Document 150611

Tremor, the most common form
of abnormal involuntary movement
(AIM), is a rhythmic oscillation of a
body region produced by alternating
contractions of reciprocally innervated
muscles.I,llt occurs across a wide spectrum of neurological disorders and is
easily distinguished from other AIMs
such as chorea, tics, and myoclonus by
its rhythmic, repetitive and stereotypical appearance. Tremor causes not only
discomfort and social embarrassment
for patients, but also disability. Since
successful treatment depends on the
correct diagnosis, it is important for the
clinician to recognize the various presentations of tremor and associated
symptoms. This article describes the
general clinical approach to the patient
who presents with tremor and reviews
the most common tremor syndromes
and their management.
When evaluating a patient who
presents with tremor, first categorize
the tremor based on its positional properties. Tremor can be divided into two
main types: rest and action. Rest
tremor occurs in a body part that is
relaxed or supported against gravity
and not involved in purposeful activities, for example, a hand tremor evident when the upper limb rests on the
arm of a chair. When intermittent or
minimal, a rest tremor can be brought
out or enhanced on examination by
having the patient concentrate on other
tasks, such as performing arithmetic or
opening and closing the contralateral
hand. The presence of a rest tremor is
virtually synonymous with parkinsonism, a condition with multiple etiologies, including drug-induced (due
mainly to neuroleptics) and other
neurodegenerative disorders such as
multiple system atrophy (MSA) or
progressive supranuclear palsy (PSP).
Parkinson's disease (PD), however" is
by far the most common cause of par-
kinsonism, comprising approximately
three quarters of all cases seen in movement disorders centers.3
Action tremor is present during the
voluntary contraction of muscles, and
can be subdivided into four types: postural, kinetic, isometric, and task-specific. Postural tremor is seen during the
maintenance of an anti-gravity posture,
such as when a patient holds a newspaper up to read, whereas kinetic tremor
happens during voluntary movement.
Often brought out using the fingernose-finger test, a kinetic tremor can
occur at the beginning of the movement, during the course of the movement, or when approaching a target. In
the latter condition, it is also known as
an intention tremor, commonly seen
with cerebellar lesions. Isometric tremors are present during voluntary muscle
contractions not accompanied by movement, for example, when standing or
when making a fist. Task-specific tremors, as the name implies, occur only
during specific activities, such as writing, singing, or playing an instrument.
The postural and kinetic tremor subtypes are seen far more frequently than
the isometric and task-specific subtypes.
Just as each tremor type has multiple etiologies, more than one tremor
type can occur in the same condition.
For example, PO patients often have an
action component in addition to their
classic rest tremor, while the postural
tremor seen in essential tremor (ET) can
sometimes persist when the hands rest
in the patient's lap. Though this overlap
can sometimes cause difficulty for the
diagnosing clinician, a tremor that diminishes with voluntaty movement is
likely to be a rest tremor, while a tremor
that is present at rest but worsens with
movement is probably an action tremor.
Once the predominant
type of
tremor is identified, a short differential diagnosis
can be generated
1) and narrowed down based on clues
obtained from the clinical history and
neurological examination. Historical
elements that are important to elicit
include: 1) age at onset of the tremor,
2) mode of onset (sudden vs. gradual),
3) anatomical site(s) affected by the
tremor, 4) rate of progression to other
sites, 5) exacerbating and remitting factors (such as alcohol responsiveness),
6) histoty of alcohol abuse, and 7) family history of tremor. Furthermore,
many pharmacologic agents can cause
tremor (Table 2), so a thorough review
of the patient's medications is essential. Associated examination findings
that may shed light on the underlying
etiology of the tremor include bradykinesia or rigidity (PO); nystagmus, scanning speech, ataxia (cerebellar lesion);
and a wide variation in tremor frequency (psychogenic).
If the diagnosis can be established
on clinical criteria and the patient responds to treatment, ancillaty studies are
usually unnecessary. However, in young
patients «50 years of age) with tremor,
Wilson's disease (WD) should always
be excluded, because it is devastating
and potentially life-threatening if left
untreated. WD is a rare, autosomal recessive disorder believed to be caused
by mutations in a gene encoding a copper transporting ATP-ase, resulting in
abnormal deposition of copper in brain,
liver and other organs of the body.
Although classically described as
"wing-beating", the tremor in WO can
occur in any pattern and is the most
common neurological manifestation of
the disease.4 Most cases can be ruled
out with a normal serum ceruloplasmin and 24-hour urinary copper excretion. Other groups of patients in
whom investigational studies may be
helpful include those with asymmetrical, cerebellar, or postural tremors.
