermittently occurring tremor during periods of
excitement and fatigue, and ultimately tremor becomes
permanent. Exacerbating factors include hunger, fatigue and
*Senior Resident; **Assistant Professor, Department of Neurology,
National Institute of Mental Health and Neurosciences,
Bangalore 560 029.
Received : 3.7.2002; Accepted : 12.12.2002
276
extremes of temperature; it disappears during sleep.2 It has
both postural and kinetic components; however, in severe
essential tremor, rest tremor may also be seen.3,7 Movement
is distal and flexion-extension. Hands are most commonly
affected followed by legs, head, voice, tongue, face and jaw.8
In the head, ‘no-no’ (tremblement negatif) movement is more
commonly seen than ‘yes-yes’ (tremblement affirmatif)
movement.9 Mild asymmetry is the rule. ET is a heterogeneous
disease and may be (i) early or late onset, (ii) sporadic or
familial and (iii) with or without head tremor.10 The early
onset (beginning < 30 years) form is associated with more
hand involvement, associated dystonias, better response to
alcohol and more rapid progression.10 If there is concomitant
head tremor, progression of hand tremor is usually slower.3,10
A practical approach to the diagnosis has been recently put
forward based on various criteria in the past.3 A genetic basis
has always been suspected as 17.4-100% patients have
positive family history.3 In the familial types, autosomal
dominant inheritance is seen and complete penetrance occurs
by age sixty five. Recently it has been linked to chromosome
3q13 (the FET1 or ETM1 gene) and chromosome 2p22-25
(the EMT2 gene). Anticipation has been demonstrated in
kindreds with the latter gene and analysis indicates that the
gene may be a triplicate repeat.3,9
TREMOR ASSESSMENT
Assessment of tremor can be broadly divided into four
categories: 1. Physiological techniques, 2. Subjective clinical
methods, 3. Objective functional performance tests and 4.
Disability, handicap and quality of life assessment scales
(Table 1).
Accelerometry3
A linear tri-axial accelerometer measures frequency and
JAPI • VOL. 51 • MARCH 2003
Table 1 : Tremor assessment
A.
B.
C.
D.
Physiological techniques
1. Mechanical systems
2. Electrophysiologic indices of tremor magnitude:
Accelerometry, EMG, Gyroscopic techniques
3. Computer tracking tasks
4. Graphic digitizing tablets
5. Infrared sensor systems
Subjective clinical methods
1. Tremor rating scales
2. Archimedes spiral drawing
3. Handwriting
Objective functional performance tests
1. Volumetry
2. Nine hole pegboard test
3. Gibson maze test
Disability, handicap and quality of life assessment
magnitude of the oscillatory cycles of the tremor. Average of
several overlapping spectra derived from overlapping samples
of tremor from 1 minute period is obtained and a single
dominant peak is identified. Its’ frequency represents the
dominant frequency of the tremor. Frequency of essential
tremor ranges widely from 4-12 Hz and hence is not
diagnostic. Though it is an objective measure of frequency
and amplitude of tremor, it is expensive, complex and timeconsuming. Most importantly, it does not measure the
functional disability resulting from the tremor.
Electromyography (EMG)3
It is a simpler and cheaper electrophysiologic index of
tremor whereby pairs of surface electrodes are placed over
tremorogenic muscles. The signal is amplified, filtered and
rectified and 24 hour recording may be done if indicated.
Synchronous bursts of activity are usually seen in essential
tremor while reciprocal bursts in Parkinson’s disease.
However reciprocal and even random activity may be seen
in ET and hence EMG is not a gold standard.
