Section III
Hyperkinetic disorders
Tremors
Chapter contents
Introduction 389
Assessment of tremors 391
Rest tremors 391
Postural tremors 394
Introduction
Tremor is a rhythmic, oscillatory movement produced by
alternating or synchronous contractions of antagonist
muscles. It is the most common form of involuntary move-
ment, but only a small fraction of those who shake will seek
medical attention. Indeed, in one epidemiologic study of
normal controls, 96% were found to have clinically detect-
able postural tremor, and 28% had a postural tremor of
“moderate amplitude” (Louis et al., 1998e).
Tremors can be classified according to their phenomenol-
ogy, distribution, frequency, or etiology (Hallett, 1991; Lou
and Jankovic, 1991a; Bain, 1993; Findley, 1993; Deuschl
et al., 1998a; Jankovic, 2000; Deuschl et al., 2001; Jankovic
and Lang, 2008; Deuschl and Elble, 2009). Phenomenologi-
cally, tremors are divided into two major categories: rest
tremors and action tremors (Table 18.1). Rest tremor is
present when the affected body part is fully supported
against gravity and not actively contracting; rest tremor is
diminished or absent during voluntary muscle contraction
and during movement. Action tremors occur with voluntary
contraction of muscles, and they can be subdivided into
postural, kinetic, task-specific or position-specific, and iso-
metric tremors. Postural tremor is evident during mainte-
nance of an antigravity posture, such as holding the arms in
an outstretched horizontal position in front of the body.
Some parkinsonian patients exhibit postural tremor that
emerges after a latency of a few seconds. This tremor, referred
to here as reemergent tremor, probably represents a rest
tremor that has been “reset” during posture holding (Jankovic
et al., 1999) (Fig. 18.1). The relationship of this reemergent
tremor to the typical rest tremor is supported by the observa-
tion that this reemergent repose tremor shares many charac-
teristics with the typical rest tremor; it has the same 3–6 Hz
frequency, and it also responds to dopaminergic therapy
© 2011 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2369-4.00018-4
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C H A P T ER 18 
Kinetic tremors 407
Pathophysiologic mechanisms of rest and action tremors 408
Other tremors 412
Appendix 414
(Video 18.1). Kinetic tremor can be seen when the voluntary
movement starts (initial tremor), during the course of the
movement (dynamic tremor), and as the affected body part
approaches the target, such as while performing the finger-
to-nose or the toe-to-finger maneuver (terminal tremor,
also called intention tremor). Task-specific tremors occur
only during, or are markedly exacerbated by, a certain
task, such as while writing (primary handwriting tremor)
(Video 18.2), while speaking or singing (voice tremor)
(Rosenbaum and Jankovic, 1988; Soland et al., 1996b),
or while smiling (Schwingenschuh et al., 2009). Besides
writing, task-specific tremors may be triggered during other
activities, such as while playing golf, particularly when
putting (Video 18.3). Position-specific tremors occur while
holding a certain posture (e.g., the “wing-beating” position
or holding a spoon or a cup close to the mouth). One
example of a task- or position-specific tremor is the tremor
that occurs in performing the dot test (“dot approximation
test”), during which the subject, seated at the desk with
elbow elevated to a 90° shoulder abduction, is asked to hold
the tip of the pen as close as possible to a dot on a horizontal
paper without touching the dot. Patients with essential
tremor (ET), to be discussed later, or other action tremors
usually exhibit exacerbation of the tremor during this spe-
cific task. A variant of this tremor occurs in performing the
modified finger–nose–finger test, during which the subject
stands in front of a paper mounted on a wall and is asked
to mark the center of the drawn target and to make a mark
with a felt-tipped pen five times (Louis et al., 2005a). Iso-
metric tremor occurs during a voluntary contraction of
muscles that is not accompanied by a change in position of
the body part, such as maintaining of a tightly squeezed fist
or while standing (e.g., orthostatic tremor; see later).
Tremors can be also classified according to their anatomic
distribution – for example, head, tongue, voice, and trunk.
Orolingual tremors include physiologic, essential, task- and
 18 Tremors

Table 18.1  Classification and differential diagnosis of tremors

A. Rest tremors (3) Drugs: β-agonists (e.g., theophylline, terbutaline, epinephrine),
1.  Parkinson disease (PD) dopaminergic drugs (levodopa, dopamine agonists), stimulants
2.  Other parkinsonian syndromes (amphetamines), psychiatric drugs (lithium, neuroleptics,
tricyclics), methylxanthines (coffee, tea), valproate, amiodarone,
a. Multiple system atrophies (SND, SDS, OPCA)
cyclosporine, interferon
b. Progressive supranuclear palsy
(4) Toxins: Hg, Pb, As, Bi, Br, alcohol withdrawal
c. Cortical-basal-ganglionic degeneration
c. Essential tremor
d. Parkinsonism–dementia–ALS of Guam
(1) Autosomal dominant
e. Diffuse Lewy body disease
(2) Sporadic
f. Progressive pallidal atrophy
d. Postural tremor associated with
(1) Dystonia
3.  Heredodegenerative disorders
(2) Parkinsonism
a. Huntington disease
(3) Myoclonus
b. Wilson disease
(4) Hereditary motor-sensory neuropathy (Roussy–Levy)
c. Neuroacanthocytosis
(5) Kennedy syndrome (X-linked spinobulbar atrophy)
d. NBIA1 (Neurodegeneration with brain iron accumulation 1)
e. PD and other parkinsonian syndromes
e. Gerstmann–Sträussler–Scheinker disease
f. Tardive tremor
f. Ceroid lipofuscinosis
g. Midbrain (rubral) tremor
h. Cerebellar hypotonic tremor (titubation)
4.  Secondary parkinsonism
i. Neuropathic tremor: motor neuron disease, peripheral
a. Toxic: MPTP, CO, Mn, methanol, cyanide, CS2 neuropathy, peripheral nerve injury, reflex sympathetic dystrophy
b. Drug-induced: dopamine receptor blocking drugs   2.  Kinetic (intention, dynamic, termination) tremors
neuroleptics (“rabbit syndrome”), dopamine-depleting  
drugs (reserpine, tetrabenazine), lithium, valproate,   a. Cerebellar disorders (cerebellar outflow): multiple sclerosis,
amiodarone, flunarizine, cinnarizine trauma, stroke, Wilson disease, drugs and toxins
c. Vascular: multi-infarct, Binswanger disease, “lower body   b. Midbrain lesions
parkinsonism” 3.  Task- or position-specific tremors
d. Trauma: pugilistic encephalopathy, midbrain injury a. Handwriting
e. Tumor and paraneoplastic b. Orthostatic
f. Infectious: postencephalitic, fungal, AIDS, subacute sclerosing c. Other (e.g., occupational) task-specific tremors
panencephalitis, Creutzfeldt–Jakob disease 4.  Isometric
g. Metabolic: hypoparathyroidism, chronic hepatic degeneration,
a. Muscular contraction during sustained exertion
mitochondrial cytopathies
h. Normal pressure hydrocephalus C. Miscellaneous tremors and other rhythmic
5.  Severe essential tremor (ET) movements
6.  Midbrain (rubral) tremor 1.  Myoclonus: rhythmical segmental myoclonus (e.g.,
palatal), oscillatory myoclonus, asterixis,
7.  Tardive tremor mini-polymyoclonus
8.  Myorhythmia 2.  Dystonic tremors
9.  Spasmus nutans 3.  Cortical tremors
4.  Epilepsia partialis continua
B. Action tremors 5.  Nystagmus
1.  Postural tremors 6.  Clonus
a. Physiologic tremor 7.  Fasciculation
b. Enhanced physiologic tremor: 8.  Shivering
(1) Stress-induced: emotion, exercise, fatigue, anxiety,   9.  Shuddering attacks
fever
(2) Endocrine: hypoglycemia, thyrotoxicosis,  
10.  Head bobbing (third ventricular cysts)
pheochromocytoma, adrenocorticosteroids 11.  Aortic insufficiency with head titubation

position-specific, dystonic, orthostatic, parkinsonian, palatal
(also termed palatal myoclonus), drug-induced, hereditary,
and psychogenic (Erer and Jankovic, 2007; Silverdale et al.,
2008). Because of the complexity of limb tremors, it is best
to describe them according to the joint about which the
oscillation is most evident – for example, metacarpal-
phalangeal joints, wrist, elbow, and ankle tremor. In most
tremors, the frequency ranges between 4 and 10 Hz, but the
cerebellar tremors may be slower, with a frequency of
2–3 Hz. The “slow” tremors (frequency: 1–3 Hz) are some-
times referred to as myorhythmia and are usually associated
with brainstem pathology (Masucci et al., 1984; Cardoso
and Jankovic, 1996; Tan et al., 2007a). The “fast” tremors
(frequency: 11–20 Hz) may be distinct tremor disorders,

390
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 Rest tremors

LATENCY OF REEMERGENT TREMOR electrical socket, a thread and needle, a strip of buttons, and
10
a telephone. Using other instruments, the modified Klove–
9 Matthews Motor Steadiness Battery and the Nine-Hole
8 Steadiness Tester, Louis and colleagues (2000c) showed that
7 these portable instruments provide a reliable and valid
Latency (s)

6 means of collecting objective quantitative data on tremor

5 severity. A Tremor Disability Questionnaire has been devel-
4 oped and found to reliably correlate with multiple measures
3 of tremor severity (Louis et al., 2000a). Another screening
2 instrument for ET, consisting of seven items and a spiral
1 drawing, has been found to have 70.5% sensitivity, 68.2%
0 specificity, and 64.9% positive predictive value (Lorenz et al.,
Essential tremor Parkinson disease 2008). A simple, user-friendly clinical tool, with even higher
Mean + SD 0.08 + 0.30 4.63 + 4.23 sensitivity, specificity and predictive value, is needed to assess
(range) (0–1.29) (0–10.00) tremors in the clinic and in the field. A teaching videotape
for assessment of ET was developed to improve the uniform
Figure 18.1  Rest tremor of Parkinson disease reemerges after a latency
when arms are outstretched or in a wing-beating position.
application of the Washington Heights–Inwood Genetic
Study of Essential Tremor (Louis et al., 2001a). Using a clini-
cal evaluation (interview and videotaped examination) and
an electrophysiologic evaluation (quantitative computerized
such as orthostatic tremor, or may represent harmonics of tremor analysis using accelerometry and EMG), Louis and
other tremors. The clinical characteristics of tremors provide Pullman (2001) found a very high concordance rate between
the most important clues to their etiology (Table 18.1). the two methods in 51 of 54 (94%) subjects, suggesting that
using either technique would arrive at a similar diagnosis.
Although not yet validated, the Unified Tremor Rating
Assessment of tremors Assessment developed by the Tremor Research Group has
been used in a number of clinical, therapeutic trials (Bain,
There have been many attempts to quantitate tremor, but it 1993; Jankovic et al., 1996). The other scale that has been
is not apparent whether electromyographic (EMG), accelero- used in several tremor studies is the Fahn–Tolosa–Marin
metric, or other methods of measuring tremor correlate Tremor Rating Scale (TRS) (Fahn et al., 1993). While the
with clinical rating scales. Indeed, one study suggested that inter-rater reliability of this scale is relatively poor, there is a
assessments of spirography and handwriting correlate better good consistency, with average Spearman correlation of
with overall functional tremor-related disability than electro- 0.87, when the same rater repeatedly assesses the tremor
physiologic methods (Bain et al., 1993). However, because (Stacy et al., 2007). Using the TRS, Putzke et al. (2006)
the physiologic measurements and the clinical ratings were showed that the total score increased by about 2 points
not performed simultaneously and because of other techni- during prospective follow-up of patients with ET over a mean
cal problems, interpretation of the study is difficult. Elble of 3.6 years and that older age, longer duration of disease,
and colleagues (1996) described the use of a digitizing tablet and asymmetric onset of tremor were associated with
in quantification of tremor during writing and drawing. increased tremor severity. Another tremor rating scale, the
Although relatively good inter-trial correlations were Tremor Research Group (TRG) Essential Tremor Rating
obtained with this method, the tablet does not capture the Scale (TETRAS), is currently being validated against the TRS
speed of writing or the amount of effort exerted by the (Elble et al., 2008). The TETRAS has been found to correlate
patient in an attempt to control the tremor while writing. well with quantitative assessments using the Kinesia™
One study found high inter-observer reliability using a (CleveMed) system (Mostile et al., 2010). Any assessment of
diagnostic protocol for ET (Louis et al., 1998a). The inves­ tremor must take into account minute-to-minute and hour-
tigators also found high specificity and sensitivity of a to-hour amplitude variability (Koller and Royse, 1985), and
screening questionnaire when compared to the physician’s potential provocations, such as voluntary isometric contrac-
examination in patients with definite and probable ET, but tion in the case of action tremors and walking and counting
actual examination of the subjects is necessary to detect mild backwards in the case of rest tremor (Raethjen et al., 2008).
ET (Louis et al., 1998b). In another study, the authors con-
cluded that when a limited number of tests are available in
large epidemiologic surveys, a test such as the finger–nose Rest tremors
maneuver may be used to screen populations for ET, whereas
to exclude normal subjects, the spiral drawing test, water
pouring test, or arm extension test may be utilized (Louis
Diagnosis
et al., 1999a). A performance-based test for ET has been Rest tremor is most typically present in patients with
validated and compared to other measures of tremor (Louis Parkinson disease (PD). In one study, all 34 patients with
et al., 1999b). Although this performance-based test was pathologically proven cases of idiopathic (Lewy body) par-
thought to objectively assess functional capacity in patients kinsonism demonstrated typical rest tremor sometime
with ET, the test seems somewhat cumbersome to perform during the course of their illness (Rajput et al., 1991).
because it requires a variety of props, such as a milk carton, Although this study suggests that parkinsonian patients
a glass, a soup spoon, a bowl, a saucer, a wallet, coins, an who do not exhibit rest tremor probably do not have

391
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 18 Tremors
idiopathic parkinsonism (PD), another study, involving 100
pathologically proven cases of PD, found that 32% of all
patients apparently never manifested tremor during the
course of their disease (Hughes et al., 1993).
Several studies have suggested that the natural course of
PD is in part related to the presence or absence of tremor
(Hughes et al., 1993). The tremor-dominant PD may be
associated with earlier age at onset, less cognitive decline,
and slower progression than the type of PD that is dominated
by postural instability and gait difficulty (PIGD) (Jankovic
et al., 1990). Clinical-pathologic correlations are needed to
answer the question as to whether the tremor-dominant
form and the PIGD-dominant form represent different dis-
eases or merely variants of one disease, namely, PD. In
support of the former is the finding that only 27% of patients
with the PIGD form of idiopathic parkinsonism had Lewy
bodies at autopsy (Rajput et al., 1993). In another clinical-
pathologic study, Hirsch and colleagues (1992) demon-
strated that patients with PD and prominent tremor have
degeneration of a subgroup of midbrain (A8) neurons,
whereas this area is spared in PD patients without tremor.
This observation supports the hypothesis that differential
damage of subpopulations of neuronal systems is responsi-
ble for the diversity of phenotypes seen in PD and other
parkinsonian disorders. It is unclear whether the occasional
patients with long-standing unilateral tremor and minimal
or no other parkinsonian findings have a benign form of PD,
as is suggested by positron emission tomography (PET)
scans showing low fluorodopa uptake in the contralateral
putamen (Brooks et al., 1992), or whether this condition
represents a separate disease entity. In contrast to patients
with the PIGD form of PD, patients with tremor-dominant
PD have increased metabolic activity in the pons, thalamus,
and motor association cortices (Antonini et al., 1998). When
rest tremors involve the fingers, hands, lips, jaw, and tongue
in the same individual, they share a common frequency,
suggesting that they are of central origin (Hunker and Abbs,
1990). This pattern, however, changes during sleep in that
non-rapid eye movement sleep transforms the alternating
tremor that is typically seen in the awake patient into sub-
clinical repetitive muscle contractions of variable frequency
and duration during sleep stages I to IV, and the tremor
disappears during rapid eye movement sleep (Askenasy and
Yahr, 1990).
Rest tremor has other causes besides PD and related par-
kinsonian disorders (see Table 18.1). Patients with severe
ET may have tremor at rest and prominent kinetic tremor. It
is not known whether the ET patients with rest tremor have
associated PD, whether they later develop other features of
PD, or whether the rest tremor is a feature of ET (Jankovic,
1989; Shahed and Jankovic, 2007). Some patients with
lesions in the cerebellar outflow pathways, particularly in
the superior cerebellar peduncle near the red nucleus (cere-
bellar outflow, midbrain or “rubral” tremor, also referred to
as Holmes tremor), also have tremor at rest, probably due
to an interruption of the nigrostriatal pathway (Remy et al.,
1995). This irregular, slow (2–5 Hz), predominantly unilat-
eral tremor may be associated with other neurologic signs,
such as ataxia, bradykinesia, and ophthalmoplegia. It is
often associated with midbrain pathology, such as multiple
sclerosis, stroke, tumor, or arteriovenous malformation (Lee
et al., 2008). It rarely responds to any medical therapy, but
392
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wrist weights, levodopa, dopamine agonists, amantadine,
propranolol, clonazepam, isoniazid, and levetiracetam
(Ferlazzo et al., 2008) may be effective in reducing the
amplitude of this, often disabling, tremor. The affected arm
or leg may be also ataxic and may be associated with third
nerve palsy (Benedikt syndrome) (Video 18.4). The cerebel-
lar outflow tremor is most often caused by trauma, stroke,
multiple sclerosis, and Wilson disease (Lou and Jankovic,
1993; Krauss et al., 1995; Miwa et al., 1996; Alarcon et al.,
2004). Strokes involving the posterior circulation may
involve the thalamus, producing slow (1–3 Hz) rest and
postural tremors, sometimes referred to as myorhythmia
(Masucci et al., 1984; Cardoso and Jankovic, 1996; Miwa
et al., 1996).
Myorhythmia is a slow (1–3 Hz) frequency, continuous or
intermittent, relatively rhythmic movement that is present at
rest but may persist during activity (Masucci et al., 1984;
Cardoso and Jankovic, 1996). It may be associated with
palatal myoclonus, and it disappears with sleep. Except for
the slower frequency, the presence of flexion–extension
rather than the typical supination–pronation pattern, and
the absence of associated parkinsonian findings, myorhyth-
mia resembles a parkinsonian tremor. In the cases that were
examined at autopsy, the sites of maximum pathology
involved chiefly the brainstem (particularly the substantia
nigra and the inferior olive) and the cerebellum. The etiol-
ogy for myorhythmia includes brainstem stroke, cerebellar
degeneration, Wilson disease, and Whipple disease (Masucci
et al., 1984; Tison et al., 1992; Cardoso and Jankovic, 1996).
Palatal myoclonus, sometimes referred to as palatal tremor,
has some features of tremor, but in contrast to tremor which
is produced by alternating or synchronous contractions of
antagonist muscles, the palatal movement is produced by
rhythmical contractions of agonist muscles, hence the term
myoclonus is preferred despite the arguments raised against
this nosology (Zadikoff et al., 2006). Palatal myoclonus, a
form of segmental myoclonus, is manifested by rhythmical
contractions of the soft palate resulting from acute or chronic
lesions involving the Guillain–Mollaret triangle linking
dentate nucleus with the red nucleus via the central tegmen-
tal tract to the inferior olivary nucleus. Symptomatic palatal
myoclonus (SPM) usually persists during sleep, while essen-
tial palatal myoclonus (EPM), frequently associated with an
ear-clicking sound, disappears with sleep. In EPM the muscle
agonist is the tensor veli palatini, which opens the eus-
tachian tube and is innervated by the trigeminal nerve. In
SPM the palatal movement is due to contractions of the
levator veli palatini, innervated by the facial nucleus and
nucleus ambiguus. When the tensor muscle contracts, as in
EPM, the entire soft palate moves, whereas only the edges of
the soft palate move when the levator muscle contracts in
SPM. Symptomatic, but not essential, palatal myoclonus is
often associated with hypertrophy of the inferior olive (Goyal
et al., 2000). SPM has been associated with a variety of
lesions involving the brainstem as well as some neurodegen-
erative disorders such as Alexander disease (Pareyson et al.,
2008).
Treatment with neuroleptics can also cause persistent
tremor, referred to as tardive tremor (Stacy and Jankovic,
1992). This rest, postural, and kinetic tremor, with a fre-
quency of 3–5 Hz, is aggravated by, and persists after, neu-
roleptic withdrawal and improves after treatment with the

