Review Article

Diagnosis and
Address correspondence to
Dr Elan D. Louis, Yale School
of Medicine, Department of
Neurology, LCI 710, 15 York St,

Management of Tremor PO Box 20818, New Haven,

CT 06520-8018,
elan.louis@yale.edu.
Elan D. Louis, MD, MS, FAAN Relationship Disclosure:
Dr Louis reports no disclosure.
Unlabeled Use of
Products/Investigational
ABSTRACT Use Disclosure:
Dr Louis discusses the
Purpose of Review: Tremor, which is a rhythmic oscillation of a body part, is among unlabeled/investigational use
the most common involuntary movements. Rhythmic oscillations may manifest in a of acetazolamide, alprazolam,
variety of ways; as a result, a rich clinical phenomenology surrounds tremor. For this baclofen, carbamazepine,
clonazepam, cyclophosphamide,
reason, diagnosing tremor disorders can be particularly challenging. The aim of this ethosuximide, gabapentin,
article is to provide the reader with a straightforward approach to the diagnosis and phenobarbital, phenytoin,
management of patients with tremor. pregabalin, primidone, and
topiramate for the treatment of
Recent Findings: Scientific understanding of the pathophysiologic basis of tremor tremor as well as carbidopa/
disorders has grown considerably in recent years with the use of a broad range of levodopa for the treatment of
neuroimaging approaches and rigorous, controlled postmortem studies. The basal orthostatic tremor and
trihexyphenidyl for the
ganglia and cerebellum are structures that seem to play a prominent role. treatment of dystonic tremor.
Summary: The diagnosis of tremor disorders is challenging. The approach to tremor * 2016 American Academy
involves a history and a neurologic examination that is focused on the nuances of of Neurology.
tremor phenomenology, of which there are many. The evaluation should begin with a
tremor history and a focused neurologic examination. The examination should attend
to the many subtleties of tremor phenomenology. Among other things, the history and
examination are used to establish whether the main type of tremor is an action tremor
(ie, postural, kinetic, or intention tremor) or a resting tremor. The clinician should then
formulate two sets of differential diagnoses: disorders in which action tremor is the
predominant tremor versus those in which resting tremor is the main tremor. Among
the most common of the former type are essential tremor, enhanced physiologic
tremor, drug-induced tremor, dystonic tremor, orthostatic tremor, and cerebellar
tremor. Parkinson disease is the most common form of resting tremor, along with
drug-induced resting tremor. This article details the clinical features of each of these as
well as other tremor disorders.

Continuum (Minneap Minn) 2016;22(4):11431158.

INTRODUCTION activating the arms during movement),

Tremor, which is the rhythmic oscilla-
tion of a body part, is among the most
common forms of involuntary move-
ment. These oscillations may manifest
in a broad variety of ways. Given this
richness of clinical phenomenology,
tremor can be classified in numerous
ways. For example, tremors can be clas-
sified based on their topographic dis-
tribution (eg, arm, neck, chin, or voice),
their frequency in Hz, their activation
condition (ie, whether the tremor is
brought on by resting the arms versus
the brain region affected (cerebellum,
midbrain), the presence of associated
medical conditions (eg, hyperthyroidism),
and the presence of associated neurologic
conditions (eg, dystonia, Parkinson dis-
ease [PD]). As a result, a sizable nomen-
clature surrounds tremor, and this can
be daunting and confusing to the clini-
cian. The aim of this article is to pro-
vide the reader with a straightforward
approach to the diagnosis and manage-
ment of the patient with tremor. This
approach includes a medical history and
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 Diagnosing Tremor
KEY POINT
h Tremors are rhythmic a neurologic examination followed by
oscillations of a diagnosis and, ultimately, treatment.
body part.
APPROACH TO THE PATIENT
WITH TREMOR
The approach to the patient with tremor,
as with any neurologic patient, begins
with a history and then includes a neu-
rologic examination.
Medical History
The first step is to elicit a medical his-
tory. This history should include an
initial set of questions used to determine
whether the patient has an action or a
resting tremor. Open-ended questions
such as, What type of tremor do you
have? may be followed by a series of
more specific questions about tremor
such as, Do you have your tremor when
you are holding a cup? This is then
followed by additional questions that
elicit information on the following:
& The body regions that are involved
& The limb and body positions or
the specific maneuvers that elicit
or suppress the tremor
& The age and time course of onset
and evolution of symptoms over time
& Whether the patient is aware or
unaware of the tremor
& The presence of any accompanying
pulling sensations or pain
& The presence of associated
movements or additional
neurologic symptoms
& The current use of potential
tremor-inducing medications
& The current use of tremor-
exacerbating substances
(eg, caffeine)
& Experiences of diarrhea, weight
loss, or heat intolerance
& Family history of tremor in first- or
second-degree relatives
Neurologic Examination
After obtaining a patients medical his-
tory, the next step is a detailed and
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focused neurologic examination. First,
the examiner should try to elicit postural
tremor in the arms (ie, tremor observed
during sustained arm extension). The
examiner should assess the following
features about the postural tremor:
& Are the movements regularly
recurrent and oscillatory?
& Across which joints are the
movements occurring and in
what directions?
& Are the tremors in each arm
occurring synchronously (ie,
in phase)?
& Does the postural tremor have a
reemergent quality (ie, is it
initially absent)?
& Is the tremor accompanied by
abnormal postures in the same
limb (eg, flexed posturing or
dystonic postures)?
& Is the tremor characterized by
distractibility (ie, a decrease or
cessation of tremor when
volitionally performing a task [eg,
finger tapping with opposite
hand]), entrainment (ie, the tremor
may be brought into a specific
rhythm), or suggestibility (ie, the
tremor may be induced with
certain stimuli)?
Next, the examiner should try to eli-
cit kinetic tremor (ie, tremor that oc-
curs during movement) by asking the
patient to perform the finger-nose-
finger maneuver, draw spirals or write
a sentence, pour water between cups,
or drink from a cup. The examiner
should assess the following features:
& Does the tremor have an
intentional component (ie, does it
worsen as the limb approaches
a target)?
& Are dystonic postures present (eg,
during the finger-nose-finger
maneuver)?
& What is the relative severity of
kinetic tremor versus postural
August 2016