Tremor Rating Scales3,11
Severity of tremor in the head, upper limb and lower limb
is indicated in an ordinal scale from 0 (no tremor) to 10
(maximum severity). The severity of the rest, postural, kinetic
and intention components is individually indicated in the
scale. For the purpose of routine assessment and therapeutic
trials, scales produce reliable results that are more valid
indices of tremor induced disability than standard postural
accelerometry.12
Archimedes Spiral Drawing and Handwriting
Assessment3,11
The patient is instructed to draw a spiral from inside to
out with at least five turns. Pen is held in the normal way and
forearm supported on the table. Spirals show a centrifugal
tendency with the tremor becoming more prominent as the
spiral grows. Severity of the tremor is rated from 0 to 10,
depending on the degree of perpendicular displacement from
the intended trajectory and the extent to which tremor persists
during each turn. Handwriting can also be assessed and has
JAPI • VOL. 51 • MARCH 2003
been rated from 0 to 10. Though tremor is more obvious in
spirals than in handwriting specimens, the latter is included
as it is readily available in the patient’s medical records, old
letters and other personal writings. 11 Assessments of
spirography and handwriting impairment are highly correlated
with one another and with disability as well as with right
upper limb postural tremor ratings. Spirography can provide
a quick and practical way of reassessing patients by postal
survey, which more likely reflects the day to day state of
tremor.12
Volumetry3,11
A 100 mL polystyrene beaker of water is held between
the thumb and fingers. It is held with arm resting on the table
to assess rest tremor and then held near the mouth with
shoulder abducted and elbow flexed to 90 degrees for one
minute to assess postural tremor. Volume of water remaining
in the cup after 60 seconds is denoted as X60. Volume of water
spilt is indicated by 100-X60 and correlates well with tremor
severity. It also indicates the patient’s capacity to suppress
tremor amplitude. Time to first spill water indicates tremor
suppressibility. Volumetry is an objective, simple and
inexpensive technique to assess tremor and also, it reflects
real life situations. However it is insensitive for fine tremors
and has a ceiling effect.
Others3,11
The nine-hole pegboard test assesses upper limb tremor.
Gibson maze test is a quantifiable spiral whereby assessment
is made based on the number of times a patient’s drawn line
crosses the boundaries of a printed spiral.
Activities of daily living and handicaps are assessed by
questionnaires and for each situation, a score of 0 to 3 is
given depending upon the degree of impairment.3,11 The scores
are summed and converted into a percentage.
Advantages and disadvantages of the commonly used
techniques are given in Table 2.
TREATMENT
Therapeutics of essential tremor is essentially medical or
surgical. If there is no functional or social disability,
reassurance is sufficient. If the tremor is intermittent and
predictable, intermittent prophylactic therapy with
propranolol can be advised. Physical modifications include
biofeedback and application of weights to the wrist during
activities so as to steady the hand. Lifestyle modification
includes avoiding caffeine.13
Pharmacotherapy
Table 3 enlists the drugs reported to be effective in essential
tremor.
Primidone
O’Brien et al first showed the utility of primidone in
essential tremor. 2 A review of 8 double-blind placebocontrolled trials and 13 open-label trials has shown primidone
to be effective. They have shown 40-50% effectiveness in
reducing tremor as well as functional improvement. It reduces
277
Table 2 : Tremor assessment : advantages and disadvantages
Technique
Advantages
Disadvantages
Accelerometry and
electromyography
Tremor rating scales
Volumetry
Spirography/handwriting
Objective measure of
frequency and amplitude
Simple, cheap, reliable
Simple, cheap, reliable
Simple, cheap, reliable, reflects
real life situations, can be serially
documented for follow up
Simple, cheap, reliable,
reflects real life situations
Expensive, complex, functional
disabilities not assessed
Tremor pattern not documented
Tremor pattern not documented
Tremor pattern not documented
ADL/handicap
questionnaire
Table 3 : Drugs useful in essential tremor
Primidone : start with 12.5 or 25 mg at night; increase
to 250 mg/day
Beta blockers such as propranolol : start with 40 mg/day;
increase to 120 mg/day
Benzodiazepines such as alprazolam (0.25-3 mg/day),
clonazepam (0.5-4 mg/day)
Topiramate
Clozapine : 6-75 mg/day
Phenobarbitone
Gabapentin : upto 1200 mg/day
Theophylline : upto 120-300 mg/day
Methazolamide : 50-300 mg/day
Flunarizine (upto 10 mg/day), clonidine and mirtazapine
(30 mg/day)
tremor amplitude but not frequency. Its role in essential head
tremor and voice tremor is minimal.3 It has a central action
and the action is mainly through primidone and an
unrecognised metabolite. Acute side effects can occur such
as vertigo, nausea and ataxia and are due to lack of hepatic
enzyme induction. They can be minimised by pretreatment
with phenobarbitone or by starting with very low doses and
gradually increasing. It is started at the dose of 12.5 or 25 mg
at night and increased to 250 mg/day; maximum dose studied
is 750 mg/day.2,3 Chronic therapy is rarely associated with
side effects, though in some patients depression may be
worsened.3
Beta blockers
A review of 16 placebo-controlled trials has shown beta
blockers to be effective in the management of ET. 2,3
Propranolol is the most studied drug. Long acting preparations
have been shown to be as effective as short acting ones and
are associated with better compliance. Timolol and sotalol
are effective while metaprolol and atenolol are less effective,
as the mechanism of action is through the peripheral beta-2
receptors. 45-75% of patients experience reduction in tremor
and functional improvement has also been proven. Like
primidone, it reduces tremor amplitude but not the frequency.