dopamine-depleting drug tetrabenazine. The tremor may be
accompanied by other tardive movement disorders, includ-
ing akathisia, chorea, dystonia, myoclonus, and stereotypy.
There is usually no family history or other explanation for
the tremor.
Spasmus nutans is characterized by the triad of nystagmus,
abnormal head position, and irregular, multidirectional
head nodding that disappears during sleep. This self-limited
and often familial condition is first noted between the ages
of 4 and 12 months, and it usually disappears within a year
or two. Another oculomotor cause of head tremor is “head-
shaking nystagmus” seen in patients with lateral medullary
infarction (Choi et al., 2007). The 2–3 Hz horizontal head
shaking has been postulated to be caused by unilateral
impairment of nodulo-uvular inhibition of the velocity
storage.
Treatment
The treatment of rest tremors is similar to that of parkinson-
ism (Jankovic and Marsden, 1998; also see Chapter 6). Sec-
ondary and potentially curable causes should be excluded,
particularly when there are associated features to suggest
disorders other than PD (see Table 18.1). Anticholinergic
and dopaminergic drugs provide the most effective relief of
rest tremors. Clozapine, an atypical neuroleptic that does not
significantly exacerbate parkinsonism but can cause poten-
tially serious side effects such as agranulocytosis, has been
shown to be effective in the treatment of parkinsonian
tremor (and ET) (Bonuccelli et al., 1997; Friedman et al.,
1997; Ceravolo et al., 1999). Ethosuximide, an anticonvul-
sant that blocks low-threshold Ca2+ conductance in the tha-
lamus, has been shown to reduce tremor in MPTP monkeys
and to potentiate the effects of a D2 agonist (Gomez-
Mancilla et al., 1992). However, ethosuximide was found
ineffective in a pilot study of six PD patients with drug-
resistant tremor (Pourcher et al., 1992). Mirtazapine
(Remeron), a novel antidepressant that enhances noradren-
ergic and serotonergic transmission and acts as a presynaptic
alpha-2, 5-HT2, and 5-HT3 receptor antagonist, has been
reported to improve rest tremor (Pact and Giduz, 1999).
Other drugs reported to have a possible beneficial effect in
patients with ET include mirtazapine, clozapine, sodium
oxybate, dimethoxymethyl-diphenyl-barbituric acid (T-2000),
and carisbamate (Lyons and Pahwa, 2008). High-amplitude
parkinsonian tremors and rest tremors caused by disorders
other than PD usually do not improve with pharmacologic
therapy. In some cases, botulinum toxin (BTX) injections in
the involved muscles produce a satisfactory reduction in the
tremor amplitude (Jankovic and Schwartz, 1991; Jankovic
et al., 1996; Hou and Jankovic, 2002). A multicenter, rand-
omized, double-blind, controlled trial confirmed the results
of an earlier study (Jankovic et al., 1996) that BTX injections
produce significant reduction in the postural hand tremor of
ET and modest functional improvement (Brin et al., 2001).
By avoiding injections of the forearm extensor muscles we
prevent finger extensor weakness, a relatively frequent com-
plication reported in the earlier studies (Pacchetti et al.,
2000).
Ventral lateral thalamotomy, particularly involving the
ventral intermediate nucleus of the thalamus (VIM), was
considered the neurosurgical treatment of choice for
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Rest tremors
disabling, drug-resistant tremors until the later 1980s when
the ablative procedure was replaced by high-frequency deep
brain (thalamic) stimulation (DBS) (Benabid et al., 1991;
Fox et al., 1991; Jankovic et al., 1995b). Although effective
in a majority of cases, the tremor recurs in about 20% of
patients, and there is a considerable risk of contralateral
hemiparesis, hemianesthesia, ataxia, speech disturbance,
and other potential complications. These are compounded
when the procedure is performed bilaterally. Thalamic DBS
is now the surgical treatment of choice for patients with
disabling tremors (Deiber et al., 1993; Benabid et al., 1996;
Pahwa and Koller, 2001; Ondo et al., 2001a, 2001b; Pahwa
et al., 2006) (see also Chapter 7). This technique has been
proposed for chronic treatment of parkinsonian, essential,
and other tremors. Using high-frequency (100 Hz) stimula-
tion, with the tip of a monopolar electrode implanted stere-
otactically in the VIM contralateral to the disabling tremor,
Benabid and colleagues (1991) noted “complete relief” of
contralateral tremor in 27 of 43 (63%) thalami that were
stimulated and “major improvement” in 11 (23%). The
series included 26 patients with PD and 6 with ET, 7 of
whom had previously been treated with thalamotomy. The
benefit of thalamic stimulation was maintained for up to 29
months (mean follow-up: 13 months). The results were
similar in their subsequent report of long-term effects of
chronic VIM stimulation in 117 patients, 74 of whom had
bilateral implantation (Benabid et al., 1996). The most
robust tremor suppression was noted in patients with PD (n
= 80); but patients with ET (n = 20) also benefited, although
18.5% deteriorated with time. Dysarthria and ataxia still
occurred, but the patients were able to adjust the intensity
of stimulation to ameliorate these side effects, though at the
expense of increased tremor. Nevertheless, the investigators
felt that the reversible nature of the side effects was the chief
advantage of DBS over the permanent lesion produced by
thalamotomy. To compare thalamic DBS with thalamotomy,
Schuurman and colleagues (2000) conducted a prospective,
randomized study of 68 patients with PD, 13 with ET, and
10 with multiple sclerosis. They found that the functional
status improved more in the DBS group than in the thalamo-
tomy group, and tremor was suppressed completely or
almost completely in 30 of 33 (90.9%) patients in the DBS
group and in 27 of 34 (79.4%) patients in the thalamotomy
group. Although one patient in the DBS group died after an
intracerebral hemorrhage, DBS was associated with signifi-
cantly fewer complications than was thalamotomy. This pro-
cedure may be also advantageous in elderly patients and
when bilateral effects are desirable (Blond et al., 1992). We
found that bilateral thalamic DBS is more effective than
unilateral DBS in controlling bilateral appendicular and
midline tremors of ET and PD, and thalamic DBS does not
seem to improve meaningfully any parkinsonian symptoms
other than tremor (Ondo et al., 2001a). In addition, we
found that VIM DBS produces modest improvement, rather
than tremor augmentation as previously suggested, in ipsi-
lateral tremor in patients with ET (Ondo et al., 2001b). A
review of long-term efficacy of VIM DBS in 39 patients (20
with PD and 19 with ET) showed that the benefits may be
maintained for at least 6 months (Rehncrona et al., 2003).
In one of our patients, minimal foreign body reaction and
gliosis around the electrodes was found 12 years after
implantation, the longest reported follow-up with autopsy
393
 18 Tremors
examination after DBS, supporting the long-term safety of
DBS (DiLorenzo et al., 2010).
In addition to improving distal tremor associated with PD
and ET, VIM DBS can effectively control ET head tremor,
which usually does not respond to conventional therapy
(Koller et al., 1999). Other midline tremors, such as voice,
tongue, and face tremor, also may improve with unilateral
VIM DBS, although additional benefit can be achieved with
contralateral surgery (Obwegeser et al., 2000). The risk of
local gliosis with chronic stimulation of the thalamus is
minimal (Caparros-Lefebvre et al., 1994). Unfortunately,
thalamic stimulation does not appear to be as effective in
patients with predominantly kinetic and axial tremors, and
it does not improve other parkinsonian features such as
bradykinesia, rigidity, and levodopa-related motor complica-
tions. Furthermore, while VIM DBS is very effective in
improving PD tremor, when performed bilaterally it is often
associated with dysarthria and postural and gait abnormality
(Pahwa et al., 2006) as a result of which the subthalamic
nucleus (STN) has been suggested as a more appropriate
target in PD patients with severe tremor (Limousin et al.,
1998; Benabid et al., 2000; Diamond et al., 2007; Fishman,
2008). The mechanism of action of DBS is unknown, but
“jamming” of low-frequency oscillatory inputs has been sug-
gested as a possible mechanism for the antitremor effects of
DBS. Regional cerebral blood flow, measured by PET scan,
demonstrated that tremor suppression was associated with
decreased cerebellar blood flow and, presumably, decreased
synaptic activity in the cerebellum (Deiber et al., 1993).
In 1992, Laitinen of Stockholm, Sweden, reported the
results of 90 pallidotomies in 86 patients with severe PD
(Laitinen et al., 1992). The external, posteroventral portion
of the medial globus pallidus interna (GPi) was the intended
target for the stereotactically placed lesion. Nearly all patients
had “marked improvement in tremor and akinesia.” In addi-
tion, some patients apparently also noted improvement in
their gait, speech, and pain. Only two patients suffered per-
manent visual field defect, and one had “minor stroke with
hemiparesis.” Several pallidotomy series have since con-
firmed the beneficial effects of pallidotomy on various par-
kinsonian symptoms, including tremor (Jankovic and
Marsden, 1998). These results provide support for the notion
that the GPi is “hyperactive” in PD and that surgical or
chemical lesions of these structures may have a therapeutic
value not only in controlling tremor but also in improving
bradykinesia (Bergman et al., 1990; Aziz et al., 1991).
Although some investigators (Subramanian et al., 1995)
have suggested that posteroventral pallidotomy is as effective
as thalamotomy in controlling parkinsonian tremor, others
(Dogali et al., 1995) feel that pallidotomy provides only
partial relief of tremor.
Postural tremors
Diagnosis and clinical features
Physiologic tremor
Normal and enhanced physiologic tremors are the most
common forms of postural tremor, but they rarely require
medical attention. Postural tremors are clinically similar
despite different etiologies. In contrast to ET, the frequency
394
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of physiologic tremor can be slowed by mass loading (Elble
and Koller, 1990). Indeed, there appear to be two compo-
nents to physiologic tremor: variable frequency (peak: 8 Hz),
which is dependent on loading, and consistent frequency
(peak: 10 Hz), which is independent of peripheral influence.
The latter suggests central origin of the tremor, as is pre-
sumed the case in ET. Thus the amplitude of ET is less
dependent on the position of the tested limb than is the
amplitude of other postural tremors, including physiologic
tremors (Sanes and Hallett, 1990).
Essential tremor
Although the term “essential” implies necessary or desirable,
it actually means that there is no known cause and the term
is synonymous with “idiopathic.” The term “essential tremor”
did not gain regular and widespread currency until a century
or so after its initial use in 1874 by Pietro Burresi, a professor
of medicine at the University of Siena, Italy (Louis et al.,
2008b). He coined the term “tremore semplice essenziale”
or “simple essential tremor” when he described the case of
an 18-year-old man suffering from severe tremor of the arms
when engaged in voluntary movement as well as head
tremor. While the amplitude of ET tends to increase with age,
the tremor frequency decreases with age (Elble et al.,1994;
Elble, 2000b). The tremor of ET is typically a postural or
kinetic tremor with frequency varying between 4 and 10 Hz.
Although the frequency of the tremor is relatively constant
in a particular individual, the amplitude may vary and in
some cases may be even suppressed by mental concentration
and distraction (Koller and Biary, 1989; Kenney et al., 2007).
Epidemiology of ET
In the past the modifier “benign” was used (“benign ET”) to
indicate favorable prognosis of ET, even though it is now
well accepted that ET can produce marked physical and psy-
chosocial disability (Busenbark et al., 1991; Jankovic, 2000;
Sullivan et al., 2004; Louis, 2005; Benito-León and Louis,
2006; Elble et al., 2006). Furthermore, in a longitudinal,
prospective, population-based study, ET has been found to
be associated with increased mortality at an estimated risk
ratio of 1.59 (95% CI 1.11–2.27, P = 0.01) (Louis et al.,
2007a). Meta-analysis of epidemiologic studies has found
the prevalence of ET to range between 0.01% and 20.5%, but
the pooled prevalence is 0.9%; the prevalence in people ≥65
years old is 4.6% and may be as high as 21.7% in people
≥95 years old; the prevalence is higher in males than females
(Louis and Ferreira, 2010). There are many other estimates
(Haerer et al., 1982; Louis et al., 1995, 1998d; Dogu et al.,
2003) such as 5.5% in people over the age of 40 years
(Rautakorpi et al., 1982) and 14% in people 65 years old or
older (Moghal et al., 1994) (Table 18.2). In one epidemio-
logic study, 108 of 1056 (10%) nondemented individuals in
upper Manhattan, aged 65 years or older, reported “shaking”
(Louis et al., 1996). Neurologic examination confirmed rest
tremor in 8.3% and action tremor in 17.6%, and the preva-
lence of PD and ET was estimated to be 3.2% and 10.2%,
respectively. In a door-to-door survey of people aged 40 years
or older in Mersin Province, Turkey, the prevalence of ET was
found to be 4% (Dogu et al., 2003). In another population-
based survey, involving 5278 subjects aged 65 years or older