tremor (or resting tremor if this is
also present)?
This should be followed by an as-
sessment of tremor at rest in any of
the limbs (while the patient is seated,
standing, walking, and lying down) as
well as an assessment of cranial tremors:
head (ie, neck) (while seated and while
lying), jaw (with mouth closed and
then while open), face, chin, tongue, and
voice (during sustained phonation).
CONSTRUCTING A DIFFERENTIAL
DIAGNOSIS
The history and physical examination
are used to establish whether the main
type of tremor is an action tremor (ie,
postural, kinetic, or intention tremor)
or a resting tremor. This point of diver-
gence is useful in order to ascertain two
sets of differential diagnoses: those in
which action tremor is the predom-
inant form of tremor versus those in
which resting tremor is the main tremor.
ACTION TREMOR
The following sections discuss the
more commonly encountered disor-
ders as well as those that, while less
common, have a particularly distinc-
tive set of clinical features.
Essential Tremor
The cardinal feature of essential tremor
is kinetic tremor, which may be ob-
served during a variety of activities on
neurologic examination (eg, spiral
drawing, pouring water between two
cups, finger-nose-finger maneuver)
(Supplemental Digital Content 6-1,
links.lww.com/CONT/A180). In gen-
eral, the tremor is mildly asymmetric,
affecting one arm more than the other,
with an approximate 30% difference
on average between sides. In approx-
imately 5% of patients, the tremor is
markedly asymmetric or unilateral.1 In
approximately 50% of patients, the
Continuum (Minneap Minn) 2016;22(4):11431158
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
tremor has an intentional component, h The cardinal feature of
worsening during the finger-nose-finger essential tremor is
maneuver as the patient approaches kinetic tremor.
the target (ie, the finger or the nose)
h In essential tremor, the
(Supplemental Digital Content 6-1, amplitude of kinetic
links.lww.com/CONT/A180). Inten- tremor is generally
tion tremor is not limited to the arms greater than that of
and is detectable in the neck in 10% postural tremor.
of patients when the patients head h Resting tremor may
approaches a target (eg, as the pa- occur in advanced
tient lowers his or her head to meet a essential tremor but is
cup or a spoon), and it can be restricted to the arms
observed in the legs as well.2 rather than the legs.
Aside from kinetic tremor, postural
tremor often occurs in patients with
essential tremor, although it is not the
predominant tremor. This tremor is
generally worse in the wing-beat posi-
tion (ie, while the arms are extended
and facing one another in the midline)
than when the arms are held straight
in front of the patient. The tremor in
the two arms is generally out of phase,
creating a seesaw effect when the arms
are held in a wing-beat position. This
accounts for the observation that func-
tionality may improve when two hands
are used, rather than one hand (eg,
while holding a cup). The postural
tremor of essential tremor is generally
greatest in amplitude at the wrist joint,
rather than more proximal or distal
joints, and generally involves wrist
flexion-extension rather than rotation-
supination. As a general rule, the am-
plitude of kinetic tremor exceeds that
of postural tremor, and the converse
pattern should raise serious questions
about the essential tremor diagnosis.3
Tremor at rest, without other cardinal
features of parkinsonism such as rigid-
ity or bradykinesia, occurs in approx-
imately 20% of patients with essential
tremor attending a specialty clinic but,
in contrast to that of PD, is a late fea-
ture and has only been observed in the
arm (ie, does not involve the leg).4
Aside from tremor, another motor
feature of essential tremor is gait ataxia,
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 Diagnosing Tremor
KEY POINTS
h Given its progressive which is in excess of that seen in
nature and propensity similarly aged controls. In most pa-