It is most effective for high amplitude low frequency tremors.
It is more effective than primidone in essential head tremor
278
Tremor pattern nor documented
and voice tremor. However hand tremors are better controlled
than head or voice tremor.3 Tolerance is less likely compared
to primidone. Starting dose is 40 mg/day and increased to
120 mg/day; maximum dose tried is 320 mg/day. Side effects
such as bronchospasm and heart block must be assessed
during follow up. When 750 mg primidone was compared to
120 mg propranolol, efficacy was found to be same. While
short term adverse effects were more for primidone, long term
adverse effects were more for propranolol and at the end of a
study, most patients preferred to continue with primidone
rather than propranolol.14
Others
Benzodiazepines such as alprazolam and clonazepam,
topiramate and clozapine have been found to be effective.2,3
Phenobarbitone was found to be as effective as propranolol.7
As the GABA-ergic system is disturbed in essential tremor,
gabapentin at a dose of 1200 mg/day has been found to be
effective.15 Interestingly, theorphylline has been found to
enhance the sensitivity to GABA and one trial has shown its
chronic use to reduce the amplitude of tremor.16 Other drugs
found to have some role include methazolamide, flunarizine,
clonidine and mirtazapine. 2,3 There is no role for antiparkinsons' drugs.7
Botulinum toxin A infiltrated in the intrinsic muscles of
the tremor dominant hand produced improvement in tremor,
though there was no substantial improvement in functional
scores.13,17
Alcohol has been observed to improve essential tremor.2,3
50-90% of patients are alcohol responsive and small amounts
produce dramatic response. Action starts within 10-15
minutes and lasts for 3 hours. However rebound tremor may
occur after the effect wears off. The risk of chronic alcoholism
is low.18 Mechanism of action is not known but alcohol has
been shown to attenuate the increased blood flow in
cerebellum that is seen in essential tremor. It may be used
judiciously before meals or at social events.3
Surgery
Fifty percent of patients have disabling tremor even with
optimal medical therapy. 3 Lesioning and stimulation
procedures target the ventral lateral thalamus, especially the
ventral intermedius nucleus (VIM) or ventral oralis posterior
nucleus, where fibres from contralateral dentate nucleus relay
and pass to area 4 of the motor cortex.3 Thalamotomy has
JAPI • VOL. 51 • MARCH 2003
been shown to be effective in the short term and long term
follow up after surgery in the form of improvement in tremor
scores, activities of daily living, writing and pouring activity.3
Complications include dysarthria, ataxia, motor weakness,
paraesthesias and mild cognitive deficit.2,3,5 However bilateral
thalamotomy has been associated with severe dysarthria and
anarthria and memory impairment and hence is not
advocated.3,19
In thalamic stimulation, deep brain stimulation (DBS) lead
is connected to an implantable pulse generator (IPG) and the
intracranial end is implanted in the VIM nucleus. Postural
tremor is more effectively controlled than kinetic tremor.3
Complications include microhematomas, contralateral
paraesthesias, limb dystonia, dysarthria and dysequilibrium.