Table 18.2  Prevalence and incidence of essential tremor
Prevalence
• 0.4%–5.5% – community-based studies
• 14% in people ≥65 years
• 4% – a door-to-door survey of people ≥40 years in Mersin
Province, Turkey
Incidence
• 616/100 000 person-years – a population-based study of 5278
subjects ≥65 years in central Spain followed for a median of 3.3
years
– 64/83 (77.1%) incident cases had not been previously
diagnosed, and only 4 (4.8%) were taking antitremor
medications
in central Spain who were followed for a median of 3.3 years,
the adjusted annual incidence was determined to be 616 per
100 000 person-years; 64 of the 83 (77.1%) incident cases
had not been previously diagnosed, and only 4 (4.8%) were
taking antitremor medications (Benito-León et al., 2005). In
yet another population-based study of northern Italian
adults in which all participants were examined and classified
by movement specialists using rigorous diagnostic criteria,
tremors comprised the most common category of movement
disorders, followed by restless legs syndrome (Wenning
et al., 2005). These epidemiologic studies provide strong
evidence that the prevalence and incidence of ET are higher
than was previously recognized.
Diagnosis of ET
Although ET was described as early as the nineteenth century
(Dana, 1887; Louis, 2010), there is still considerable contro-
versy about the diagnostic criteria for ET (Chouinard et al.,
1997; Louis et al., 1998c; Jankovic, 2000; Louis, 2010; Quinn
et al., 2011). In one study of 71 patients, 37% diagnosed with
ET based on the criteria for ET adapted from the consensus
statement of the Movement Disorders Society (Deuschl
et al., 1998a) were misdiagnosed, usually either as PD or
dystonia (Jain et al., 2006). This is partly due to a lack of a
disease-specific marker for ET. No specific pathologic changes
indicative of PD were noted in 20 brains of ET patients that
were examined at autopsy (Rajput et al., 2004). However,
this study is fundamentally flawed, since all patients who
were selected for the study had a diagnosis of ET at the time
of death and patients who started with ET and later devel-
oped PD would have been excluded (Jankovic, 2004). It is
of interest that one patient with severe ET that began at age
45 and no parkinsonian features, at the time of her death at
age 91 years had Lewy bodies localized to the locus coeru-
leus, providing further evidence of a connection between ET
and Lewy body disease (Louis et al., 2005b). The controversy
about the possible association of ET and PD should be clari-
fied once the genetic basis and pathophysiology of ET are
understood. Until then, the operational diagnostic criteria
must rely on the presence of typical clinical characteristics.
The presence or absence of certain clinical characteristics
may be used to categorize ET into “definite,” “probable,” and
“possible” (Table 18.3). The diagnostic criteria may be used
or modified according to specific needs. For example, for
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Postural tremors
Table 18.3  Proposed classification of essential tremor
A. Definite essential tremor
1. Inclusions
a. Bilateral postural tremor with or without kinetic tremor involving
hands or forearms, which is visible and persistent and is
long-standing in duration (>5 years)
b. Tremor involving body parts other than the upper limbs may be
present, the tremor may be asymmetrical, amplitude may
fluctuate, and the tremor might or might not produce disability
2. Exclusions
a. Neurologic signs, except for Froment sign
b. Causes of enhanced physiologic tremor
c. Concurrent or recent exposure to tremorgenic drugs
d. Direct or indirect trauma to the central and peripheral nervous
systems
e. Historical or clinical evidence of psychogenic origins of tremor
f. Convincing evidence of sudden onset or evidence of stepwise
deterioration
B. Probable essential tremor
1. Inclusions
The same as for definite ET, but the tremor may be confined to body
parts other than hands and the duration is greater than 3 years
2. Exclusions
a. Primary orthostatic tremor, which is an isolated, high-frequency
(14–18 Hz), bilaterally synchronous leg tremor on standing or
voluntary contraction of leg muscles
b. Isolated voice, tongue, or chin tremors
c. Position- and task-specific tremors
C. Possible essential tremor
1. Inclusions
a. Type 1. Satisfy criteria for definite or probable ET but exhibit
other recognizable neurologic disorders, such as:
(1) Parkinsonism, dystonia, myoclonus, peripheral neuropathy, or
restless legs syndrome
(2) Other neurologic signs of uncertain significance not sufficient
to make a diagnosis of a recognizable neurologic disorder,
such as mild extrapyramidal signs (hypomimia, decreased
armswing, and mild bradykinesia)
b. Type 2. Monosymptomatic and isolated tremors of uncertain
relationship to ET. This includes position- and task-specific
tremors, such as occupational tremors (primary writing tremors);
primary orthostatic tremor; isolated voice, chin, tongue, and leg
tremor; and unilateral postural hand tremor
2. Exclusions
Same as points 2a–f for definite ET
Members of the Tremor Research and Investigation Group: M. Brin, C. Contant,
R. Elble, L. Findley, J. Jankovic, W. Koller, P. LeWitt, A. Rajput.
From Findley LJ, Koller WC. Definitions and behavioural classifications. In Findley LJ,
Koller WC (eds): Handbook of Tremor Disorders. New York, Marcel Dekker, 1995,
pp 1–5.
genetic linkage studies, only “definite” ET may be acceptable,
whereas in studies that are designed to explore the clinical
spectrum of ET, including associated features, the “possible”
ET category might be more appropriate (Table 18.4). Family
history, alcohol sensitivity, and propranolol responsiveness,
while characteristic of ET, should not be considered neces-
sary for the diagnosis. More recently, core and secondary
395
 18 Tremors
Table 18.4  NIH Essential Tremor Consortium diagnostic
criteria for essential tremor
Definite
1. Bilateral arm tremor with 2+ amplitude rating in at least one arm
and 1+ in the other arm
or
2. Predominant cranial-cervical tremor with 2+ amplitude rating and
1+ rating in at least one arm. The head tremor is rhythmic, without
directional preponderance, and without asymmetry of cervical
muscles
3. Exclude obvious secondary causes of tremor: for example,
physiologic, drug-induced, Charcot–Marie–Tooth (CMT), chronic
inflammatory demyelinating polyradiculoneuropathy (CIPD), PD
(Coexistent dystonia is allowed, but coexistent PD is not)
Probable
1. 1+ arm tremor bilaterally
or
2. Isolated cranial-cervical tremor with 2+ amplitude rating
or
3. Convincing history of ET
4. Exclude obvious secondary causes of tremor: for example,
physiologic, drug-induced, CMT
(Coexistent dystonia is allowed; coexistent PD is allowed if there is a
convincing history of preexisting ET)
Possible
1. Isolated 1+ cranial-cervical tremor
2. Task/position specific hand/arm tremor
3. Unilateral arm tremor
4. Orthostatic tremor
Tremor rating: 0, none perceived; 1, slight (barely noticeable); 2, moderate,
noticeable, probably not disabling (<2 cm excursions); 3, marked, probably partially
disabling (2–4 cm excursions); 4, severe, coarse, disabling (>4 cm excursions).
Participants in the July 1996 NIH meeting: J. Beach, S.B. Bressman, M.F. Brin, D. De
Leon, L. Goldfarb, M. Hallett, J. Jankovic, W. Koller, D. Mirel, K. Wilhemsen.
From Brin MF, Koller W. Epidemiology and genetics of essential tremor. Mov Disord
1998;13(Suppl. 3),55–63.
criteria were proposed to facilitate a practical approach to
the diagnosis of ET (Elble, 2000a). Core criteria include
bilateral action tremor of the hands and forearms (but not
rest tremor), absence of other neurologic signs, except for
the Froment sign (a “cogwheel” phenomenon on passive
movement of the affected limb with voluntary movement of
the contralateral limb), and isolated head tremor without
signs of dystonia, although the latter is rare. A recent analysis
of ET patients from two large population-based studies and
one large clinic-based cohort revealed no cases of pure head
tremor in 583 patients (Louis and Dogu 2009). Therefore,
patients with pure head tremor probably should not be
regarded as definite ET. Head tremor is seen in about 18%
of population-based cases of ET and in 37% of clinical
samples of ET (Louis and Dogu, 2009). Secondary criteria
include long duration (>3 years), a positive family history,
and a beneficial response to alcohol (Mostile and Jankovic,
2010). Another feature, seen in about a third of patients with
ET, is mirror movements (Louis et al., 2009d), more typi-
cally observed in patients with focal dystonia (Sitburana
et al., 2009). There are red flags that indicate a diagnosis
other than ET, such as unilateral tremor, present in only
396
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4.4% of cases of ET (Phibbs et al., 2009), leg tremor, rigidity,
bradykinesia, rest tremor, gait disturbance, focal tremor, iso-
lated head tremor with abnormal posture (head tilt or
turning), sudden or rapid onset, and drug treatment that
may cause or exacerbate tremor. Thus head tremor is usually
a manifestation of ET or cervical dystonia; it is almost never
seen in PD unless there is coexistent ET (Roze et al., 2006;
Gan et al., 2009).
A review of the clinical features in 350 consecutive patients
who were referred to the Movement Disorders Clinic at
Baylor College of Medicine and diagnosed with ET has
shown that although tremor is clearly the most troublesome
symptom, it is not necessarily the only symptom in patients
with ET (Lou and Jankovic, 1991b) (Tables 18.1 and 18.3).
This is supported by the reports of well-studied families in
which some members have typical ET, while others have
dystonia, parkinsonism, or a combination of all three disor-
ders (Jankovic et al., 1997; Farrer et al., 1999; Bertoli-Avella
et al., 2003; Yahr et al., 2003; Spanaki and Plaitakis, 2009).
One multigenerational family, 36 members in five genera-
tions, had an admixture of ET, PD, and dystonia (Yahr et al.,
2003). Two twin brothers with ET and PD had the classic
pathologic features of PD at autopsy. The authors concluded,
“This unusual set of clinical and pathologic circumstances
can hardly be attributed to chance occurrence and raises the
question of a specific genetic mutation and/or clustering,
which may link ET with PD.” In a study of the first-degree
relatives of 303 PD probands and 249 controls from Crete,
ET was present in the relatives of PD patients more often
than in those of controls (OR: 3.64, P < 0.001) and the risk
was even greater (OR: 4.48) when the affected proband had
tremor-dominant or mixed PD (Spanaki and Plaitakis,
2009). Twelve subjects had both ET and PD phenotypes. The
authors concluded that “in certain families ET and PD are
genetically related probably sharing common hereditary pre-
disposition.” Retrospective chart review at the Neurological
Institute (NI) of New York showed that 56.7% of 210
PD patients versus 33.3% of 210 Parkinson-plus syndrome
patients (P < 0.001) had kinetic tremor on examination and
patients with PD were more likely to have a diagnosis of ET
assigned by an NI neurologist (5.3% vs. 0.0%, OR 12.85,
95% CI 1.66–99.8, P = 0.001) (Louis and Frucht, 2007).
Patients with PD were three to thirteen times more likely to
have diagnoses of ET than patients with Parkinson-plus syn-
dromes, thus confirming “the link between ET and PD, and
possibly, between ET and Lewy body disease.” In another
large family, originally from Cuba, manifested by parkinson-
ism and ET, the parkinsonism was linked to a marker on
chromosome 19p13.3–q12, but it did not cosegregate with
ET (Bertoli-Avella et al., 2003). Other gene mutations associ-
ated with PD have not been found in patients with ET alone
(Deng et al., 2006a). Some, but not all (Adler et al., 2011)
studies have suggested that there is an association between
ET and dystonia and between ET and parkinsonism (Janko-
vic et al., 1997; Yahr et al., 2003; Shahed and Jankovic, 2007;
Fekete and Jankovic, 2011) (Fig. 18.2). In addition to dys-
tonic tremor, patients with dystonia frequently have postural
ET-like tremor present in body parts distal to the dystonia,
and they have a higher-than-expected family history of pos-
tural tremor (Chan et al., 1991; Jankovic et al., 1991; Deuschl
et al., 1997; Jankovic and Mejia, 2005; Schneider et al.,
2007). Asymmetric dystonic hand tremor may be initially

ET ET-PD
• Bimodal age at onset • Rest-action tremor
• Action/postural > rest tremor • Olfactory deficit
• Hand, head, voice tremor • Families with ET-PD
• Task-, position-specific • Dopaminergic
variants (writing, orthostatic) deficit by imaging
• Loss of hearing, gait ataxia studies
• Cerebellum plays a role • Lewy bodies at
• Improves with ETOH, beta autopsy
blockers, primidone,
topiramate, pregabalin?
Figure 18.2  Overlap between and differentiation of essential tremor and Parkinson disease. ETOH, ethanol. SN, substantia nigra.
misdiagnosed as PD-related tremor and, along with rest
tremor associated with ET, may be responsible for scans
without evidence of dopamine deficiency (SWEDDs) (Sch-
neider et al., 2007; Bain, 2009; Schwingenschuh et al., 2010;
Stoessl, 2010). When 25 tremulous SWEDDs patients were
compared to 25 tremor-dominant PD patients, the former
group lacked true bradykinesia, they had evidence of dysto-
nia, and head tremor, whereas reemergent tremor, true
fatiguing or decrement, good response to dopaminergic
drugs, and presence of nonmotor symptoms favored PD
(Schwingenschuh et al., 2010). Whether the hand tremor
that is seen in about 25% (10–85%) of patients with cervical
dystonia represents an enhanced physiologic tremor, ET,
dystonic tremor, or some other form of postural tremor
is unknown (Jankovic et al., 1991; Deuschl et al., 1997).
Although the frequency of ET and the limb tremor in patients
with cervical dystonia are similar, the tremor amplitude in
patients with dystonia is smaller and the tremor is more
irregular, suggesting that the two types of tremors, while
similar, arise from different types of oscillators (Shaikh et al.,
2008). The observation of significant overlap in association
between variants in LINGO1 and ET and PD (see below)
provides support for the genetic association between the two
common movement disorders (Vilariño-Güell et al., 2010a).
The clinical heterogeneity of ET suggests that there may be
different subtypes. Indeed, Louis and colleagues (2000b)
found that patients with older onset (>60 years) and those
without head tremor progressed more rapidly than did
patients with young-onset tremor and those with head
tremor. They also later found that head tremor was present
four times more frequently in women than in men (Louis
et al., 2003; Hardesty et al., 2004). Using the medical records
linkage system of the Rochester Epidemiology Project, the
authors identified ET patients who also had an autopsy
report and found that women with ET were six times more
likely to develop head tremor than men (Hardesty et al.,
2004). The presence of jaw tremor, seen in 7.5–18.0% of
patients with ET, has been found to be associated with older
age at onset, more severe action tremor in arms, and the
presence of head and voice tremor (Louis et al., 2006a). In
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Postural tremors
PD
• Increases with age
• Rest > action/postural tremor
• Reemergent tremor
• Upper, lower limb, chin tremor
• Rigidity, bradykinesia,
postural instability, freezing
• Nonmotor features
• SN, caudal brainstem
degeneration
• Improves with levodopa,
dopamine agonists
a study of 34 patients with voice tremor, 93% were female
and the voice tremor typically began in the seventh decade
(62.9 ± 15.0 years) (Sulica and Louis, 2010). More than a
third had a first-degree relative with tremor and more than
a quarter reported a beneficial effect of ethanol. In this study
only 11 (32.3%) were aware of an arm tremor and 10 (29.4%)
had been misdiagnosed as spasmodic dysphonia. Only 56%
of treated patients found botulinum toxin helpful and the
response was often incomplete. Jaw tremor was also signifi-
cantly associated with rest tremor, suggesting that some
patients with ET and jaw tremor may convert to PD. Besides
ET and PD, jaw tremor may be a manifestation of dystonia
(Schneider and Bhatia, 2007). Lower extremity tremor is
usually mild or asymptomatic (Poston et al., 2009).
The ongoing debate as to whether ET is a monosympto-
matic or heterogeneous disorder or phenotypic manifesta-
tion of multiple entities will probably not be resolved until
disease-specific physiologic, genetic, or other biologic
markers are identified (Schrag et al., 2000; Elble, 2002;
Jankovic, 2002; Elble and Tremor Research Group, 2006;
Louis, 2009; Deuschl and Elble, 2009). One hypothesis is
that the various nonmotor signs linked to ET could be sec-
ondary to “abnormal neuronal oscillation” (Deuschl and
Elble, 2009), but his would not explain the heterogeneous
presentation of ET. Also, the proposed classification of ET
into “hereditary” (unequivocal family history), “sporadic”
(no immediate family member with ET), and “senile” (onset
after age 65) is too artificial and not easily applicable. Some
studies have suggested that there is an association between
ET and parkinsonism (Jankovic et al., 1997; Yahr et al., 2003;
Shahed and Jankovic, 2007; Fekete and Jankovic, 2011), but
other studies have not found a link (Adler et al., 2011)
(Fig. 18.2). Differentiation between ET and PD is critical
particularly in early stages since ET has been found to be
erroneously treated with anti-PD drugs in 12.4% of 402
community cases re-evaluated by a movement disorder spe-
cialist (Meara et al., 1999). Postural tremor, similar to ET, has
been reported to occur in as many as 93% of patients with
PD and to correlate with the ipsilateral rest tremor but not
with age at onset or disease duration (Louis et al., 2001e).
397
 18 Tremors
Furthermore, in 22 patients with PD with family history of
ET, 90% (20 of 22) had a tremor-predominant subtype of
PD, suggesting that “these patients have inherited a genetic
susceptibility factor for tremor, which affects the motor
phenotype of PD” (Hedera et al., 2009). Phenomenologi-
cally similar to ET, the postural tremor of PD has been linked
by some investigators to coexistent ET (Geraghty et al., 1985;
Jankovic, 1989; Jankovic et al., 1997; Jankovic 2000). Others,
however, believe that the coexistence of the two disorders
simply “represents a chance occurrence of two common dis-
eases” (Pahwa and Koller, 1993). On the basis of an analysis
of 678 patients diagnosed as having ET, some by movement
disorder specialists and others by private practice neurolo-
gists, 6.1% were found to have concomitant PD, and 6.9%
had coexisting dystonia (Koller et al., 1994). The authors
concluded that “the frequency of PD in ET is more than
would be reported in the general population.” In the Neu-
rological Disorders in Central Spain (NEDICES) study, a
longitudinal, population-based study of 3813 people (mean
age 73.4 ± 6.6 years), after a median of 3.3 years, 12 (5.8%)
of 207 ET cases developed parkinsonism compared with
56 (1.6%) of 3606 controls, with adjusted relative risk (RR)
of 3.47 (95% confidence interval 1.82–6.59; P < 0.001)
(Benito-León et al., 2009b). Six (3.0%) of 201 ET cases
developed incident PD versus 24 (0.7%) of 3574 controls,
with adjusted RR of 4.27 (95% confidence interval 1.72–
10.61; P = 0.002). The authors concluded that “Patients with
ET were four times more likely than controls to develop
incident PD during prospective follow-up.”
The coexistence of ET and PD may be difficult to recognize
because once a patient develops PD, the postural tremor is
usually attributed to the disease, and it is therefore difficult
to diagnose ET in a patient who already has symptoms of
PD (Shahed and Jankovic, 2007; Louis, 2009; Fekete and
Jankovic, 2011) (Fig. 18.2). While rest tremor may be
observed in patients with advanced ET, it may also be the
initial manifestation of coexistent PD (Shahed and Jankovic,
2007; Fekete and Jankovic, 2010). The “postural tremor” that
is seen in many patients with PD may represent an enhanced
physiologic tremor (Forssberg et al., 2000), coexistent ET
(Geraghty et al., 1985; Jankovic, 1995), or a reemergent
classical rest tremor (Jankovic et al., 1999) with the same
frequency and clinical characteristics as the typical rest
tremor. This reemergent tremor is also often exacerbated
during walking. In contrast to ET, which is seen immediately
when patients outstretch their arms, the reemergent tremor
of PD usually appears after a latency of several seconds
(Jankovic et al., 1999). Furthermore, this PD-related tremor
often responds to levodopa, whereas the postural tremor of
ET does not (Kulisevsky et al., 1995). It is actually this action
tremor that seems to correlate with motor disability rather
than the typical rest tremor, which correlates chiefly with
social handicap (Zimmermann et al., 1994). The clinical
characteristics, however, may not always reliably differenti-
ate between the two types of postural tremor (Henderson
et al., 1995). We found a higher frequency of the 263 bp
allele of the NACP-Rep1 polymorphism not only in patients
with PD (odds ratio: 3.86) but also in patients with ET
(odds ratio: 6.42), but not in patients with Huntington
disease, supporting a genetic link between PD and ET (Tan
et al., 2000). Further evidence that ET and PD may be related
is the observation that patients with ET have an olfactory
398
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deficit that is similar, although milder, than that noted in
patients with PD (Louis et al., 2002; Louis and Jurewicz,
2003; Djaldetti et al., 2008). In one study, however, there
was no difference in results of olfactory testing between ET
patients and controls (Shah et al., 2008). We and others
(Gimenez-Roldan and Mateo, 1991) have noted that patients
with ET seem to have a higher propensity toward neuroleptic-
induced parkinsonism than do patients without ET, although
a formal epidemiologic study is needed to confirm this clini-
cal observation. To examine an ET–PD relationship, we
described 22 patients with childhood-onset ET who later
developed PD (Shahed and Jankovic, 2007; Fekete and
Jankovic, 2011). Of 11 patients reporting asymmetric ET, PD
symptoms began on the same side as the more severe ET
tremor in 10 (90.9%, χ2 = 0.66, P = 0.024), with 68.2%
reporting change in tremor as their first PD manifestation.
These findings, supported by another study (Tan et al.,
2006), suggest that in some patients, childhood ET evolves
into adult tremor-dominant PD, explaining the coexistence
of ET and PD within the same patient and family. It has
been postulated that ET-related gene mutations may predis-
pose some patients to subsequent development of PD. In a
study of 53 patients with ET–PD combination, compared to
53 PD and 150 ET patients, the side of the greatest initial ET
severity corresponded to the side of the greatest PD severity
(Minen et al., 2008). In another study involving 13 patients
who presented originally with asymmetrical postural tremor
and no rest tremor for at least 10 years (mean: 19.2 years)
and were initially diagnosed with ET, all patients subse-
quently developed evidence of PD (Chaudhuri et al., 2005).
The onset of levodopa-responsive PD was manifested by rest
tremor for a mean of 2.5 years before final presentation in
the clinic. Furthermore, five patients who had β-CIT single
photon emission computed tomography (SPECT) all
showed reduced uptake in the contralateral striatum. It is
not clear whether these patients with a long-standing history
of asymmetrical postural tremor have PD at onset, whether
patients with unilateral postural tremor (isolated tremor) or
asymmetrical postural tremor (atypical ET) who later
develop PD represent an overlap between ET and PD, or
whether this type of postural tremor is an early marker for
PD (Grosset and Lees, 2005).
In a population-based study (981 first-degree relatives of
162 patients with PD and of 838 first-degree relatives of 147
controls), the risk of ET was significantly increased for rela-
tives of patients with onset of PD (P = 0.006) (Rocca et al.,
2007). Also, in a referral-based sample (981 first-degree rela-
tives of 162 patients with PD and of 838 first-degree relatives
of 147 controls), the risk of ET among relatives increased
with younger onset of PD in patients (P = 0.001) and
was higher in relatives of PD patients with the tremor-
predominant or mixed form when compared with relatives
of patients with the akinetic-rigid form, and in men com-
pared with women. The authors concluded that “These find-
ings suggest that PD and ET may share familial susceptibility
factors.” In a case-control study of 600 subjects evaluated for
tremor, ET was significantly more frequent in patients with
PD (12/204, 5.9%) compared to diseased controls (2/206,
1%) and healthy controls (1/190, 0.5%) (Tan et al., 2008).
The authors concluded that “PD patients were 5–10 times
more likely to have ET compared diseased and healthy
controls.”