Asymmetrical or cerebellar tremors
may result from focal lesions such as
neoplasm, stroke, hemorrhage or demyelinating disease and may be de-
MAY 2004
tected with a magnetic resonance imaging stUdy of the brain. Patients who
present with postural tremor may have
hyperthyroidism as an underlying etiology and should have their thyroid
function checked.
hol, but these features are not present
in every patient. Although ET can
occur at any age, its prevalence generally increases with age.
ET tends to start distally in the
arms with a typical flexion-extension
motion at the wrists or abduction-ad-
duction movement of the fingers. Although it may be unilateral in onset,
both sides will eventually be involved.
The most common anatomical sites of
involvement after the hands are (in
decreasing order) the head, voice, legs,
and chin.6 The tremor tends to in-
The most common tremor syndromes encountered in clinical practice are ET and PD. Although
cerebellar and psychogenic tremors are
less frequently seen, they are important
for the general clinician to be aware of
and will be briefly reviewed. Iatrogenic
causes of tremor are common, and may
even mimic ET or PD. If a patient is
taking a medication known to induce
tremor (Table 2), that medication
should be discontinued before initiating other therapy.
ET is the most common move-
ment disorder.2 The diagnosiscan be
made when a persistent, bilateral,
mainly symmetrical, postural and/or
kinetic tremor of the hands or arms is
present, without other neurological
signs or exposure to drugs that may
cause tremor.5 A head tremor can also
be part of the syndrome, either in addition to the hand tremor or in isolation, as long as there is no dystonic
postUring. Clinical or historical features consistent with a diagnosis ofET
include a positive family history and
improvement of the tremor with alco-
crease with stress, anxiety, excitement,
emotional upset, fatigue or cold temperature. Although ET is sometimes
preceded by the term "benign", many
patients dispute the adjective. ET
causes both physical and social disability. Simple tasks such as signing a
check, eating, drinking from a cup,
shaving, brushing teeth, and dressing
can become frustrating ordeals, and
embarrassed patients often avoid social
Primidone (Mysoline) and propranolol (Inderal) continue to be the
mainstays of treatment
for ET.
Primidone, an anticonvulsant, may be
the more effective agent, with approximately 70% of patients experiencing
benefit, compared to 50% of patients
on propranoloU Though dosages between 50 and 250 mg of primidone
daily are usually needed to reduce
tremor,8 this medication should be
started at a low dose and titrated slowly
up in order to minimize adverse effects.
Primidone is usually prescribed in one
Table 1. Common Tremor Types, Characteristics,
single daily dose at bedtime, beginning
with 25 mg, and increased by 25 mg
weekly until the desired tremorlytic
effect is obtained or side effects occur.
Drowsiness is the most common side
effect, but patients may also experience
nausea, vertigo and unsteadiness. Propranolol, a beta-blocker, is usually effective between 240 and 320 mg daily.9
Patients are frequently referred to
movement disorders centers and labeled as having "failed" propranolol
treatment, when in fact, an adequate
dose was never administered. As with
primidone, propranolol should be
started at low doses and increased over
weeks, while monitoring blood pressure and pulse. Contraindications for
the use of propranolol include cardiac
conduction block, heart failure, asthma
and diabetes; side effects include
lightheadedness, fatigue, nausea and
Other medications for ET are generally not proven to be as effective as
primidone or propranolol, though
topiramate was recently shown to reduce tremor in a double-blind, placebo-con trolled
trial. 10
Benzodiazepines such as alprazolam or
clonazepam may also help if the patient
has concurrent anxiety.
When the medications fail to control the tremor, surgery should be considered. Stereotactic ablation of the
ventral intermediate nucleus (Vim) of
the thalamus used to be the preferred
surgical procedure for control of ET
tremor, but has become obsolete with
the advent of deep brain stimulation
and Examples
Type of Tremor
Clinical Characteristics
Common Examples
Occurs when body part is supported
against gravity and not engaged in activity
Parkinson's disease, drug-induced
parkinsonism, multiple system atrophy,
progressive supranuclear palsy
Occurs when body part is maintained
against gravity
Physiologic, essential tremor, druginduced, alcohol withdrawal, post-
Occurs during voluntary movement
Occurs toward the end of a goal-directed
traumatic, psychogenic
Physiologic, essential tremor, druginduced, post-traumatic, psychogenic,
cerebellar lesions
(DBS) of the thalamus.]] Thalamic
DES involves the placement of an electrode in the Vim nucleus. This electrode is connected to a wire, which is
tunneled under the skin and attached
to an implantable pulse generator located in the subcutaneous tissue overlying the pectoralis muscle. This pulse
generator can then be switched on or
off and programmed using a portable
computer. The clinical effect of DES
is identical to that of ablation, but DBS
holds an advantage over ablation in
that turning the stimulator off can reverse its effects. Thalamic stimulation
can also be performed bilaterally with
fewer side effects than thalamotomy.