Tolerance may occur, especially for action tremor. Significant
improvement in tremor and activities of daily living has been
proven.3 Bilateral staged thalamic DBS is associated with
mild and modifiable complications such as dysarthria and
dysequilibrium.2,3,19 It has been shown to be as effective as
thalamotomy for reducing tremor amplitude. However DBS
is associated with better functional outcome and less adverse
effects.20 Its advantages include reversibility, adaptability and
the possibility of bilateral staged procedure. But it is
expensive, involves leaving behind a foreign body, batteries
must be replaced regularly and time and effort is required for
optimising the stimulus variable.3
CONCLUSION
Essential tremor is the most common movement disorder.
Diagnosis is based on clinical features supplemented by
various tremor assessment techniques. Management is
essentially medical and primidone and propranolol are the
preferred drugs. Surgery is indicated where medicines fail to
give adequate response and deep brain stimulation has shown
the best results.
REFERENCES
1.
Deuschl G, Brain PG, Brin M, et al., and an Ad Hoc Scientific
Committee. Consensus Statement of the Movement Disorder
Society on tremor. Mov Disord 1998;13(suppl3):2-23.
2.
Zesiewicz TA, Hauser RA. Phenomenology and treatment of
tremor disorders. Neurologic Clin 2001;651-80.
3.
Koller WC, Deuschl G. Essential tremor. Neurology
2000;54(Suppl4):S1-S45.
4.
Payami H, Larsen K, Bernard S, Nutt J. Increased risk of
Parkinson’s disease in parents and siblings of patients. Ann
JAPI • VOL. 51 • MARCH 2003
Neurol 1994;36:659-61.
5.
Deuschl G, Wenzelburger R, Raethjen J. Tremor. Current
Opinion Neurol 2000;13:437-44.
6.
Busenbark KL, Nash J, Nash S, Hubble JP, Koller WC. Is
essential tremor benign? Neurology 1991;41:1982-3.
7.
Findley LJ, Koller WC. Essential tremor: A Review. Neurology
1987;37:1194-7.
8.
Deuschl G, Krack P. Tremors : Differential diagnosis,
neurophysiology, and pharmacology. In: Jankovic J, Tolosa E,
editors. Parkinson’s Disease and Movement Disorders. 3rd
ed. Baltimore: Williams and Wilkins. 1988;419-52.
9.
Bain PG, Findley LJ, Thompson PD, Gresty MA, Rothwell JC,
Harding AE, et al. A study of hereditary essential tremor.
Brain 1994;117:805-24.
10. Louis ED, Ford B, Barnes LF. Clinical subtypes of essential
tremor. Arch Neurol 2000;57:1194-8.
11. Bain PG, Findley LJ. Assessing tremor severity. A clinical
handbook. London: Smith-Gordon and Company Limited.
1993.
12. Bain PG, Findley LJ, Atchison P, Behari M, Vidailhet M, Gresty
M, et al. Assessing tremor severity. J Neurol Neurosurg Psychiatry
1993;56:868-73.
13. Louis ED. Essential tremor. N Engl J Med 2001;345:887-91.
14. Gorman WP, Cooper R, Pocock P, Campbell MJ. A
comparison of primidone, propranolol, and placebo in essential
tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry
1986;49:64-8.
15. Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J.
Gabapentin for essential tremor: a multiple-dose, double-blind,
placebo-controlled trial. Mov Disord 2000;15:678-82.
16. Mally J, Stone TW. Efficacy of an adenosine agonist,
theophylline, in essential tremor: comparison with placebo
and propranolol. J Neurol Sci 1995;132:129-32.
17. Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J.
A randomized, double-blind, placebo-controlled study to
evaluate botulinum toxin type A in essential hand tremor.
Mov Disord 1996;11:250-6.
18. Koller WC. Alcoholism in essential tremor. Neurology
1983;33:1074-6.
19. Starr PA, Vitek JL, Bakay RAE. Surgery for movement disorders.
In : Kaye AH, Black PMcL, editors. Operative Neurosurgery.
London: Harcourt Publishers. 2000;1447-66.
20. Schuurman PR, Bosch DA, Bossuyt PMM, Bonsel GJ, van
Someren EJW, de Bie RMA, et al. A comparison of thalamic
stimulation and thalamotomy for suppression of severe
tremor. N Engl J Med 2000;342:461-8.
279