DIAGNOSIS AND MANAGEMENT OF

THE PATIENT WITH TREMOR

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.
CLASSIFICATION OF TREMOR
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 druginduced (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- KELVIN L.
CHOU, MD kinsonism, comprising
approximately three quarters of all cases
seen in movement isorders 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 antigravity posture, such as when a patient holds
a newspaper up to read, whereas kinetic
tremor happens during voluntary movement.
Often brought out using the fingernosefinger 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. Taskspecific 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 ostural
tremor seen in essential tremor (ET) can
ometimes persist when the hands rest in the
patient's lap. Though this overlap can

sometimes cause difficulty for the

diagnosing clinician, a tremor that
iminishes 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.
CLUES TO THE DIAGNOSIS OF
TREMOR
Once the predominant type of tremor is
identified, a short differential diagnosis can
be generated (Table 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 detected 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.
COMMON TREMOR
SYNDROMES AND THEIR
MANAGEMENT
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.
ESSENTIAL TREMOR (ET)
ET is the most common movement
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 alcohol,
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-adduction
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 increase
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
sitUations.
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
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

depression.
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, placebocon 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
Table 1. Common Tremor Types,
Characteristics, and Examples
Type of Tremor
Rest
Clinical Characteristics
Occurs when body part is supported
against gravity and not engaged in
activity
Action
Postural Occurs when body part is
maintained
against gravity
Kinetic
Occurs
during
voluntary
movement
Intention Occurs toward the end of a
goal-directed
movement
Common Examples
Parkinson's disease, drug-induced
parkinsonism, multiple system atrophy,
progressive supranuclear palsy
Physiologic,
essential
tremor,
druginduced,

alcohol withdrawal, posttraumatic,

psychogenic
Physiologic,
essential
tremor,
druginduced,
post-traumatic, psychogenic,
cerebellar lesions
Cerebellar lesions
MEDICINE AND HEAL TH / RHODE
ISLAND
136
(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.
PARKINSON'S DISEASE (PD)
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.!
As a general rule, if the patient
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
Although carbidopa/levodopa
(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,!6The 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
weekly until a therapeutic dose is
reached.
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
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-

Table 2. Drugs that commonly

cause tremor
Alcohol (chronic use or withdrawal)
Anti-arrhythmic drugs
Amiodarone
Procainamide
Antiepileptic agents
Carbamazepine
Valproic acid
Benzodiazepine withdrawal
Cyclosporine
Lithium
Neuroleptics
Stimulants
Albuterol
Amphetamines
Caffeine
Cocaine
Theophylline
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 adjunctivetherapy
for a tremor that is resistant to the
dopaminergic medications mentioned
earlier. Sedation is the main side effect
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
for PD include the thalamus, globus
pallidus interna (GPi) and the subthalamic
nucleus (STN). Thalamic
stimulation is effective only for tremor,
137
VOL. 87 NO.5 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
Cerebellar tremor most often presents
as a kinetic tremor with a prominent
intention component.5 The
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, or
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
PSYCHOGENIC TREMOR
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.
138
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.
SUMMARY
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.
REFERENCES
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.
1997:623-638.
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. KollerWC, Busenbark K, Gray C, et al.
Clin NeuropharmacoI1992; 15:81-87.
8. Koller WC and Royse VL. Neurol

1986; 36:121-124.
9. KollerWe. ArchNeurol 1986; 43:42-43.
10. Connor GS. Neuro12002; 59:132-134.
11. Benabid AL, Pollak P, Gao D, et al.]
Neurosurg 1996; 84:203-214.
12. Van Den Eeden SK, Tanner CM,
Bernstein AL, et al. Am ] Epidemiol
2003; 157:1015-1022.
13. Hoehn MM and Yahr MD. Neurol
1967; 17:427-442.
14. Olanow CW, Watts RL and Koller
We. Neuro12001; 56:S1-S88.
15. Rascol 0, Brooks DJ, KorczynAD, et
al. NE]M2000; 342:1484-1491.
16. Parkinson Study Group. ]AMA 2000;
284:1931-1938.
17. Deep Brain Stimulation for Parkinson's
Disease Study Group. NE]M 2001;
345:956-963.
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.
CORRESPONDENCE:
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]
MEDICINE AND HEALTH I RHODE
ISLAND