In addition to genetic factors, there may be environmental
factors that determine the occurrence of ET and its relation-
ship to PD. For example, heavy cigarette smoking has been
associated with lower risk of PD and ET (Louis et al., 2008a).
Although some studies have concluded dementia is more
frequent in patients with ET than in controls (Bermejo-
Pareja et al., 2007), and one study reported the adjusted
odds ratios to vary between 1.64 and 1.84 (Thawani et al.,
2009), a relationship between ET and Alzheimer disease has
not been established (Elble et al., 2007a).
The possibility of additional cochlear involvement in ET
is supported by the observation of high occurrence of partial
or complete deafness in patients with ET (Ondo et al., 2003).
Among 250 patients with ET, 42 (16.8%) patients wore
hearing aids, compared to only 2 of 127 (1.6%) PD patients
and 1 of 127 (0.8%) controls (P < 0.0001). Pure tone audi-
ometry demonstrated age-dependent higher-frequency loss
among patients with ET as compared to the general popula-
tion. High risk of hearing loss among patients with ET has
been confirmed by other studies (Benito-León et al., 2007).
The combination of ET, sensorineuronal hearing loss, and
early graying has been suggested to be a unique disorder,
separate from Waardenburg syndrome (Karmody et al.,
2005). Although mental functioning is usually intact in
patients with ET, detailed testing of cognitive performance
has found some subtle abnormalities on tests of verbal
fluency, naming, mental set-shifting, verbal working memory,
and other tests of cognitive function (Benito-León et al.,
2006a) and elderly patients with ET may possibly have an
increased risk of dementia compared with those without ET
(Benito-León et al., 2006b). Furthermore, depression has
been found to occur in about a third of the patients with ET,
almost as frequently as in PD (Lombardi et al., 2001; Miller
et al., 2007). These deficits have been interpreted as suggest-
ing involvement of frontocerebellar circuits. In a cross-
sectional study of personality, patients with ET were found
to have a tendency to have increased levels of pessimism,
fearfulness, shyness, anxiety, and easy fatigability, but none
of these traits correlated with the severity of the tremor
(Chatterjee et al., 2004).
ET appears to be a heterogeneous disorder, as is suggested
by the multiple gene loci that have so far been identified and
by the frequent association with other disorders, such as
parkinsonism, dystonia, and myoclonus (Jankovic et al.,
1997; Jankovic, 2002; Yahr et al., 2003; Deng et al., 2006b;
Shahed and Jankovic, 2007) (Fig. 18.2). Postmortem studies
of patients with ET have not provided evidence for nigros-
triatal pathology in ET, but patients who had a diagnosis of
PD at time of death (even though ET might have preceded
the onset of PD) would have been excluded from these
clinical-pathologic studies (Jankovic, 2004; Rajput et al.,
2004). Furthermore, there is indirect evidence suggesting
nigrostriatal impairment in some patients with ET. We found
that relatives of patients with PD have at least a 2.5 times
higher (those with the combination of ET–PD: 10 times
higher) frequency of tremor than normal controls, providing
additional support for the association of ET and PD
(Jankovic et al., 1995a). Furthermore, about 20% of patients
with ET have a rest tremor that has the clinical and physio-
logic characteristics of PD tremor (Cohen et al., 2003).
However, when 9 brains of patients who exhibited advanced
ET and upper extremity rest tremor (without any other
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Postural tremors
evidence of parkinsonism) were examined with alpha-
synclein staining, only two had Lewy bodies in the dorsal
vagus nucleus and locus ceruleus, but none had Lewy body-
containing neurons and/or Lewy neurites in the basal ganglia
(Louis et al., 2011). Although this pathological study sug-
gests that rest tremor in patients with ET is not associated
with PD pathology, 19 of 24 (80%) patients with ET and rest
tremor without other parkinsonian features had abnormal
DAT uptake on DaTscan, particularly in the putamen (deVer-
dal et al., 2011). Similarly, a fourfold increase in prevalence
of isolated tremor among relatives of patients with PD as
compared to controls was found by Payami and colleagues
(1994). Interestingly, among 196 twins with postural or
kinetic tremors, Tanner and colleagues (2001) found that
137 had PD or had a twin with PD.
Imaging studies have been helpful in providing insight
into the relationship between ET and PD. A 10–13% reduc-
tion in 18F-dopa uptake in the striatum of patients with ET
as compared to controls (Brooks et al., 1992) suggests a
physiologically important compromise of the dopaminergic
system in patients with ET (Jankovic et al., 1993). Further-
more, 18F-dopa uptake constants (Ki) in 5 of 32 asympto-
matic relatives of patients with PD who had isolated postural
tremor were reduced on average by 23% (P < 0.001) (Piccini
et al., 1997). The mean Ki for the other 27 asymptomatic
relatives was decreased by 17% (P < 0.001). Using 123I-IPT
SPECT to image the striatal dopamine transporter, Lee and
colleagues (1999) found the mean bilateral uptake in nine
patients with isolated postural tremor (ET) to be slightly
lower than that in normal control subjects (3.60 vs. 3.80),
but this did not reach statistical significance. Six other
patients in whom rest tremor developed 4–18 years (mean:
11.5 ± 6.7) after the onset of postural tremor without other
parkinsonian features, however, had a significant reduction
in the dopamine transporter compared to normal controls
(2.61 vs. 3.83, P < 0.05) but lower than PD patients (1.97
contralateral and 2.35 ipsilateral). They concluded that some
patients with postural tremor may acquire rest tremor in
association with mild substantia nigra neuronal loss.
Although the majority of ET patients have normal dopamine
transporter (DAT) SPECT, some cases may start with isolated
postural tremor, phenomenologically identical to ET, and
later develop PD. In one study the mean latency between the
onset of asymmetrical postural tremor and PD was 19.2
years whereas the mean latency between onset of rest tremor
and PD was 2.5 years (Chaudhuri et al., 2005). In one study
of 61 subjects presenting with “isolated atypical tremors
defined as unilateral either postural, resting or mixed” fol-
lowed at baseline and at mean 28.4 ± 7.2 months with 123I-
FPCIT SPECT, those (n = 25) with normal baseline scan had
only tremor at follow-up, and of the 36 with abnormal
baseline scan, 23 (64%) developed PD, while the remaining
patients had only tremor (presumably ET) (Ceravolo et al.,
2008). They suggested that term “isolated tremor with
dopaminergic presynaptic dysfunction” is used for the
patients with unilateral or asymmetrical tremor with abnor-
mal DAT SPECT. Whether the use of 123I-FPCIT SPECT in
differentiating ET from PD is cost-effective is not clear,
although one Italian study suggested some cost savings when
using this diagnostic tool (Antonini et al., 2008). In one
study FP-CIT SPECT showed that the pattern of dopaminer-
gic loss over time is different between ET and PD, but both
399
 18 Tremors
disorders exhibit impairment of DAT in the caudate nucleus
(Isaias et al., 2010). Although this and other imaging studies
reported by the same group (Isaias et al., 2008) provide
important insights into the selective caudate dopaminergic
deficit as a possible link between the two common disorders,
some studies have reported that DAT SPECT remains normal
over time in patients with mixed tremor (a combination of
postural and rest tremor) (Arabia et al., 2010). Since medial
substantia nigra (that predominantly projects to the caudate
nucleus) is particularly involved in the tremor-dominant PD
and is associated with more caudate loss of DAT, it is pos-
sible that tremor-dominant PD and ET share a selective
dopaminergic loss in the caudate nucleus. This, in turn, may
lead to a dysfunction of the caudate-thalamic pathway and
disinhibition of the thalamic autorhythmic pacemakers,
clinically expressed as tremor. Indeed, β-CIT SPECT, which
mainly reflects serotonin transporters, is lower in the thala-
mus of patients with tremor-dominant PD as compared to
those with non-tremor PD (Caretti et al., 2008). In addition
to thalamus, the caudate also projects to the inferior olive
and cerebellum, both implicated in the pathophysiology of
ET, and supported by growing evidence or cerebellar pathol-
ogy in ET. The clinical overlap between the two disorders
undoubtedly contributes to the 10–15% frequency of
patients diagnosed with mild PD who have SWEDDs
(Schneider et al., 2007; Bain, 2009; Schwingenschuh et al.,
2010; Stoessl, 2010).
A relationship between ET and nigral degeneration is sup-
ported by the finding of hyperechogenicity of substantia
nigra on midbrain sonography in 16% of 44 ET patients as
compared to 3% of 100 controls and 75% of 100 patients
with PD (Stockner et al., 2007). Although not demonstrated
by all studies (Doepp et al., 2008; Budisic et al., 2009), the
slightly increased hyperechogenicity of the substantia nigra
on midbrain sonography provides further support for
the notion that some ET patients may later develop
parkinsonism.
Although the relatively frequent coexistence of ET and
dystonia supports the notions that there is a pathogenetic
link between the two disorders, linkage analysis has excluded
the dystonia (DYT1) gene on chromosome 9 in hereditary
ET (Conway et al., 1993; Dürr et al., 1993). This suggests
that the genes for these two disorders are on separate loci or
that the relationship between the two disorders is physio-
logic rather than genetic. Münchau and colleagues (2001)
studied 11 patients with classic ET and compared them to 19
patients with cervical dystonia and arm tremor. They found
that the latency of the second agonist burst during ballistic
wrist flexion movements was later in ET patients than in
those with arm tremor associated with cervical dystonia.
Furthermore, the latter group had a greater variability in
reciprocal inhibition than the ET group. Patients with normal
presynaptic inhibition had simultaneous onset of their arm
tremor with onset of their cervical dystonia (mean age: 40
years), whereas patients with reduced or absent presynaptic
inhibition had an earlier age at onset (mean 14 years), and
the interval between the onset of the tremor and the onset
of cervical dystonia was longer (mean: 21 years). This sug-
gests that the mechanisms of arm tremor in patients with ET
and cervical dystonia are different. The association between
ET, dystonia, and PD is suggested by reports of families with
manifestations of these three disorders in different or same
400
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members of the families (Jankovic et al., 1997; Yahr et al.,
2003).
ET-like tremor has been described in patients with heredi-
tary myoclonus and with hereditary motor-sensory neuropa-
thy (sometimes referred to as Roussy–Levy syndrome)
(Cardoso and Jankovic, 1993). ET-like tremor occurs in
other genetic diseases, the study of which may provide
important insights into possible genetic heterogeneity in
families with clinically similar tremor. For example, postural
tremor similar to that seen in ET has been reported in
patients with Kennedy disease, also called X-linked recessive
spinal and bulbar muscular atrophy, which is caused by a
mutation characterized by expansion of CAG repeats in the
gene on the X chromosome (Sperfeld et al., 2002). ET may
also be associated with higher-than-expected frequency with
restless legs syndrome (Ondo and Lai, 2006). The validity
and meaning of such associations, however, are disputed,
and the controversies are not likely to be resolved until a
disease-specific marker (e.g., an ET-linked genetic locus) is
identified. A diagnostic marker for ET would also help to
resolve the question as to whether site-, position-, and task-
specific tremors, such as primary handwriting tremor and
orthostatic tremor, are distinct entities or whether these
tremors represent clinical variants of ET (Rosenbaum and
Jankovic, 1988; FitzGerald and Jankovic, 1991; Britton et al.,
1992b; Danek, 1993; Soland et al., 1996b; Sander et al.,
1998) (Table 18.5). It is still not clear whether primary
writing tremor is a variant of ET, a type of focal dystonia such
as writer’s cramp, or a separate nosological entity (Hai et al.,
2010; Quinn et al., 2011).
Orthostatic tremor, first described by Heilman in 1984, is
a fast (14–16 Hz) tremor, involving mainly the legs and
trunk, but cranial muscles may be also involved (Koster
et al., 1999) (Video 18.5). The latter observation suggests
that supraspinal mechanisms play a role in the pathophysi-
ology of orthostatic tremor. This is further supported by the
finding of high intermuscular coherence between the two
sides, providing evidence that the tremor originates from a
common site (Lauk et al., 1999), and a high degree of EMG
coherence between right and left muscle groups. This is in
contrast to ET or PD tremors, in which there is no such left/
right coherence, and these tremors are probably generated
by more than one oscillator (Raethjen et al., 2000). Some
authors have suggested that coherent high-frequency tremor
in the legs may be a normal response to perceived unsteadi-
ness when standing still and that orthostatic tremor may be
an exaggeration of this response (Sharott et al., 2003).
Others have postulated that orthostatic tremor merely
unmasks 16 Hz central oscillators involved in postural
tremor (McAuley et al., 2000). While there is robust evi-
dence for a supraspinal origin of orthostatic tremor, the
spinal cord may also serve as the generator of the tremor as
suggested by the presence of a 16 Hz tremor in a man with
complete paraplegia (Norton et al., 2004). Present chiefly on
standing, orthostatic tremor may be precipitated also by iso-
metric contraction of the upper limbs as well as facial and
jaw muscles (Boroojerdi et al., 1999; Koster et al., 1999).
This suggests that the generation of orthostatic tremor is
more likely related to isometric force control rather than to
regulation of stance. Orthostatic tremor is often associated
with a feeling of unsteadiness and calf cramps, relieved by
sitting or a supine position. Fung and colleagues (2001)

Table 18.5  Categorization of tremors
Rest Action
Postural
• Parkinsonian • Physiologic
– PD • Enhanced physiologic
– Secondary – Stress
– P-plus – Endocrine
• ET variants – Drugs, toxins
• Midbrain • Essential tremor
• Myorhythmia • Orthostatic
• Other position-specific tremors
• PD (reemergent)
• Dystonic
• Cerebellar
• Myorhythmia
• Cortical
• Neuropathic
• Fragile X-associated tremor/ataxia syndrome (FXTAS)
postulated that “the sensation of unsteadiness arises from a
tremulous disruption of proprioceptive afferent activity from
the legs”. The leg cramps are presumably due to a high-
frequency (tetanic) contraction of the calf muscles. The
muscle contraction can be “heard” by auscultating over the
thigh or calf and listening for the characteristic thumping
sound (Brown, 1995).
The pathophysiology of orthostatic tremor is not well
understood, but some have suggested that it is a variant of
ET. In support of the association between ET and orthostatic
tremor is the relatively high occurrence of postural tremor,
phenomenologically identical to ET, and the presence of
family history of tremor in the majority of patients with
orthostatic tremor (FitzGerald and Jankovic, 1991). Further-
more PET findings indicative of bilateral cerebellar (and con-
tralateral lentiform and thalamic) dysfunction, similar to
those observed in ET, have been also reported in patients
with orthostatic tremor (Wills et al., 1996). Some studies
have also suggested that there is a dopaminergic deficit in
orthostatic tremor. Leg tremor, phenomenologically similar
to orthostatic tremor, may be the initial manifestation of PD,
particularly due to parkin mutation (Kim and Lee, 1993;
Deng et al., 2006b). Some patients with orthostatic tremor
respond to levodopa (Wills et al., 1999) and dopamine
agonists (Finkel, 2000). Furthermore, [123I]-FP-CIT SPECT
showed evidence of marked reduction of dopamine trans-
porter in patients with orthostatic tremor (Katzenschlager
et al., 2003).
Tremor that is present predominantly or only on standing,
but usually of much lower frequency than the classic ortho-
static tremor, can be also seen in other conditions, including
parkinsonism, ET, head trauma, pontine lesions, and other
disorders (Gabellini et al., 1990; Benito-León et al., 1997).
In contrast to ET, orthostatic tremor does not respond to the
conventional anti-ET medications, but usually improves
with clonazepam and gabapentin (Rodrigues et al., 2006).
In one study, five of nine patients with orthostatic tremor
benefited from levodopa (Wills et al., 1999). In a review
of 41 patients with orthostatic tremor, Gerschlager and
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Postural tremors
Kinetic Miscellaneous
• Cerebellar • Idiopathic
– Multiple sclerosis • Psychogenic
– Stroke • Other involuntary
– Degenerative rhythmic movements
– Wilson disease – Convulsions
– Drugs, toxins – Myoclonus
• Midbrain – Asterixis
• Task-specific – Nystagmus
• Cortical – Fasciculations
– Clonus
colleagues (2004) found that 24 (58%) patients had associ-
ated postural arm tremor, and 10 (25%) had “orthostatic
tremor plus”; 6 (15%) patients had parkinsonism. The
response to medications was generally poor, but some, par-
ticularly those with associated parkinsonism, responded to
dopaminergic therapy. Whether dopamine agonists and
other antiparkinsonian treatments, including thalamotomy
and VIM or STN/GPi DBS, will provide benefit to patients
with orthostatic tremor remains to be determined. VIM DBS
may be an effective treatment for patients with medically
resistant orthostatic tremor (Guridi et al., 2008; Espay et al.,
2008). Chronic spinal cord stimulation has been reported
to be effective in two patients with medically intractable
orthostatic tremor (Krauss et al., 2006).
The age at onset for ET showed a bimodal distribution
with peaks in the second and sixth decades (Lou and
Jankovic, 1991b). This was evident in both genders and in
patients with and without dystonia and parkinsonism.
Patients with early-onset (<30 years) ET had significantly
more hand involvement, were more likely to have associated
dystonia, and were more likely to improve with alcohol than
were those with later onset (>40 years) ET (P < 0.05). There
were no significant differences in any clinical variables
between patients with and without a family history of
tremor. Patients with older-onset ET, sometimes also referred
to as “senile tremor,” tend to have more rapid progression
and more degenerative pathology than the younger-onset
patients (Louis et al., 2009b). The relative lack of important
differences between subgroups (early versus late onset,
familial versus sporadic, mild versus severe, low versus high
frequency) suggests that ET represents a single disease entity
with a variable clinical expression. This conclusion is sup-
ported by a recent study by Koller and colleagues (1992). In
their clinical and physiologic study of 61 patients, they found
a frequency below 7 Hz in 79% of the patients, a positive
family history in 72%, an amelioration with alcohol in 75%,
an amelioration with primidone in 71%, and an ameliora-
tion with propranolol in 46%. Since no significant correla-
tions could be found to suggest any particular grouping, they
401
 18 Tremors
concluded that “essential tremor cannot be classified into
subtypes.”
Epidemiologic studies indicate that up to 5% of the adult
population has ET, and 5–30% of adults with ET report
symptom onset during childhood (Ferrara and Jankovic,
2009). Childhood-onset ET is usually hereditary, begins at a
mean age of 6 years, and affects boys three times as often as
girls. In a study of 39 patients with childhood-onset ET, a
mean age at onset of 8.8 ± 5.0 years, and a mean age at
evaluation of 20.3 ± 14.4 years, we found that some had
their initial symptoms as early as infancy (Jankovic et al.,
2004). A family history of tremor was noted for 79.5% of
the patients. Eighteen (46.2%) patients had some neurologic
comorbidity, such as dystonia, which was noted in 11
(28.2%) patients. Only 24 (61.5%) patients were treated
with a specific antitremor medication; 5 of the 12 patients
who were treated with propranolol experienced improve-
ment. Other studies of childhood-onset ET also found
male preponderance and paucity of head tremor (Louis
et al., 2001b; Tan et al., 2006). Some investigators have sug-
gested that “shuddering attacks” of infancy might be the
initial manifestation of ET (Vanasse et al., 1976; Kanazawa,
2000).
Some isolated site-specific tremors, such as those involving
the head and trunk (Rivest and Marsden, 1990) and some
task- or position-specific tremors, might actually represent
forms of dystonic tremor (Elble et al., 1990; Jedynak et al.,
1991; Bain et al., 1995). Dystonic tremor is typically irregu-
lar and position-sensitive and when the patient is allowed
to move the affected body part into the position of the
maximal “pull”, the tremor often ceases, the so-called “null
point” (Videos 18.6 and 18.7). Some patients with dystonic
tremor present with asymmetric rest hand tremor and
decreased armswing which may lead to initial misdiagnosis
of PD (Jankovic and Mejia, 2005; Schneider et al., 2007;
Bain, 2009). Although there is some overlap between primary
writing tremor and dystonic writer’s cramp, the former is not
usually associated with an excessive overflow of EMG activity
into the proximal musculature, and the reciprocal inhibition
of the median nerve H-reflex on radial nerve stimulation is
normal (Bain et al., 1995; Modugno et al., 2002). The latter
two features are typical of dystonia, and their presence in
patients with task-specific tremors suggests that despite the
absence of overt dystonia, these tremors represent forms of
focal dystonia (Rosenbaum and Jankovic, 1988; Soland
et al., 1996b). The overlap with primary handwriting tremor
is supported by the observed activation of brain areas on
functional magnetic resonance imaging (MRI) that are com-
monly activated in ET and dystonic writer’s cramp. Other
causes of postural tremor include midbrain (rubral) lesions.
In a study of six patients with midbrain tremors, PET studies
indicated dopaminergic striatal denervation, supported by
markedly decreased fluorodopa uptake in the ipsilateral
striatum (Remy et al., 1995). This nigrostriatal denervation,
however, was not accompanied by striatal dopamine recep-
tor supersensitivity, and the density of striatal D2 receptors
did not change. Furthermore, the density of dopamine trans-
porter is the same as that in normal controls (Antonini et al.,
2001). Another form of postural tremor with bilateral high-
frequency (14 Hz) synchronous discharges was reported in
a patient with sporadic olivopontocerebellar atrophy (Manto
et al., 2003).
402
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Genetics
A family history of tremor has been reported in 17–100% of
patients with ET (Busenbark et al., 1996; Louis and Ottman,
1996). The reason for such a large discrepancy is that unless
all the symptomatic and asymptomatic members of the
family are examined, the number of affected relatives will be
under-ascertained (Jankovic et al., 1997; Louis et al., 1999b).
Tremor in relatives is often wrongly attributed to aging,
stress, nervousness, PD, alcoholism, or an associated illness
or medications. In a study of 169 relatives of 46 ET patients,
12 (7.5%) were diagnosed as having probable or definite ET,
but only 2 were reported by probands to have tremor (sen-
sitivity: 16.7%); only 1 of 136 normal relatives were reported
to have tremor (specificity: 99.3%) (Louis et al., 1999b). In
other studies, the investigators found that 23% of elderly
individuals had ET, and relatives of ET patients were five
times more likely to develop the disease than a control
population (Louis et al., 2001c), and first-degree relatives
were more likely to have tremor compared to relatives of
controls than were second-degree relatives (Louis et al.,
2001d). Factors that were associated with more accurate
reporting were female informant, increased tremor severity,
sibling relationship, and higher level of education. In a com-
prehensive study of 20 index patients with hereditary ET and
their 93 first-degree relatives and 38 more distant relatives,
Bain and colleagues (1994) examined 53 definite and 18
possible cases. Similar to the findings of Lou and Jankovic
(1991a), the investigators found a bimodal distribution and
autosomal dominant inheritance with nearly complete pen-
etrance by the age of 65 years. In contrast to some previous
studies, they found no cases of dystonia, PD, task-specific
tremors, or primary orthostatic tremors, but migraine head-
aches occurred with a higher-than-expected frequency of
26%. About 50% were alcohol-responsive, but there was
marked heterogeneity of responsiveness between and within
families (Mostile and Jankovic, 2010). In contrast, in a study
of 252 members in four large kindreds with ET, three of the
kindreds had a total of 41 members with the combination
of ET and dystonia, and two had associated parkinsonism
(Jankovic et al., 1997). Besides the one kindred with “pure”
ET without any associated disorders (Jankovic et al., 1997),
we subsequently studied 216 individuals of another large
kindred with “pure” ET. The observation of earlier age at
onset in successive generations suggests the phenomenon of
anticipation, although the relatively small number of sub-
jects and the possibility of ascertainment bias preclude any
definite conclusions. Since ET is so common in the general
population, bilineal transmission is not rare, and the ampli-
tude of tremor appears to be greater in the children than in
either affected parent (Rajput and Rajput, 2006). The younger
the age at onset of ET, the higher the frequency of positive
family history. In one study, 91% of cases with onset before
the age of 20 years had a family history of tremor (Louis and
Ottman, 2006).
Although the genetic origin of ET is widely recognized, the
gene or genes responsible for ET have eluded intensive search
by several groups of investigators (Deng et al., 2007) (Table
18.6). A genome scan of 16 ET Icelandic families containing
75 affected relatives with “definite” ET identified a marker
for the familial ET gene, FET1 or ETM1, on chromosome
3q13.1 (Gulcher et al., 1997). An analysis of a large