PD is a slowly progressive
neurodegenerative disorder characterized clinically by the classic triad of rest
tremor, bradykinesia and rigidity. Although a fourth feature, postural instability, is sometimes included among
the cardinal manifestations, this symptom is often absent until the later stages
of disease. The diagnosis ofPD is made
clinically, based on the presence of two
out of the three cardinal features and
an unequivocal, sustained response to
dopaminergic therapy.3 PD is uncommon under the age of 40 and increases
rapidly in incidence above the age of
60 for both males and females, with a
mean age at diagnosis of70.5 yearsY
Approximately 70% of PD patients will have tremor as the initial
symptom.!3 The rest tremor in PD has
a frequency of 4-6 Hz and a characteristic "pill-rolling" action when the arm
and hands are involved. As mentioned
earlier, it is not unusual to see an action or postural tremor with PD, especially in the later stages of disease,
although this action component generally has a higher frequency (~7 to 12
Hz). In addition to the arms, PD
tremor can also affect the legs, lips, jaw,
chin, and tongue, but rarely involves
the head, differentiating it from ET.
The tremor tends to start intermittently in one arm, but gradually becomes more constant, and generally
progresses to the contralateral side a few
years into the course of the disease.
Similar to ET, factors that exacerbate
tremor in PD include anxiety,
stress, or emotional states or extremes in temperature.
The treatment of PD remains symptomatic. Although
research efforts are focusing on
neuroprotective strategies and
treatment, there are no therapies
that unequivocally slow the progression of PD. Therefore, if the
patient's symptoms are not limiting, treatment does not need
to be initiated. Nevertheless,
most patients with prominent
rest tremor will opt for treatment because the tremor is annoying
or embarrassing.
Unfortunately, the response of
parkinsonian tremor to pharmacologic treatment is highly variable.!
Table 2. Drugs that commonly
cause tremor
Alcohol (chronic use or withdrawal)
Anti-arrhythmic drugs
Antiepileptic agents
Valproic acid
Benzodiazepine withdrawal
As a general rule, if the pa-
tient is young «70 years of age) and
has other features
of PD such as
bradykinesia or rigidity in addition to
tremor, most PD experts would recommend initiating treatment with a
dopamine agonist such as pramipexole
(Mirapex) or ropinirole (Requip).!4
(Sinemet) is clearly the most effective
anti-parkinsonian drug overall, it is
associated with long term motor complications such as fluctuations and
dyskinesias, which can be delayed by
initiating therapy with a dopamine
agonist.!5,!6 The dopamine agonists are
administered three times a day; common side effects include nausea, dizziness, confusion
and excessive
sleepiness. In order to minimize these
adverse effects, the agonists should be
started at a low dose and increased
tion independently.
The anticholinergic trihexyphenidyl
hydrochloride (Artane) can improve
tremor in PD, but is ineffective in controlling the other cardinal motor features
of PD. Therefore, its use is limited to
the PD patient who presents with a predominant tremor, but minimal bradykinesiaand rigidity,or as adjunctive therapy
for a tremor that is resistant to the
dopaminergic medications mentioned
earlier. Sedation is the main side effect
When the patient presents with PD
symptoms at a more advanced age (>70
years of age), carbidopa/levodopa is a
more appropriate choice. Carbidopa/
levodopa comes in both standard and
controlled release formulations, but patients tend to respond less predictably
to the controlled release formulation. It
in addition to anticholinergic symptoms
such as blurred vision, dry mouth and
urinary retention, and is usually the limiting factor in the use of this agent.
Trihexyphenidyl should alsobe used cautiously in elderly patients because they
are more prone to developing cognitive
difficulties. Dosages needed to suppress
tremor can range from 2 to 12 mg daily
(maximum dosage 32 mg); again, it is
wise to start at a low dose and titrate up
for effect. If trihexyphenidyl is ineffective or poorly tolerated, propranolol
(Inderal) or amantadine hydrochloride
(Symmetrel) can be tried.
If the tremor is refractory to pharmacologic modalities, DES should be
considered. The three anatomical sites
in which stimulation has been studied
is reasonable to begin with the 25/100
mg dose of carbidopa/levodopa two to
three times a day, and then increase the
dosage as needed for the patient to func-
for PD include the thalamus, globus
pallidus interna (GPi) and the subthalamic nucleus (STN). Thalamic
stimulation is effective only for tremor,
weekly until a therapeutic
dose is
MAY 2004
and therefore is helpful for only a small
proportion of PO patients. Both GPi
and STN stimulation have been shown
to improve all cardinal features of PO,
-including tremor,17 and either would
be an appropriate option for the majority of patients.
Cerebellar tremor most often presents as a kinetic tremor with a prominent intention component.5
ipsilateral arm or leg is usually affected
when a cerebellar hemisphere in involved. Lesions of the cerebellar vermis, or midline, often cause an isolated
postural tremor of the trunk and head,
commonly referred to as "titubation".
Multiple sclerosis (MS) is the most
common cause; other causes include
tumors, ischemic or hemorrhagic
strokes, alcoholic cerebellar degeneration, vitamin
E deficiency,
paraneoplastic syndromes. Treatment
of the underlying
cause (i.e.
immunomodulatory therapy in MS,
resection of a tumor) can sometimes
resolve the tremor. For persistent cerebellar tremor, however, no medication
has been proven to be helpful. A sensible approach is first to try the agents
that are helpful for ET. If these fail to
relieve the tremor, isoniazid or DBS
can be considered. Isoniazid resulted
in mild improvement in one small randomized crossover trial of six patients
with severe postural cerebellar tremor, 18
while thalamic DBS showed some benefit for cerebellar tremor in a small
number of patients with MS.19
Although there are no precise estimates of the incidence and prevalence
of psychogenic tremors, clinical experience suggests that it is not rare. While
it can be difficult to differentiate between psychogenic and organic tremors, the characteristic
that all
psychogenic tremors have in common
is variability in the tremor amplitude
and frequency.2 Because of this variability, the tremor often cannot be easily classified. Psychogenic tremors
frequently increase in severity with attention, and decrease when the patient
is forced to concentrate on other tasks.
Other criteria useful in the diagnosis
of this tremor include sudden or abrupt
onset, variable course with spontaneous remissions, ability to perform some
functions despite severe tremors, and
unresponsiveness to anti-tremor medications.2O Often, "false" signs will appear on the neurologic examination,
such as give-way weakness or bizarre
sensory findings. Psychotherapy is the
main treatment approach.
Tremor is a common and disabling
symptom that is associated with a large
number of neurological disorders, including ET and PD. The positional
properties of the tremor allow the clinician to generate a short list of diagnostic possibilities, which can then be
narrowed down based on the clinical
history and the neurological examination. A number of medical and surgical therapies are availablefor tremor, but
a successful response to treatment depends on an accurate diagnosis.
1. Wasielewski PG, Burns JM and Koller
We. Mov Disord 1998; 13 SuppI3:90100.
2. Zesiewicz TA and Hauser RA. Neurol
Clin 2001; 19:651-680.
3. Colcher A and Simuni T. Med Clin
NorthAm 1999; 83:327-347.
4. Pfeiffer RF. Wilson's Disease. In Watts
RL and Koller WC, ed. Movement
Disorders: Neurologic Principles and
Practice. New York: McGraw-Hill.
5. Deuschl G, Bain P and Brin M. Mov
Disord 1998; 13 SuppI3:2-23.
6. Koller WC, Busenbark K and Miner
K. Ann Neuro11994; 35:717-723.
7. Koller WC, Busenbark K, Gray C, et al.
Clin NeuropharmacoI1992; 15:81-87.
Koller WC and Royse VL. Neurol
1986; 36:121-124.
KollerWe. ArchNeurol 1986; 43:42-43.
Connor GS. Neuro12002; 59:132-134.
Benabid AL, Pollak P, Gao D, et al.]
Neurosurg 1996; 84:203-214.
Van Den Eeden SK, Tanner CM,
Bernstein AL, et al. Am ] Epidemiol
2003; 157:1015-1022.
Hoehn MM and Yahr MD. Neurol
1967; 17:427-442.
Olanow CW, Watts RL and Koller
We. Neuro12001; 56:S1-S88.
Rascol 0, Brooks DJ, KorczynAD, et
al. NE]M2000; 342:1484-1491.
Parkinson Study Group. ]AMA 2000;
Deep Brain Stimulation for Parkinson's
Disease Study Group. NE]M 2001;
18. Hallett M, Lindsey JW, Adelstein BD,
et al. Neuro11985; 35:1374-1377.
19. Montgomery EB,Jr., Baker KB, Kinkel
RP, et al. Neuro11999; 53:625-628.
20. Koller W, Lang A, Vetere-Overfield B,
et al. Neuro11989; 39:1094-1099.
Kelvin L. Chou,MD, is a Movement DisordersFellow at the Parkinson's
Disease and Movement Disorders Center, Pennsylvania Hospital, University of
Pennsylvania School of Medicine, and
will bejoining the Department ofClinical Neurosciences at Brown Medical
School as an Assistant Professorof Neurology in July.
Kelvin L. Chou, MD
Parkinson's Disease and Movement
Disorders Center
330 South Ninth Street
Philadelphia, PA 19107
Phone: (215) 829-8593
Fax: (215) 829-7552
e-mail: [email protected]