Table 18.6  A review of genetic studies in essential tremor
• ETM1 – 3q13.1
– A genome scan of 16 ET Icelandic families containing 75
affected relatives with “definite” ET (and in Tajikistan)
• ETM2 – 2p24.1
– Linkage established in 3 “pure” ET families and in 1 family with
ET-parkinsonism, dystonia
• 6p22.3–24.1
– Linkage in two ET families
• D3 receptor gene (DRD3) – 3q13.3
– Ser9Gly variant associated with increased risk and younger   Güell et al., 2010a, 2010b). Furthermore, a slightly higher
age at onset of ET
• Lingo 1 and 2
Czech-American family established linkage to a locus ETM2
on chromosome 2p22–p25 (Higgins et al., 1997). Two of
our families with “pure” ET and one with ET–parkinsonism–
dystonia also mapped to the same locus (Higgins et al.,
1998). On the basis of studies of genetically diverse popula-
tions of ET, the locus has been narrowed to 2p24.1 with a
candidate interval to a 192-kilobase interval between the loci
etm1231 and APOB (Higgins et al., 2004). More recently, a
missense mutation (828C→G) in the HS1-BP3 gene was
identified in two American families with ET and was absent
in 150 control samples (300 chromosomes) (Higgins et al.,
2005, 2006). The 828C→G mutation causes a substitution
of a glycine for an alanine residue in the HS1-BP3 protein
(A265G), which is normally highly expressed in motor
neurons and Purkinje cells and regulates the Ca2+/calmodulin-
dependent protein kinase activation of tyrosine and tryp-
tophan hydroxylase. Studies in our own population of
patients with ET and suitable controls, however, have led us
to conclude that the variant might not be pathogenic for ET
and might simply represent a polymorphism in the HS1-BP3
gene (Deng et al., 2005). A linkage to 6p23 with a LOD score
ranging from 1.265 to 2.983 was identified in two ET fami-
lies, but further studies are needed to determine whether this
merely represents a susceptibility locus or whether this gene
region contains a causative gene (Shatunov et al., 2006).
Variants in the coding region of the D3 receptor gene
(DRD3), localized on 3q13.3, have been found to be associ-
ated with ET in some families and in a case-control study
(Lucotte et al., 2006). In a genome-wide scan involving fam-
ilies from France and North America, Ser9Gly variant in the
DRD3 gene was found to increase dopamine affinity 4–5-
fold and produce a gain-of-function abnormality as demon-
strated by increased cAMP dopamine-mediated response
and prolonged mitogen-associated protein kinase (MAPK)
signal (Jeanneteau et al., 2006). The DRD3Gly was found to
be associated with an increased risk for and age at onset of
ET in Spanish (García-Martín et al., 2009) and French popu-
lations (Lorenz et al., 2009). This variant, however, has not
been found in the majority of Asian (Tan et al., 2007b) or
Italian (Vitale et al., 2008) patients with ET, and some have
argued against the role of DRD3 gene in the pathogenesis of
ET (Blair et al., 2008).
When the genome-wide scan of 452 ET patients was
compared to that of 14 378 controls, a marker in intron 3
of LINGO1 gene on chromosome 15q24.3 was found to be
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Postural tremors
significantly associated with ET (Stefansson et al., 2009). In
several large European and American populations, the odds
ratios for carriers of one G allele averaged 1.55, with P = 10−9.
Odds increased to 2.4 for carrying two G alleles. Based on
this and the prevalence of the allele, the population attribut-
able risk of the variant was 20%. Another study involving a
North American population demonstrated a significant asso-
ciation between LINGO1 rs9652490 and essential tremor (P
= 0.014) and PD (P = 0.0003), again suggesting that varia-
tions in LINGO1 can increase risk of ET and provide the first
evidence of a genetic link between ET and PD (Vilariño-
frequency of the allele G of LINGO1 marker rs9652490 was
found in ET patients of Asian origin (Tan et al., 2009).
LINGO1 may be potentially pathogenic as it has been
implicated in axon regeneration, and when mutated it
may be responsible for fusiform swellings of Purkinje cell
axons, similar to those found in autopsied brains of patients
with ET.
Another marker for ET has been mapped to chromosome
4p14–p16.3 (MIM 168601) in a family with autosomal
dominant PD (Farrer et al., 1999, 2004). This family,
however, was later found to have α-synuclein gene (SNCA)
triplication, and this SNCA triplication segregated with
parkinsonism but not the postural tremor (Singleton et al.,
2003). This suggests that the postural tremor is a coinciden-
tal finding. Since not all families map to the three known
loci (ETM1, ETM2, or the 4p locus) (Kovach et al., 2001), it
is likely that familial tremor has not only marked phenotypic
but also genetic heterogeneity and that additional gene loci
will be identified in the near future. Furthermore, models
other than autosomal dominant, including interaction
between susceptibility genes and environmental risk factors,
should be considered (Ma et al., 2006).
In 1935, Minor (1935), a Russian neurologist, not only
stated that “the older one is, the more likely one displays
tremor (ET),” but also suggested “that a factor for longevity
was also contained in the tremor gamete.” In support of the
latter hypothesis, he offered the description of 51 cases of
“hereditary tremor” associated with longevity. The longevity
was based on patients’ parents and grandparents usually
being older than 70 years. His “control group” consisted of
11 cases of parkinsonism in which “no example of longevity
was found out.” However, the author did not state who in
the ET families had tremor, and he did not provide any
details on his parkinsonian patients (clinical features, ages
of the subjects and relatives), and normal controls were not
examined. Supporting the clinical observation that patients
with ET live longer than a controlled population, Jankovic,
Beach and colleagues (Jankovic, 1995) found that parents of
patients with ET who had tremor (presumably ET) lived on
the average 9.2 years longer than did parents without tremor.
The association of familial tremor with significantly increased
longevity suggests that familial tremor confers some anti-
aging influence. Alternatively, patients with ET might have
an underlying personality trait that encourages dietary, occu-
pational, and physical habits that promote longevity. Fur-
thermore, the small amounts of alcohol to calm the tremor
might prolong life; and finally, the tremor itself might be
viewed as a form of exercise that would have long-standing
beneficial effects on general health (Mostile and Jankovic,
2010). Despite the overwhelming evidence that ET is of
403
 18 Tremors

genetic origin, some researchers have suggested that environ-
mental factors might also play a role, particularly since con-
cordance among monozygotic twins is only 60% (Louis,
2001; Tanner et al., 2001). However, in another study involv-
ing 92 twins with ET from the Danish twin registry, the
concordance rate was 93% among monozygotic twins and
29% among dizygotic twins when the Tremor Research and
Investigation Group consensus criteria were used (Lorenz
et al., 2004).
Treatment
In designing protocols to study the effects of a therapeutic
intervention on tremor-related functional impairment and
on the mean amplitude (and frequency) of tremor, it is
important to take into account the marked intraindividual
and interindividual and diurnal variations in physiologic
and pathologic tremors (van Hilten et al., 1991; Deuschl
et al., 2011). Factors such as anxiety, caffeine, or alcohol
intake, drugs, and even temperature (Lakie et al., 1994) can
affect hour-to-hour variations in the amplitude of tremor.
Caffeine, a nonselective adenosine receptor antagonist, can
trigger or exacerbate tremor and the observed marked
increase in the DBS-induced release of ATP from local astro-
cytes, which metabolizes to adenosine, has been suggested
as one possible mechanism of DBS in suppression of tremor
(Bekar et al., 2008).
Even without specific triggers or exacerbating factors, the
ET amplitude may vary by 30–50% from hour to hour
(Koller and Royse, 1985). The antitremor drugs exert their
ameliorating effects by reducing tremor amplitude without
any effect on tremor frequency. Reduction of tremor ampli-
tude, however, does not always translate into improvement
in function. There are currently no uniformly accepted ET
rating scales, but the Unified Tremor Rating Assessment
developed by the Tremor Research and Investigation Group
(Jankovic et al., 1996; Ondo et al., 2000) and the Tremor
Rating Scale developed by the Tremor Research Group
(Tintner and Tremor Research Group, 2004) have been used
in several studies.
The treatment of postural tremor depends largely on its
severity; many patients require nothing more than simple
reassurance. Most patients who are referred to a neurologist,
however, have troublesome tremors that require pharmaco-
logic or surgical treatments (Ondo and Jankovic, 1996; Bain,
1997; Lyons et al., 2003) (Fig. 18.3). The large-amplitude
and slow-frequency postural tremors usually do not respond
to any pharmacologic therapy. Since alcohol reduces the
amplitude of ET in about two-thirds of patients, some use it
regularly for its calming effect, and some use it prophylacti-
cally – for example, before an important engagement at
which the presence of tremor could be a source of embar-
rassment. Although evidence concerning the risk of alcohol-
ism among ET patients is contradictory, regular use of alcohol
to treat ET is inadvisable (Mostile and Jankovic, 2010).
One epidemiologic, prospective, population-based study
in central Spain involving 3285 elderly participants, 76
of whom developed incident ET, concluded that baseline
alcohol consumption was associated with substantially
higher risk of developing ET (Louis et al., 2009a). They sug-
gested that the alcohol may be in part responsible for the
cerebellar toxicity associated with ET. Although the authors
dismiss the possibility that the participants who developed
incident ET between the baseline and follow-up evaluations
had preclinical ET at baseline, because they answered “no”
when asked at baseline whether their arms or legs shook,
many patients deny having tremor before the onset of
alcohol consumption but validation by other family
members often confirms that they had tremor prior to
alcohol. Furthermore, family members of ET patients some-
times consume alcohol without being aware that it “calms”
their tremor. Arguing against alcohol as contributing to the

Figure 18.3  Therapeutic algorithm in

essential tremor.
Establish Education Is there a need No
Tremor diagnosis of ET and support for medication?

Rule out Yes

other conditions

Administer as-needed therapy Administer continuous therapy

Judicious use Primidone Propranolol

Parkinson disease Propranolol
of ethanol 12.5 mg/day 20–60 mg/day
Cerebellar disease 20–80 mg
(60 mL) 10 to initially, initially,
Dystonia 2 hours before OR
15 min before increase increase
Neuropathy anticipated
anticipated to 250 mg/day to 120 mg/day
event
event

If tremor is not controlled,

administer combination therapy Benzodiazepines, gabapentin, topiramate
(primidone and propranolol)
Is therapy successful?
Is therapy successful? No No

BTX injection OR VIM DBS

404
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cause of ET is also the observation that many patients with
ET never drink alcohol (Mostile and Jankovic, 2010).
The mechanism by which alcohol reduces tremor (effec-
tive blood level is only 300 mg/L (0.03%)) is unknown, but
it is thought to act centrally, since infusion of alcohol into
the brachial artery of a tremulous arm is ineffective (Growdon
et al., 1975). Furthermore, the amplitude of the central but
not peripheral components of ET is decreased after alcohol
consumption (Zeuner et al., 2003a). Alcohol is known to
affect multiple neurotransmitters, and it might stabilize neu-
ronal membranes by potentiating gamma-aminobutyric acid
(GABA) receptor-mediated chloride influx. A pilot trial (n =
12) of 1-octanol, a food additive approved by the Food and
Drug Administration that was previously demonstrated to
suppress harmaline tremor (see below), found that it signifi-
cantly decreased amplitude of ET for about 90 minutes after
oral dose of 1 mg/kg (Bushara et al., 2004). The benefits and
tolerance (except for unusual taste) of this drug were dem-
onstrated in an open-label trial at doses up to 64 mg/kg
(Shill et al., 2004).
Treatment of ET and other action tremors is not optimal.
In a survey of 261 patients with ET about a third who had
been prescribed medication for tremor had discontinued the
therapy and another third of cases with severe tremor had
stopped medication (Louis et al., 2010). Propranolol, a
β-adrenergic blocker, remains the most effective drug for the
treatment of ET and enhanced physiologic tremors, but other
beta-blockers may also ameliorate postural tremor (Caccia
et al., 1989; Calzetti et al., 1990; Koller et al., 2000) (Table
18.7). Propranolol is less effective in head tremor than hand
tremor (Calzetti et al., 1992). Although a central mechanism
of action has been suggested for this group of drugs, some
beta-blockers exert potent antitremor activity even though
they are not lipid soluble and hence do not cross the blood–
brain barrier. This suggests that the therapeutic effect of beta-
blockers may be mediated, at least in part, by the peripheral
β-adrenergic receptors (Guan and Peroutka, 1990). The
major side effects of propranolol and, to a lesser degree,
other beta-blockers include fatigability, sedation, depres-
sion, and sexual impotence. A critical review of 42 articles,
based on controlled trials, concluded that despite the con-
ventional wisdom, “there is no significant increased risk of
depressive symptoms and only small increased risk of fatigue
and sexual dysfunction” associated with beta-blocker therapy
(Ko et al., 2002). These drugs are contraindicated in the
presence of asthma, second-degree atrioventricular block,
and insulin-dependent diabetes. Contrary to traditional
Table 18.7  Evidence-based recommendations for treatment of
ET (Quality Standards Subcommittee of the AAN)
• Propranolol and primidone reduce limb tremor (Level A)
• Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and
topiramate (Level B)
• Propranolol reduces head tremor (Level B)
• Clonazepam, clozapine, nadolol, and nimodipine (Level C)
• Botulinum toxin A in limb, head and voice tremor (Level C)
• Chronic DBS and thalamotomy (Level C)
• Surgical treatment of head and voice tremor and the use of
gamma knife thalamotomy (Level U)
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Postural tremors
recommendations, they may be used safely in patients with
stable congestive heart failure due to left ventricular systolic
dysfunction (Packer et al., 1999). The efficacy of sotalol, a
nonselective β-antagonist, in reducing ET is comparable to
that of propranolol and atenolol, even though both atenolol
and sotalol have very low lipid solubility and therefore act
mainly through peripheral mechanisms (Leigh et al., 1983).
Arotinolol, an alpha- and beta-blocker that is used as an
antiobesity drug, was found to be as effective as propranolol
in a randomized crossover study (Lee et al., 2003).
The antitremor effect of primidone has been confirmed by
several open trials and placebo-controlled studies (Koller
and Royse, 1986). By starting primidone at a very low dose
(25 mg at bedtime), the occasional idiosyncratic acute, toxic
side effects (nausea, vomiting, sedation, confusion, and
ataxia) can be prevented. Since there is little or no correla-
tion between blood levels and tremolytic effects, the daily
dosage should be gradually increased over a period of several
weeks until the optimal therapeutic response is achieved.
Dosages above 250 mg/day are only rarely necessary. The
antitremor effect of primidone is largely attributed to the
parent compound rather than to its metabolites, phenylethyl-
malonamide (PEMA) or phenobarbital (Sasso et al., 1991).
In one study (Koller and Royse, 1986), primidone alone was
found to decrease tremor more than propranolol alone, but
a combination of the two drugs might be more efficacious
than either drug alone. In a double-blind, placebo-controlled,
crossover study, Gorman and colleagues (1986) found that
both propranolol and primidone significantly reduced
tremor compared to placebo. There is no evidence that either
one of these primary anti-ET drugs is more efficacious than
the other, but acute adverse effects with primidone and
chronic side effects of propranolol limit therapy. The com-
bination of the two drugs might be more efficacious than
monotherapy (Koller and Royse, 1986). Although the ben-
efits are usually maintained, the dosages might have to be
increased after the first year to sustain the antitremor effec-
tiveness. A double-blind study of 87 patients with ET,
however, showed that low doses of primidone (250 mg/day)
were as effective as, or more effective than, high doses
(750 mg/day) (Serrano-Duenas, 2003).
In addition to beta-blockers and primidone, the benzodi-
azepine drugs, such as diazepam, lorazepam, clonazepam,
and alprazolam (Gunal et al., 2000), as well as barbiturates,
also may have some ameliorating effects on ET or its variants
(Ondo and Jankovic, 1996). In a double-blind, crossover,
placebo-controlled study, 22 patients with ET received in
random order alprazolam, acetazolamide, primidone, and
placebo for 4 weeks, each separated by a 2-week washout
period. The study demonstrated that alprazolam was supe-
rior to placebo and equipotent to primidone, whereas there
was no statistically significant difference between acetazola-
mide and placebo (Gunal et al., 2000). The mean effective
daily dose of alprazolam was 0.75 mg, and no troublesome
side effects were reported by the patients who took alpra-
zolam. Clonazepam was shown to be ineffective in control-
ling ET in one double-blind study, but at a mean dose of
2.2 mg/day, it improved kinetic tremor (Biary and Koller,
1987). Methazolamide (Neptazane), a sulfonamide that is
used in the treatment of glaucoma, was reported to be effec-
tive in the treatment of ET (Muenter et al., 1991). Ten of 28
patients apparently achieved moderate to complete relief of
405
 18 Tremors
their tremor. The average maintenance dose was 129 mg/day,
and reported side effects included sedation, nausea, epigas-
tric discomfort, and parasthesias. Aplastic anemia, the most
feared complication, did not occur during the 6-month (10
weeks to 29 months) follow-up. The beneficial effects of
methazolamide suggested by this open trial, however, could
not be confirmed by a double-blind controlled study
(Busenbark et al., 1993). Although our personal experience
with this drug has been disappointing, we have found that
up to 10–20% of patients who were previously unresponsive
to other antitremor treatments note a marked improvement
in their tremor with methazolamide. Flunarizine, a calcium
channel blocker, was reported to improve ET in 13 of 15
patients (Biary and Deeb, 1991). This drug, however, is not
available for use in the United States, and it can produce
parkinsonism and tardive dyskinesia. Another calcium
channel blocker, nimodipine at 120 mg/day, was found to
improve ET in 8 of 15 patients who completed a double-
blind, placebo-controlled trial (Biary et al., 1995). Anecdo-
tally, fenofibric acid (Trilipix), a lipid regulating agent, has
been reported to also improve ET.
Despite some encouraging results with gabapentin based
on pilot studies, subsequent double-blind controlled studies
showed mixed results (Louis, 1999), ranging from no benefit
(Pahwa et al., 1998) to modest improvement (Ondo et al.,
2000) to a marked benefit comparable to that obtained with
propranolol (Gironell et al., 1999). Topiramate, a broad-
spectrum anticonvulsant, has been also reported to reduce
ET in a double-blind, placebo-controlled trial at 400 mg/day
dose (Connor, 2002). Although well tolerated, topiramate
may cause parasthesias and weight loss and may adversely
affect cognition (Thompson et al., 2000). Some patients
who are unresponsive to conventional treatments do improve
even with low-dose (50 mg/day) topiramate (Gatto et al.,
2003). In a multicenter, double-blind, placebo-controlled
trial involving 208 patients (topiramate, 108; placebo, 100)
the final visit score (last observation carried forward) was
lower in the topiramate group than with placebo (P < 0.001)
(Ondo et al., 2006). Mean percentage improvement in
overall TRS scores was 29% with topiramate at a mean final
dose of 292 mg/day and 16% with placebo (P < 0.001) and
topiramate was associated with greater improvement in
function and disability (P = 0.001). The most common
adverse effects were parasthesias (28%), weight loss (22%),
and taste perversion (19%), but only the following adverse
effects resulted in discontinuation of the drug: paresthesia
(5%), nausea (3%), concentration/attention difficulty (3%),
and somnolence (3%). Overall, adverse events were treat-
ment limiting in 31.9% of topiramate patients and 9.5% of
placebo patients. Thus, this multicenter study showed that
topiramate was effective in the treatment of ET with accept-
able tolerability profile. In a pilot, open-label, crossover trial
designed to compare zonisamide and arotinolol in 14
patients with ET using the Fahn–Tolosa–Marin clinical rating
scale at baseline and 2 weeks after administration of each
drug, both drugs were found to have significant and equal
antitremor effect, but zonisamide was more effective for
voice, face, tongue, and head tremors (Morita et al., 2005).
In a subsequent double-blind, placebo-controlled trial
involving 20 patients with ET, zonisamide failed to provide
any improvement in clinical rating scales, although it
reduced tremor by accelerometry (Zesiewicz et al., 2007a).
406
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Zonisamide was, however, found to be more effective than
propranolol in the treatment of isolated head tremor (Song
et al., 2008). One study showed that 200 mg/day seemed to
the optimal dose for zonisamide in the treatment of ET
(Handforth et al., 2009). Levetiracetam, another antiepilep-
tic, was shown to have a significant antitremor effect in one
double-blind, placebo-controlled trial at 1000 mg as a single
dose (Bushara et al., 2005), but not in other studies
(Handforth and Martin, 2004; Ondo et al., 2004; Elble
et al., 2007b). Pregabalin has been found effective in a
pilot, double-blind, placebo-controlled trial (Zesiewicz
et al., 2007b), but not in a double-blind, placebo-controlled
trial (Ferrara et al., 2009b).
Mirtazapine has been reported to improve rest tremor
(Pact and Giduz, 1999), but in a double-blind, placebo-
controlled trial, the drug was not found to exert a significant
benefit in ET (Pahwa and Lyons, 2003). Finally, clozapine
has been found to effective in selected drug-resistant patients
with ET (Ceravolo et al., 1999). Gabapentin (Onofrj et al.,
1998), levodopa (Wills et al., 1999), primidone, clon-
azepam, and phenobarbital seem to be particularly useful in
patients with orthostatic tremor (Cabrera-Valdivia et al.,
1991; FitzGerald and Jankovic, 1991). Despite earlier reports,
amantadine has not been found effective in patients
with ET in a randomized, placebo-controlled trial, and in
some patients actually exacerbated the postural tremor
(Gironell et al., 2006). Sodium oxybate, a salt of gamma-
hydroxybutyrate (GHB), may suppress tremor in a manner
similar to alcohol (Frucht et al., 2005).
Other treatment modalities for postural tremors include
injections of BTX into muscles that are involved in the pro-
duction of the oscillatory movement and various surgical
approaches. In one open trial of BTX treatment, 67% of 51
patients with various disabling tremors noted at least some
improvement (Jankovic and Schwartz, 1991). The average
duration of improvement was 10.5 weeks, and side effects
were chiefly related to local muscle weakness; 40% of 42
patients who were injected in the neck muscles to control
head tremor and 60% of 10 patients who were injected in
the forearm muscles to control hand tremor improved.
Other studies have demonstrated the usefulness of BTX in
the treatment of hand tremor (Trosch and Pullman, 1994).
A double-blind, placebo-controlled trial has demonstrated
a mild to moderate efficacy of BTX injections in patients
with severe hand ET (Jankovic et al., 1996) and in patients
with ET involving the head (Pahwa et al., 1995; Wissel
et al., 1997). Although in one study, only 20–30% of
patients with voice tremor were found to benefit from vocal
cord injections of BTX, the majority of patients benefited
from a subjective reduction in vocal effort that might have
been attributable to reduced laryngeal airway resistance
(Warrick et al., 2000). In another study involving 27
patients with adductor spasmodic dysphonia and vocal
tremor and in four patients with severe vocal tremor alone,
a significant improvement in various acoustic measures was
observed after thyroarytenoid and interarytenoid BTX injec-
tions and less tremor was demonstrated in 73% of the
paired comparisons (Kendall and Leonard, 2010). Although
67% of the patients with spasmodic dysphonia and vocal
tremor wished to continue to receive BTX injections, only
one patient with severe vocal tremor wished to continue
with injections. BTX may also be effective in primary

writing tremor, although a specially designed writing device
might be a simpler and at least as effective treatment (Espay
et al., 2005).
Peripheral deafferentation with anesthetic is currently
being re-explored as a potential treatment of focal dystonia
and tremor (Rondot et al., 1968; Pozos and Iaizzo, 1992;
Kaji et al., 1995). An injection of 5–10 mL of 0.5% lidocaine
into the target muscle not only improved focal dystonia, but
also reduced the amplitude of the postural tremor. This
short effect (<24 hours) can be extended for up to several
weeks if ethanol is injected simultaneously (Kaji, personal
communication). In a study of 10 patients with ET, Gironell
and colleagues (2002) reported a transient (<1 hour)
improvement in tremor after transient magnetic stimulation
of the cerebellum.
The neurosurgical treatments, including DBS, that were
discussed in the section on rest tremors may be also effica-
cious in patients with action hand tremors (Benabid et al.,
1991; Blond et al., 1992; Deiber et al., 1993; Jankovic
et al., 1995b; Koller et al., 1997), head tremors (Koller
et al., 1999), and even task-specific tremors (Racette et al.,
2001). It is of interest that cerebellar lesions can abolish ET,
but it is unlikely that this observation will lead to surgically
induced cerebellar lesions as a therapeutic modality in
patients with ET (Dupuis et al., 1989). On the other hand,
chronic cortical stimulation has been reported to improve
contralateral action tremor (Nguyen et al., 1998). The obser-
vation that injection of muscimol, a GABAA agonist, into the
VIM thalamus improved tremor in patients with ET suggests
that GABA agonists might be useful in the treatment of ET
(Pahapill et al., 1999). On the basis of the observation that
vagus nerve stimulation has a nonspecific calming effect in
treated epileptic patients and that it suppresses harmaline-
induced tremor (see below) in rats (Handforth and Krahl,
2001), a multicenter trial was conducted to study the effects
of vagus nerve stimulation in patients with essential and
parkinsonian tremor, but no meaningful benefit was dem-
onstrated (Handforth et al., 2003).
Kinetic tremors
Diagnosis
Kinetic tremor is typically associated with lesions or diseases
that involve the cerebellum or its outflow pathways. The
term kinetic tremor more accurately describes the oscillation
occurring with limb movement than the classic term inten-
tion tremor, which is ambiguous because it implies tremors
that are present when “contemplating, initiating, perform-
ing, or completing a movement” (Lou and Jankovic, 1993).
It is important to recognize that kinetic tremor is not simply
a consequence of cerebellar ataxia (Diener and Dichgans,
1992), hypotonia, dysmetria, or dysdiadochokinesia but
that the different motor disorders may coexist, often causing
severe functional disability (Sabra and Hallett, 1984).
Although kinetic tremor was traditionally considered a pre-
dominantly proximal tremor, using wrist (distal) or whole-
arm (proximal) visually guided tracking in patients with
multiple sclerosis showed a major frequency component at
4–5 Hz, most of the action tremor being distal rather than
proximal (Liu et al., 1999).
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Kinetic tremors
In addition to this action, kinetic tremor patients with
cerebellar lesions often exhibit postural tremors and tituba-
tion. The term titubation simply refers to a rhythmic oscilla-
tion of the head or trunk, presumably caused by hypotonia
of the axial muscles. Kinetic cerebellar outflow tremor might
be a component of the thalamic ataxia syndrome character-
ized in addition to the tremor by contralateral ataxia,
hemisensory loss, and transient hemiparesis caused by a
lesion in the mid to posterior thalamus involving the
dentatorubrothalamic and ascending sensory pathways
(Solomon et al., 1994). Kinetic terminal and postural
tremors have been reported to result from repetitive transcra-
nial magnetic stimulation, possibly by interfering with cer-
ebellar inflow to the motor cortex (Topka et al., 1999).
Although kinetic tremors are more difficult to assess than ET
or PD tremors, by using handwriting, spirals, and other tests,
objective assessments of kinetic tremors, such as those seen
in multiple sclerosis, can be reliably obtained (Alusi et al.,
2000). In a study of 100 patients with definite multiple
sclerosis, Alusi and colleagues (2001b) found 58 with tremor,
but it was symptomatic in only 38 and incapacitating in 10.
The authors concluded that multiple sclerosis tremors are
usually related to involvement of the cerebellum.
Treatment
Some causes of tremor, such as alcohol withdrawal, pheny-
toin, lithium, amiodarone, and valproate toxicity (Nouzeilles
et al., 1999) and cerebellar tumors and abscesses are specifi-
cally treatable. Tremor and ataxia in such cases can resolve
after the underlying cause is removed. Some kinetic tremors
can be reduced by attaching weights to the wrist, but this
method provides only limited improvement in function
(Aisen et al., 1993).
No drugs have been shown to reduce cerebellar tremor
satisfactorily and reproducibly, but the application of wrist
weights before eating may enable to patient feed himself.
Isoniazid was initially thought to improve cerebellar, pos-
tural tremor more than kinetic tremor (Sabra and Hallett,
1984), but the results of a double-blind trial were disap-
pointing (Hallett et al., 1991). Sechi and colleagues (1989)
reported that carbamazepine was effective in the treatment
of cerebellar tremor, possibly by reducing hyperactivity in
thalamic neurons. Ten patients, seven with multiple sclerosis
and three with cerebrovascular disease, were followed for
2–24 months. All patients improved on a clinical rating scale
and by accelerometric recording when given carbamazepine,
400–600 mg daily. There was no improvement with placebo.
Trelles and colleagues (1984) reported that cerebellar kinetic
tremor secondary to multiple sclerosis and to olivopontocer-
ebellar degeneration responded to clonazepam treatment at
a daily dose of 8–15 mg. Alcohol not only improves ET but
also may improve tremor associated with multiple sclerosis
(Hammond and Kerr, 2008). Glutethimide, a piperidinedi-
one derivative with sedative and anticholinergic effects, has
recently been reported to be effective at doses of 750–
1250 mg/day in action tremors, including ET, cerebellar
tremors, and midbrain tremors (Aisen et al., 1991). The
encouraging results from this open trial await confirmation
by properly designed controlled studies. Even if it is found
to be effective, however, the potential side effects of gluteth-
imide, including respiratory depression, aplastic anemia,
407
 18 Tremors
and physical and psychological dependence, will limit its
usefulness. Buspirone, a serotonin (5-HT1A) agonist was
reported to be useful in some patients with mild cerebellar
ataxia, but placebo-controlled study is needed before it can
be concluded that this drug is effective in cerebellar ataxia
or tremor (Lou et al., 1995). Baker and colleagues (2000)
found that cannabinoids control tremor in a mouse model
of multiple sclerosis, but the effects of tetrahydrocannabinol
in patients with cerebellar outflow tremor are unknown.
Levetiracetam has been also found to be effective in rare
cases (Ferlazzo et al., 2008).
Stereotactic thalamotomy has been reported to success-
fully relieve kinetic tremor in patients with multiple sclerosis
and other etiologies (Andrew, 1984). Radiofrequency lesions
in the VIM seem to provide the best control of tremor with
the lowest risk of neurologic deficit (Speelman and Manen,
1984; Nagaseki et al., 1986; Alusi et al., 2001a), although
thalamic DBS has been also reported to be useful in selected
patients with cerebellar-outflow tremor due to multiple scle-
rosis or other causes (Whittle et al., 1998; Montgomery
et al., 1999). A recent report of the Quality Standards Sub-
committee of the American Academy of Neurology, based
on a review of evidence-based publications, published the
following practice parameters related to therapies for ET.
Propranolol and primidone reduce limb tremor (Level A);
alprazolam, atenolol, gabapentin (monotherapy), sotalol,
and topiramate are probably effective in reducing limb
tremor (Level B); propranolol reduces head tremor (Level B);
clonazepam, clozapine, nadolol, and nimodipine possibly
reduce limb tremor (Level C); BTX type A may reduce limb,
head, and voice tremor, but this treatment is limited by
potential adverse effects (Level C); chronic DBS and tha-
lamotomy are highly efficacious but potentially risky proce-
dures (Level C); and there is insufficient evidence regarding
surgical treatment of head and voice tremor and the use of
gamma knife thalamotomy (Level U) (Zesiewicz et al., 2005)
(Table 18.7).
Pathophysiologic mechanisms of
rest and action tremors
Our understanding of mechanisms that are involved in gen-
eration of tremors has been facilitated by the development
of neurophysiologic and other quantitative techniques such
as EMG recordings and uniaxial and triaxial accelerometers
and by the application of computer technology to analyze
the frequency spectra and other tremor-related physiologic
variables (Elble and Koller, 1990; Gresty and Buckwell, 1990;
Elble et al., 1994; Louis et al., 2001b). A frequency of 6 Hz
is usually the maximum rate of oscillation produced by a
voluntary effort. During a voluntary contraction, motor units
usually start firing at 8 Hz, and tetanic fusion frequency is
reached at 15–20 Hz. Different parts of the human limb
have mechanical characteristics (inertia and stiffness) that
determine its natural resonant frequency. Such frequency is
inversely related to the mass of the body part: finger, 25 Hz;
wrist, 9 Hz; and elbow, 2 Hz.
There is a growing body of evidence supporting the notion
that central oscillators are important in the generation of
physiologic and pathologic tremors (Pare et al., 1990; Plenz
and Kitai, 1999; McAuley and Marsden, 2000; Brown, 2003;
408
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Gatev et al., 2006). Using microelectrode recordings in
awake or decerebrate monkeys who have been curarized and
whose limbs were deafferented by sectioning C2 to T4 dorsal
roots, Lamarre (1984) demonstrated spontaneous 3–6 Hz
rhythmic discharges in the ventral thalamus and 7–12 Hz
activity in the olivocerebellar system. Deafferenting the tha-
lamus by a lesion in the ventromedial tegmentum of the
midbrain facilitates synchronization of thalamic neurons,
which is ultimately expressed as a spontaneous, 3–6 Hz,
parkinsonian rest tremor. The amplitude of these discharges
and associated tremors is markedly enhanced by the tremor-
genic drug harmaline. Harmaline-induced tremor is cur-
rently considered the most reliable animal model of ET as it
generates both postural and kinetic tremors. It has been
postulated that harmaline induces release of glutamate and
acts as a potent reversible monoamine oxidase inhibitor.
These and possibly other pharmacologic effects of harmaline
result in facilitating low-threshold calcium conductance with
resultant oscillatory activity of the olivocerebellar system,
and eventual coupling and synchrony in the inferior olivary
nucleus. Ethanol reduced harmaline-induced tremor, and
possibly ET, by desynchronizing the olivary discharges, in
part by decreasing glutamate (Manto and Laute, 2008).
There are two types of harmaline-induced tremors, both of
which appear to originate in the inferior olivary nucleus: an
8–12 Hz tremor in normal animals (analogous to physio-
logic tremor) and a 6–8 Hz tremor in monkeys with lesions
in the dentate nucleus. Single-unit recordings from patients
with parkinsonian tremors showed that neurons in the tha-
lamic ventral nuclear group show rhythmic activity that cor-
related with EMG activity. Some, but not all, of these cells
responded to somatosensory activity, indicating the impor-
tance of peripheral modulation (Lenz et al., 1994). In addi-
tion to the thalamus, there are other subcortical nuclei
– particularly the subthalamic nucleus (STN) and external
globus pallidus (GPe) – that contain neuronal populations
that produce synchronized oscillating bursts at 0.4, 0.8, and
1.8 Hz in a cell-culture environment (Plenz and Kitai, 1999).
In addition to the low-frequency (<10 Hz) oscillations, there
are 11–30 Hz and >60 Hz oscillatory activities within the
subthalamopallidal-thalamocortical circuit (Brown, 2003).
In PD, synchronized oscillatory activity in the 10–50 Hz
band (often termed “β-band”) prevalent in the basal ganglia
thalamocortical circuit may be important in mediating
certain parkinsonian features, including bradykinesia and
tremor, and can be reduced by dopaminergic treatments
(Gatev et al., 2006). Furthermore, there is evidence that as a
result of dopaminergic deficiency, the normal independent
firing of pallidal neurons changes to both low-frequency
(4–7 Hz) and high-frequency (10–16 Hz) oscillatory activ-
ity, which can be also recorded from the STN, and these
oscillations often correlate with arm tremor (Bergman et al.,
1998). This pacemaker could be responsible for the genera-
tion of tremor under pathologic conditions such as dopamin-
ergic deficiency in PD. Therefore, surgical treatments of PD,
such as lesion or stimulation of the GPi or STN, might
act by desynchronizing the oscillatory basal ganglia–
thalamocortical network activity. Such microelectrode-
guided stereotactic operations in PD allow for single-cell
recordings in the globus pallidus, thalamic nuclei, and other
subcortical structures, leading to hypotheses about the
normal and abnormal function of the basal ganglia. One

such study, for example, found tremor-locked cells in the
center median-parafascicular complex of the thalamus with
low-threshold calcium spike type bursts in central lateral
nucleus and the paralamellar division of mediodorsal
nucleus of the thalamus (Magnin et al., 2000).
Intracellular recordings from brainstem sections have
demonstrated that neurons in the inferior olive have spon-
taneous oscillatory activity (Llinas, 1988; Kepler et al., 1990;
Bevan et al., 2002). The autorhythmic properties of these
neurons make this brainstem nucleus a prime candidate as
a neuronal generator for tremor. In the olivary neurons,
low-threshold Ca2+ conductance at the somatic membrane
enables these neurons to generate action potentials (low-
threshold spike) even at subthreshold depolarization. A fast-
action potential, generated by Na+ current into the cell body,
is followed by a slow, high-threshold Ca2+ spike that activates
prolonged (80–100 ms), K+-mediated hyperpolarization.
This is followed by an abrupt rebound response, generated
by low-threshold Ca2+ conductance, often large enough to
generate a second, Na+-dependent, action potential, and the
cycle repeats itself. In addition to the olivary nucleus, there
are other areas of the brain, particularly the STN and globus
pallidus, that display spontaneous rhythmic activities. In the
STN neurons, voltage-gated Na+ channels inactivate slowly
during the depolarizing phase of the oscillation. In addition,
Ca2+-dependent K+ current is activated by Ca2+ entry through
high-voltage Ca2+ channels that open briefly during each Na+
action potential (Bevan et al., 2002). Harmaline enhances
normal hyperpolarization, which is terminated by Ca2+
influx and rebound excitation, leading to rhythmic activa-
tion of the neurons. Besides harmaline, there are many
toxins that can produce tremors in animals and provide
useful models for the study of tremors (Wilms et al., 1999).
Microelectrode-guided single-cell recordings in patients with
PD showed that the average firing rate in the GPi was 91 ±
52 Hz, and that in the globus pallidus externa was 60 ±
21 Hz (Magnin et al., 2000). In addition, rhythmic, low-
threshold calcium spike bursts are often recorded in the
pallidum and medial thalamus; some, but not all, are syn-
chronous (in phase) with the typical rest tremor. It has been
postulated that the low-threshold calcium spike bursts con-
tribute to rigidity and dystonia by activating the supplemen-
tary motor area.
Physiologic tremor is present in all humans. It is an asymp-
tomatic oscillation of a body part, resulting from a complex
interaction between local mechanical-reflex mechanisms
and central oscillators (McAuley and Marsden, 2000) (Fig.
18.4). The mechanical-reflex component is determined
partly by the ballistocardiogram, mechanical properties of
the muscle, motor neuron firing characteristics, stretch reflex
and muscle spindle feedback, supraspinal influences, and
state of activation of the muscle beta receptors (Marsden,
1984). The frequency of this component is inversely propor-
tional to the mass and stiffness of the limb; thus, increasing
the external mass load decreases the tremor frequency (Elble
and Koller, 1990). Besides this variable frequency compo-
nent, which is determined largely by the mechanical proper-
ties of the oscillating body part, spectral analyses of normal
physiologic tremor show another, generally smaller, compo-
nent with a relatively consistent frequency peak at about
10 (8–12) Hz. This 10 Hz frequency component is inde-
pendent of peripheral influence, and it persists even after
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Pathophysiologic mechanisms of rest and action tremors
Higher centers
Tremor oscillator
Central coupling
Motor neuron pool
Mechanical
reflex
oscillator
Mass
Figure 18.4  Central and peripheral mechanisms of tremors.
deafferentation, suggesting that this component of physio-
logic tremor is centrally generated. Supraspinal influence on
physiologic tremor is supported by the observation that the
loss of visual input when the eyes are closed reduces or
abolishes this tremor. The amplitude of physiologic tremor
is determined largely by the degree of synchronization of
motor unit discharges, modulated by muscle spindle Ia affer-
ents. This process is exaggerated during anxiety, exercise,
fatigue, and other conditions that are known to enhance
peripheral β-adrenergic activity, and it may result in a visible
tremor called enhanced physiologic tremor (Table 18.1).
In most pathologic tremors, such as the rest or reemergent
tremor of PD (Jankovic et al., 1999), the central oscillators
are thought to drive the tremor, and the peripheral mecha-
nisms are thought to merely modify or modulate its ampli-
tude (Marsden, 1984; Britton et al., 1992a). Magnetic brain
stimulation can also modify certain pathologic tremors, pro-
viding further evidence that these tremors are centrally gen-
erated (Britton et al., 1993). The motor pathways that are
involved in transmission of signals from these central gen-
erators are not well understood. Inhibition of tremor by
lesions in the basal ganglia outflow nuclei and in the thala-
mus suggests that these subcortical nuclei are involved in the
pathophysiology of tremors. In parkinsonian states, as a
result of nigrostriatal dopamine depletion, excessive GABA-
mediated inhibition of the GPe within the indirect striat-
opallidal pathway leads to a disinhibition of the STN and
enhanced glutamate-mediated excitatory drive to the basal
ganglia output nucleus (GPi) (DeLong, 1990). This increased
drive from the output nuclei is reinforced by reduced inhibi-
tory input to the GPi through the direct pathway. The typical
3–6 Hz rest tremor of PD possibly results from increased
inhibition of the thalamic neurons that normally suppress
the oscillators or from hyperpolarization of the oscillator
neurons. In PD, the increased inhibitory output from the
GPi leads to deafferentation of the thalamus, particularly the
409
 18 Tremors
reticular nucleus, and synchronization of local neuronal net-
works with intrinsic properties to spontaneously discharge
(Lamarre, 1984; Huntsman et al., 1999). This spontaneous
bursting is transmitted via the thalamocortical-spinal cir-
cuitry to the motor neurons in the spinal cord, causing syn-
chronization of motor unit discharges, ultimately expressed
as an oscillatory movement.
Pathophysiology of Parkinsonian tremor
In support of the role of the thalamus in the generation of
parkinsonian rest tremor is the observation that the ventral
thalamus of patients with PD contains a population of
neurons that fire spontaneously and rhythmically and that
their firing frequency correlates relatively well with the fre-
quency of tremor, recorded by EMG in the contralateral limb
(Lenz et al., 1988). Furthermore, a lesion in the nucleus
ventralis intermedius (VIM) or electrical stimulation of the
nucleus, so-called deep brain stimulation (DBS), abolishes
contralateral rest tremor (Kelly et al., 1987; Benabid et al.,
1991, 1996; Hubble et al., 1997; Koller et al., 1997; Ondo
et al., 1998; Limousin et al., 1999). That parkinsonian
tremor is centrally driven is supported by the observation
that complete paralysis of extensor forearm muscles as a
result of radial nerve palsy actually increased the amplitude
of the tremor without changing its frequency (Pullman et al.,
1994). Volkmann and colleagues (1996) used magnetoen-
cephalography to study parkinsonian resting tremor, and on
the basis of these studies, they concluded that the typical
3–6 Hz parkinsonian tremor is generated by the same central
mechanisms that are involved in voluntary rapid alternating
movements. They proposed the following sequence of events
for typical parkinsonian rest tremor: increased inhibitory
output from GPi → hyperpolarization and activation of low-
threshold calcium conductance in anterior ventrolateral
nucleus (VLa) → 5–10 ms → activation of lateral premotor
and motor cortex → 25–30 ms → EMG activity → 100 ms
→ activation of the central sulcus (reafferent input from
muscle spindle to area 3a) → second activation of the soma-
tosensory cortex by the antagonist contraction. The study of
pacemaker neuronal networks as well as fast and slow oscil-
lations within the basal ganglia circuitry will undoubtedly
provide important insights into the pathophysiology of
rhythmic involuntary movements such as tremors (Plenz
and Kitai, 1999; Ruskin et al., 1999).
Pathophysiology of essential tremor
It has been suggested that the postural tremor of ET arises
from spontaneous firing of the inferior olivary nucleus,
which drives the cerebellum and its outflow pathways via the
thalamus to the cerebral cortex and then to the spinal cord
(Deuschl and Elble, 2000). In contrast to physiologic tremor,
the frequency of ET does not decrease with mass loading,
indicating a primary role of central mechanisms in ET (Elble
and Koller, 1990). On the other hand, local cooling may
significantly reduce the amplitude of ET, without changing
its frequency (Lakie et al., 1994). Abnormal triphasic pattern
with a delayed second agonist burst and other kinematic
problems in response to a ballistic movement further support
impaired cerebellar function in patients with ET (Koster
et al., 2002). In addition, impaired eyeblink conditioning in
410
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patients with ET has been used as evidence of functional
disturbance in the olivocerebellar circuits (Kronenbuerger
et al., 2007). MRI scans, including diffusion-weighted
imaging, have found no abnormalities associated with ET
(Martinelli et al., 2007). Using a 3-tesla MRI in 19 ET patients
(mean age 69.8 ± 9.4 years) and 20 age- and gender-matched
controls, Benito-León et al. (2009a) found that ET patients
with severe tremor had significantly more white matter
changes in the midbrain, both occipital lobes, and right
frontal lobe, and gray matter changes bilaterally in the cer-
ebellum. Diffusion tensor imaging (DTI) MRI showed
microstructural abnormalities in the dentate nucleus and
superior cerebellar peduncle in patients with ET, providing
further support for neurodegenerative pathology of cerebel-
lar structures in ET (Nicoletti et al., 2010).
The involvement of the olivocerebellar-thalamocortical
circuitry in ET is supported by changes in the cerebellar
blood flow as measured by PET during inhalation of C15-
labeled O2 (Jenkins et al., 1993). Using this technique, the
authors compared the cerebellar and cerebral blood flow in
patients with ET and normal controls. They found that when
the control subjects were holding one arm outstretched (in
the absence of tremor), there was increased blood flow
in the contralateral sensorimotor cortex and the supplemen-
tary motor area. In contrast, unilateral postural arm tremor
in patients with ET was associated with markedly increased
blood flow to both cerebellar hemispheres; in both premotor
cortices; and to the contralateral striatal, thalamic, and sen-
sorimotor cortex (but not the supplementary motor area).
Passive and voluntary flexion–extension movements of the
wrist significantly increased the blood flow only in the ipsi-
lateral cerebellum. The investigators suggested that the
increased flow in the cerebellum reflected increased activity
of neurons involved in generation of tremor and that ET was
due to oscillation within the olivocerebellar pathways,
relayed by way of the thalamus and motor cortex to the
spinal cord. Using a higher-resolution camera, the investiga-
tors were additionally able to demonstrate bilateral mid-
brain activation in the region of the red nuclei during
tremor, but there was no change in the activity of the infe-
rior olive either at rest or during postural tremor (Wills
et al., 1994). Additional evidence of increased activation of
the cerebellum and red nucleus in ET has been provided by
functional MRI studies (Bucher et al., 1997). The prepon-
derance of evidence, based on PET and functional MRI
studies, indicates that the inferior olive probably does not
play an important role in the generation of ET. This is in
contrast to one previous study that indicated the involve-
ment of the inferior olive in ET, suggested by the finding of
glucose hypermetabolism during activation (finger-to-
nose) of tremor in patients with ET (Dubinsky and Hallett,
1987). The absence of activity in the inferior olive and the
bilateral overactivity of cerebellar-rubral-thalamic connec-
tions suggest that the tremor generator for ET is located in
the cerebellum rather than the inferior olive. This conclu-
sion is further supported by the finding of abnormal bilat-
eral overactivity of cerebellar connections, as measured by
regional cerebral blood flow determined by PET with
15
O-labeled water, in patients with primary writing tremor
and primary orthostatic tremor (Wills et al., 1995, 1996).
Furthermore, alcohol has been found to suppress cerebellar
synaptic overactivity in patients with ET, which in turn

increases afferent input to the inferior olive (Boecker et al.,
1996). In one study, 25% of ET patients were found to
have moderate or severe kinetic tremor and other elements
of cerebellar dysfunction (Deuschl et al., 2000). The dem-
onstration by magnetic resonance spectroscopy of reduced
N-acetyl-L-aspartate/creatine and N-acetyl-L-aspartate/
choline ratios in the cerebellum of patients with ET com-
pared to controls provides additional evidence for cerebellar
dysfunction in ET (Pagan et al., 2003).
Cerebellar pathology, including loss of Purkinje cells,
has been also described in some brains of patients with
ET (Louis et al., 2006b; Axelrad et al., 2008; Louis and Von-
sattel, 2008) but this finding has not been replicated by
others (Rajput et al., 2011). In one of the largest clinical-
pathologic studies, involving 33 ET and 21 control brains, 8
(24.2%) brains were found to have Lewy bodies in the brain-
stem, mainly in the locus coeruleus, and these patients were
older than those ET cases without Lewy bodies (Louis et al.,
2007b). The major pathologic changes, however, were
observed in the cerebellum, particularly marked reduction
in the number of Purkinje cells and 7-fold increase in
Purkinje cell torpedoes (Louis et al., 2009c). Other findings
included degeneration of the dentate nucleus, Purkinje cell
heterotopias and dendrite swellings. Lewy body ET cases
were older than ET cases without Lewy bodies. Increased
cerebellar gliosis and depletion of pigmented neurons in the
locus coeruleus and substantia nigra (of which 3 had Lewy
bodies) were found in a prospective study of 24 subjects
enrolled in the Sun Health Research Institute and Body
Donation Program (Shill et al., 2008). In a subsequent
study, presumably based on the same pathologic cases, they
found no difference in the putaminal tyrosine hydroxylase
concentration between the ET cases (91.7 ± 113.2 ng/mg)
and controls (96.4 ± 102.7 ng/mg) and concluded that “This
study provides neurochemical support that ET does not
appear to be pre-clinical PD.” The data, however, do not
support the conclusion for several reasons. First, the mean
age in the pathologic series was 86.2 years and mean dura-
tion of tremor was 11.1 years; and 19/24 (79%) had a dura-
tion of ≤8 years. Although the authors do not provide the
mean age at onset, based on their demographic data, the
mean age at onset of ET in their population was about 81
years, which is 50 years later than the usual mean age at
onset of ET of 31 years. It is, therefore, likely that most of
the patients in the Shill et al. (2008) pathologic series had
“senile tremor” rather than typical ET. Furthermore, patients
with prior history of a movement disorder, including those
with parkinsonian features, were excluded; thus, by defini-
tion, clinical, pathologic, or biochemical evidence of PD
could not be demonstrated in this selected ET population.
Cerebellar dysfunction in ET is also suggested by abnor-
malities in tandem gait, noted in 50% of ET patients (Singer
et al., 1994; Stolze et al., 2001), and by mild postural insta-
bility (Henderson et al., 1996; Overby et al., 1996). Although
ataxic gait is rare, some ET patients exhibit a slightly slow or
cautious pattern of walking (Kronenbuerger et al., 2009).
This gait ataxia improves with alcohol at blood level of
0.45% (Klebe et al., 2005). Posturographic analysis in
patients with ET showed that balance control is only mini-
mally impaired in ET, but patients with head tremor and
longer disease duration may have slightly reduced postural
stability (Bove et al., 2006). ET patients also show eye
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Pathophysiologic mechanisms of rest and action tremors
movement abnormalities indicative of cerebellar dysfunc-
tion, such as impaired smooth pursuit initiation and patho-
logic suppression of the vestibular-ocular reflex time constant
by head tilts (otolith dumping) (Helmchen et al., 2003).
Further evidence of cerebellar involvement in ET is suggested
by a delay in second agonist EMG burst during rapid wrist
movements (Britton et al., 1994). That the cerebellum might
be involved in ET is also supported by the report of a 71-year-
old man with ET in whom postural tremor disappeared on
the right side after an ipsilateral cerebellar infarct (Dupuis
et al., 1989). Since the amplitude of ET can be substantially
reduced by thalamic lesions or thalamic stimulation
(Benabid et al., 1991) and close correlation has been dem-
onstrated between thalamic neuronal activity and forearm
EMG in patients with ET (Hua et al., 1998), it is likely
that the thalamus also plays an important role in
the generation or transmission of ET. Despite the reported
evidence of cerebellar dysfunction in patients with ET,
voxel-based morphometry, however, shows no reduction in
cerebellar gray matter volume (Daniels et al., 2006).
In addition to proposed cerebellar involvement in ET,
there is some evidence that cerebral cortex plays a role in the
generation of ET (McAuley, 2001). Using simultaneous elec-
troencephalogram (EEG)-EMG recordings, Hellwig and
colleagues (2001) showed significant corticomuscular coher-
ences in five of nine patients with ET. This is in contrast
to a previous study that used magnetoencephalography
(Halliday et al., 2000). That study found that in contrast to
PD rest tremor, which is associated with marked disruption
to the organization of the descending motor signals, there
was no coherence between the magnetoencephalogram and
EMG in patients with ET. However, the interpretation of the
study that primary motor cortex does not contribute to the
generation or maintenance of ET has been challenged
because of possible insensitivity of the method (Elble,
2000c). The limitations of the various methods that were
used in these studies have been pointed out by McAuley
(2001), who also noted that EEG-EMG coherence does not
necessarily establish cortical origin of the tremor (McAuley,
2001). Some patients with ET have abnormal vibration-
induced illusion of movement, suggesting abnormal senso-
rimotor processing (Frima and Grunewald, 2005).
Rarely, postural tremor that occurs during sustained iso-
metric muscle contraction can be a manifestation of cortical
reflex myoclonus (Toro et al., 1993). This “cortical tremor,”
with or without seizures, usually starts between 19 and 30
years of age as tremulous finger movements, with a benign
course and marked response to anticonvulsants, possibly
cognitive decline, and a family history suggestive of ET
(Okuma et al., 1998; van Rootselaar et al., 2005). It is
characterized physiologically by an 8–15 Hz, synchronous,
agonist-antagonist, EMG burst lasting less than 50 ms (10–
50 ms). The condition shares neurophysiologic features with
myoclonus, including giant somatosensory evoked responses
and C-reflexes, and it responds well to anticonvulsants such
as clonazepam, primidone, and valproate but not to beta-
blockers (Okuma et al., 1998). Since the EMG pattern can
be influenced by transcranial magnetic and electrical stimu-
lation but not by peripheral nerve stimulation, the rhythmic
movement is thought to arise from central, possibly cortical,
generators. Jerk-locked back-averaging revealed a positive
EEG wave 15 ms preceding the EMG burst of the wrist
411
 18 Tremors
extensor muscle (Okuma et al., 1998). In contrast to ET,
strong cortico- and intermuscular coherence in the 8–30 Hz
range was demonstrated in patients with familial cortical
myoclonic tremor with epilepsy (van Rootselaar et al., 2006).
The syndrome of autosomal dominant cortical tremor, myo-
clonus, and epilepsy has been linked to three genetic markers,
on 8q24 and 2p11.1–q12.2 (Striano et al., 2005) and
5p15.31–p15 (Depienne et al., 2010). The term familial corti-
cal myoclonic tremor with epilepsy has been suggested for
this disorder, which has been reported in over 50 Japanese
and European families (van Rootselaar et al., 2005)
and in patients with spinocerebellar ataxia type 6 (Bour
et al., 2008).
Other abnormalities that are found in patients with ET
include high blood levels of β-carboline alkaloids. Interest-
ingly, these endogenous compounds, also found in plant-
derived foods, increase the synchrony of neuronal firing in
the inferior olive and cause tremor in experimental animals
and humans. Some investigators have suggested that a loss
of GABAA receptors may impair signaling by cerebellar
Purkinje cells and cause tremor, as has been demonstrated
in mice in which the gene coding for the GABAA receptor α1
subunit has been knocked out (Jankovic and Noebels, 2005;
Kralic et al., 2005). Mutations in the coding region of the
GABRA1 gene, however, do not seem to be a major genetic
cause of ET (Deng et al., 2006c).
Clinical-anatomic correlations indicate that kinetic tremor
is usually associated with lesions in the cerebellar outflow
pathways (Lou and Jankovic, 1993). Lesions of the dentate
nucleus or the superior cerebellar peduncle proximal to the
decussation correlate with kinetic tremor ipsilateral to the
side of the lesion, whereas lesions that are distal to the dec-
ussation result in kinetic tremor contralateral to the side of
the lesion (Carrea and Mettler, 1955). Lesions in the cerebel-
lar hemisphere tend to produce kinetic tremors with a vari-
able frequency ranging from 5 to 11 Hz; high brainstem
lesions are usually associated with tremor frequency in the
range of 5–7 Hz; and lower brainstem lesions produce faster
tremors, ranging from 8 to 11 Hz (Cole et al., 1988). In
contrast, the frequency of classical midbrain (red nucleus)
tremor is relatively slow, at 2–3 Hz. In one study of patients
with multiple sclerosis, two types of action tremors were
identified. One group of patients had pure kinetic tremor
with a frequency of 5–8 Hz and an EMG burst duration of
75–100 ms; the other group had coexisting kinetic and pos-
tural tremor. In contrast to kinetic tremor, postural tremor
had a slower (2.5–4 Hz) frequency and a higher amplitude
with a longer burst duration (125–200 ms) (Sabra and
Hallett, 1984). The postural tremor was thought to result
from a lesion in the cerebellar outflow pathway. Cerebellar
kinetic tremor is associated with errors in timing and ampli-
tude of the EMG activities of agonists and antagonists
(Flament and Hore, 1986; Hore and Flament, 1986). The
important role of peripheral reflex mechanisms in the patho-
genesis of cerebellar kinetic tremor is supported by the
observation that the character of the tremor can be altered
by mechanical loading to the tremulous limb (Sanes et al.,
1988) and by improvement in writing after 3–5 min of com-
pressive ischemia of the affected arm (Dash, 1995). Lakie
and colleagues (2004) showed that reduction of tremor by
ischemia may be due to an accumulation of interstitial
potassium in the muscle. The frequency of the tremor can
412
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be increased by increasing the spring stiffness and by decreas-
ing the mass.
Other tremors
Fragile X-associated tremor/ataxia syndrome
Other causes of kinetic tremor, phenomenologically
similar to ET, include premutation in the fragile X gene
(FMR1) (Hagerman et al., 2001; Berry-Kravis et al., 2003;
Jacquemont et al., 2003, 2004; Leehey et al., 2003;
Hagerman and Hagerman, 2004, 2008; Amiri et al., 2008).
While healthy individuals have about 30 CGG repeats in the
FMR1 gene, the carriers of this premutation syndrome have
55–200 repeats. The FMR1 CGG repeat length has been
found to predict motor dysfunction in premutation carriers
(Leehey et al., 2008). In addition to the ET-like tremor,
frequently affecting the head, and ataxia, this fragile X-
associated tremor/ataxia syndrome (FXTAS) is also associ-
ated with mild cognitive impairment with frontal executive
deficit, dementia, parkinsonism, dysautonomia, erectile
dysfunction, peripheral neuropathy, and generalized brain
atrophy, regardless of family history (Berry-Kravis et al.,
2007) (Table 18.8). FXTAS may also, rarely, occur in females
with a similar phenotype but in early menopause due to
ovarian failure. One of our patients with severe FXTAS-
associated tremor improved markedly with thalamic DBS
(Ferrara et al., 2009a). Unusual bilateral T2 middle cerebel-
lar hyperintensities have been identified on magnetic
resonance imaging in some cases (Leehey et al., 2003). Over-
expression and CNS toxicity of the FMR1 mRNA has been
thought to cause this fragile-X-associated tremor/ataxia syn-
drome (Berry-Kravis et al., 2007; Jacquemont et al., 2007;
Hagerman and Hagerman, 2008).
Although some features overlap with those of multiple
system atrophy, FXTAS is a rare cause of multiple system
atrophy (Biancalana et al., 2005). Patients with FXTAS and
parkinsonism have been found to have normal dopamine
transporter as determined by CIT-SPECT, indicating a postsy-
naptic dopaminergic deficit (Ceravolo et al., 2005). Post-
mortem studies on brains of four elderly premutation carriers
showed eosinophilic intranuclear inclusions in both neuro-
nal and astrocytic nuclei throughout the brain, particularly
involving the hippocampus (Greco et al., 2002). Subsequent
neuropathologic studies of patients with FXTAS showed:
Table 18.8  Clinical features of fragile X-associated tremor/ataxia
syndrome (FXTAS)
• 55–200 CGG repeats (FMR1 premutation)
• ET-like postural tremor
• Kinetic tremor
• Mild cognitive impairment with frontal executive deficit
• Ataxia
• Parkinsonism (MSA)
• Erectile dysfunction
• Peripheral neuropathy
• Premature ovarian failure
• MRI: Bilateral T2 middle cerebellar peduncle hyperintensities

(1) cerebral and cerebellar white matter disease with spongi-
osis in the middle cerebellar peduncles, (2) astrocytic pathol-
ogy with enlarged inclusion-bearing astrocytes, and (3)
intranuclear inclusions in the brain and spinal cord, includ-
ing the cranial nerve nucleus XII (Greco et al., 2006). The
number of inclusions seem to correlate with the number of
CGG repeats (Cohen et al., 2006). The inclusions contain a
variety of proteins, such as RNA binding proteins, but ubi­
quinated proteins represent only a small portion of all the
proteins, suggesting that breakdown of proteasomal degra-
dation is not the main mechanism of the inclusions (Iwa-
hashi et al., 2006).It has been postulated that premutation
RNA is responsible for the observed neurodegeneration (Orr,
2004). Marked loss of Purkinje cells in the cerebellum,
Purkinje axonal torpedoes, and Bergmann gliosis were also
found. SCA12, a rare autosomal-dominant ataxia, may also
present with ET-like tremor before other signs of ataxia
become evident. This form of ataxia has been associated with
CAG repeat expansion in the PPP2R2B gene (5q31–q33)
coding for protein phosphatase PP2A (Fujigasaki et al.,
2001). The frequency of fragile X premutation, even in
patients with tremor, parkinsonism, and ataxia, is so low that
it is not cost-effective to routinely test for it even in an
enriched movement disorders population (Arocena et al.,
2004; Deng et al., 2004; Tan et al., 2004). Interestingly, the
location of the CAG repeat expansion in the 5′ region is
similar to that of the CGG repeat in FMR1, in which an
expansion results in CpG hypermethylation and disruption
of transcription, resulting in the fragile X phenotype.
Neuropathic tremors
Tremor has been described in patients with various types of
peripheral neuropathy (Said et al., 1982; Shahani, 1984).
Distal postural tremor was noted in patients with chronic
relapsing and dysgammaglobulinemic polyneuropathies
(Bain et al., 1996). The amplitude was not related to the
severity of weakness or proprioceptive sensory loss, and pro-
pranolol improved the tremor in some patients. Hereditary
motor and sensory neuropathy is associated with tremor,
clinically similar to ET, in nearly half of cases (Cardoso and
Jankovic, 1993). The frequent association between tremor
caused by peripheral nerve injury and reflex sympathetic
dystrophy suggests that the sympathetic nervous system con-
tributes to the pathogenesis of peripherally induced tremor
(Jankovic and Van der Linden, 1988; Deuschl et al., 1991;
Cardoso and Jankovic, 1995; Jankovic, 1994; van Rooijen
et al., 2011).
Tremors caused by trauma or stroke
Tremor can also occur after severe or even minimal
head trauma (Biary et al., 1989; Goetz and Pappert, 1992;
Jankovic, 1994; Krauss et al., 1995). Biary and colleagues
(1989) described seven patients who developed postural and
kinetic tremors involving various body parts up to several
weeks after mild head injury without loss of consciousness.
Ipsilateral predecussational dentatothalamic lesion was
involved in the majority (56%) of 25 instances of severe
post-traumatic tremor in 19 patients, followed by involve-
ment of the contralateral predecussational dentatothalamic
pathway (28%), dentate nucleus (4%), and thalamus (4%);
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Other tremors
no lesion was identified by neuroimaging in 2 (8%) patients
(Krauss et al., 1995). Clonazepam was effective in reducing
tremor in 3 patients, and propranolol was effective in 1.
Post-traumatic midbrain tremor may improve with anti-
cholinergic and dopaminergic drugs (Samie et al., 1990),
but in general, this tremor only rarely responds satisfactorily
to drug therapy. Many of our patients with post-traumatic
tremors have benefited from VIM thalamotomy; additional
patients may benefit from thalamic stimulation (Broggi
et al., 1993). In addition to trauma, a variety of tremors can
occur following ischemic or hemorrhagic strokes (Ferbert
and Gerwig, 1993; Miwa et al., 1996).
Trauma can also cause injury to the peripheral nerves,
producing a form of neuropathic tremor, which was dis-
cussed earlier. Traumatic neck injury may cause cervical
radiculopathy, which may be associated with a postural
tremor in the ipsilateral arm (Hashimoto et al., 2002).
Loading and ischemic nerve block reduced the frequency of
the tremor, suggesting a role of the mechanical reflex mecha-
nism and stretch reflex loop in this peripherally induced
tremor.
Psychogenic tremor
One of the most challenging tasks in the diagnosis of tremors
is differentiating between psychogenic and neurogenic
tremors (Kenney et al., 2007) (Table 18.9). Koller and col-
leagues (1989) provided the following diagnostic criteria
useful in the diagnosis of psychogenic tremors: (1) abrupt
onset, (2) static course, (3) spontaneous remission, (4) dif-
ficulty in classifying (various combinations of rest, postural,
and kinetic tremors), (5) selective disability, (6) changing
amplitude and frequency, (7) unresponsiveness to anti-
tremor drugs, (8) increasing of tremor with attention, (9)
lessening of tremor with distractibility, (10) responsiveness
to placebo, (11) absence of other neurologic signs, and (12)
remission with psychotherapy (Video 18.8). Deuschl and
colleagues (1998b) found the following features particularly
characteristic of psychogenic tremor: sudden onset and
Table 18.9  Distinguishing psychogenic from essential tremor
• A “blinded” rater evaluated video segments of subjects using a
standardized protocol
• N = 33 subjects with ET (56.8 ± 17.0 years) and 12 with psychogenic
tremor (42.5 ± 11.0 years)
• Patients with psychogenic tremor were significantly more likely to
have a history of sudden onset (P = 0.03), spontaneous remissions
(P = 0.03), and shorter duration of tremor (P = 0.001)
• Family history of tremor was significantly more common in the ET
group (P = 0.001)
• A moderate to marked degree of distraction with alternate finger
tapping (P = 0.01) and mental concentration on serial 7 s (P = 0.01)
was more common in psychogenic tremor
• Suggestibility with a tuning fork (P = 0.04) and exacerbation with
hyperventilation (P = 0.06) seemed predictive of psychogenic
tremor
• Entrainment was not different in the two groups
Data from Kenney C, Diamond A, Mejia N, et al. Distinguishing psychogenic and
essential tremor. J Neurol Sci 2007;263:94–99.
413
 18 Tremors
variable (rarely remitting) course, coactivation sign (fluctua-
tions in muscle tone and in tremor during passive move-
ments), and absent finger tremor. Although overt signs of
hysteria were often lacking, evidence of depression and psy-
chosomatic conditions were common. In another study of
70 patients with psychogenic tremor, 73% had an abrupt
onset, and 46% had their maximal disability at onset (Kim
et al., 1999). Additional features that were found helpful in
confirming the diagnosis of psychogenic tremor included
spread from a focal onset to generalized tremor, variability,
and entrainment. Electrophysiologic studies are rarely
helpful in differentiating organic tremor from psychogenic
tremor (McAuley et al., 1998). Using accelerometry, Zeuner
and colleagues (2003b) demonstrated that in contrast to
essential and parkinsonian tremor, patients with PT showed
larger tremor frequency changes and higher individual vari-
ability while tapping. Longitudinal studies are needed to
determine the natural history of psychogenic tremors. In one
study, a 6-year follow-up of 64 patients with unexplained
motor disorders, only 3 were later found to have an organic
diagnosis (Crimlisk et al., 1998). In the Parkinson’s Disease
Center and Movement Disorders Clinic at the Baylor College
of Medicine, psychogenic tremor is the most common of all
psychogenic movement disorders, accounting for 4.1% of all
patients (Jankovic and Thomas, 2006). Clinical information
was obtained on 228 of 517 (44.1%) patients, who were
followed for a mean of 3.4 ± 2.8 years. Among the 127
patients who were diagnosed with psychogenic tremor, 92
(72.4%) were female, the mean age at initial evaluation was
43.7 ± 14.1 years, and the mean duration of symptoms was
4.6 ± 7.6 years. The following clinical features were consid-
ered to be characteristic of psychogenic tremor: abrupt onset
(78.7%), distractibility (72.4%), variable amplitude and fre-
quency (62.2%), intermittent occurrence (35.4%), incon-
sistent movement (29.9%), and variable direction (17.3%).
In the majority of patients, some precipitating event could
be identified prior to the onset of tremor, including personal
life stress (33.9%), physical trauma (23.6%), major illness
(13.4%), surgery (9.4%), or reaction to a medical treatment
or procedure (8.7%). Coexistent organic neurologic disorder
was present in 37% of patients with psychogenic tremor;
psychiatric comorbidities included depression in 50.7% and
anxiety in 30.7%. Evidence of secondary gain was present
in 32.3%, including maintenance of a disability status in
21.3%, pending compensation in 10.2%, and litigation in
9.4%. Improvement in tremor, reported on a global rating
scale at last follow-up by 55.1%, was attributed chiefly to
“effective treatment by physician” and “elimination of stres-
sors.” On the basis of the analysis of data in this largest
longitudinal study of patients with psychogenic tremor, we
have concluded that accurate diagnosis is not only based on
exclusion of other causes but also dependent on positive
414
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clinical criteria, the presence of which should avoid unneces-
sary investigation.
Miscellaneous tremors
There are many other causes of tremors. One of the most
common causes of tremors are certain drugs, such as
anti­psychotics, amiodarone, cyclosporine, lamotrigine,
lithium, tricyclic antidepressants, selective serotonin
reuptake inhibitors (SSRIs), valproate, and other drugs
(Morgan and Sethi, 2005). In one study of 707 patients
treated with amiodarone, 2.8% had some neurotoxic effects,
including de novo tremor and exacerbation of essential
tremor, gait ataxia, peripheral neuropathy, and cognitive
impairment (Orr and Ahlskog, 2009). These side effects cor-
related with duration of exposure and were not always
reversible. The bobble-head doll syndrome is a form of slow
(2–30 Hz) oscillatory movement that is usually associated
with cystic enlargement of the third ventricle, suprasellar
arachnoid cysts, aqueductal stenosis, and other lesions
involving the third ventricle (Goikhman et al., 1998; Bhat-
tacharyya et al., 2003). Hereditary chin tremor, or hereditary
geniospasm, is an autosomal dominant disorder character-
ized by recurrent episodes of chin tremor (Soland et al.,
1996a; Erer and Jankovic, 2007) (Video 18.9). Usually a
benign condition with a peak in the mid-twenties (although
it may be persistent in men), this condition has been
mapped to a marker on chromosome 9q13–q21 (Jarman
et al., 1997). Some investigators have suggested that “iso-
lated generalized polymyoclonus” may present as “whole
body tremulousness” and that some of the cases are drug-
induced (e.g., SSRI) or due to an autoimmune disorder
(McKeon et al., 2007). Genetic phenocopies of ET include
FXTAS, Kennedy syndrome, SCA12, hereditary neuropathies,
Klinefelter (XXY) syndrome (Harlow et al., 2008), and the
48,XXYY syndrome, which is also associated with gait ataxia,
dysarthria, and nystagmus (Tartaglia et al., 2009).
References available on Expert Consult:
www.expertconsult.com
Appendix
International Essential Tremor Foundation (IETF)
PO Box 14005
Lenexa, KS 66285-4005
Telephone: (888) 387-3667
Fax: (913) 341-1296
Email: info@essentialtremor.org
Website: http://www.essentialtremor.org