to result in functional tients, this is mild, although in some
disabilities, the term it may be of moderate severity. Some
benign essential tremor evidence indicates that this gait ataxia
is no longer favored. is more pronounced in patients who
h The jaw tremor of have midline cranial tremors (eg, tremors
essential tremor typically of the neck, jaw, and voice).5
occurs when the Initially in essential tremor, the
mouth is open rather tremor may be mild and asymptomatic
than closed. and may not worsen for many years.
However, in most individuals, the
tremor worsens with time. Several pat-
terns of progression have been de-
scribed. The two most common are:
(1) late-life onset (after the age of 60)
with progression and (2) early-life
onset (before the age of 40) with mild,
stable tremor for many years that
then has a late-life progression. The
least common pattern is that of early-
life onset with marked worsening over
the ensuing years to decade.6 Few
prospective, longitudinal natural his-
tory studies exist, but the best esti-
mates of rate of change indicate that
arm tremor worsens by 2% to 5% per
year.7 With the progression of time,
the tremor tends to spread beyond
the hands and arms so that patients
develop cranial tremors (neck, voice,
jaw). These are particularly prevalent
in women with essential tremor,
among whom the risk of neck tremor
is several times higher than that of men
with essential tremor (Supplemental
Digital Content 6-1, links.lww.com/
CONT/A180). The prevalence of neck
tremor is the highest of these cranial
tremors, with voice tremor being less
so, and jaw tremor being even less
common. The jaw tremor is more often
one that is seen when the mouth is
held open or during speech rather
than at rest; the latter is more a feature
of PD-related jaw tremor. Neck tremor
often begins as a unidirectional tremorV
no no (ie, horizontal) or yes yes
(ie, vertical)Vbut with time can evolve
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into a more complex, multidirectional
tremor. Unless it is severe, the neck
tremor, which is a postural tremor,
should subside and then resolve when
the patient is lying on his or her back
with the head fully at rest. Isolated
neck tremor, with minimal or no ac-
companying arm tremor, is extremely
rare and should raise suspicion that
the diagnosis is dystonia rather than
essential tremor. A curious feature of
the neck tremor of essential tremor is
that patients are often unaware of its
presence, particularly when it is mild
(Case 6-1). The presence of dystonic
posturing in essential tremor cases is
controversial, although it is likely that
the presence of a mild dystonic posture
in the tremulous arm in some cases
does not preclude a diagnosis of essen-
tial tremor, especially when the dys-
tonic posture is a late finding in a
case with long-standing and severe
essential tremor.
Thirty percent to 50% of essential
tremor cases are misdiagnosed, with
many of these patients having PD or
dystonia rather than essential tremor.
Differentiation from PD may be made
readily, however, by the absence of ri-
gidity, the absence of other signs of
parkinsonism (eg, hypomimia), the ab-
sence of bradykinesia that is in excess
of age (ie, absence of slowness that is
above and beyond that seen in normal
aging), and the absence of bradykinesia
accompanied by decrement (ie, absence
of a sequential decrement in amplitude
during finger taps).8 The characteristics
of the tremor are also important in dis-
tinguishing a patient with essential
tremor from one with PD. The presence
of isolated postural tremor (ie, postural
tremor with minimal kinetic tremor),
a postural tremor predominantly in-
volving the metacarpophalangeal
joints rather than the wrist, or a postural
tremor characterized by greater wrist ro-
tation than wrist flexion and extension,
August 2016
 KEY POINTS

Case 6-1 h Flexed posturing of the

hand during arm
A 72-year-old woman presented with a tremor that affected her hands
extension is an early sign
when she wrote and when she held eating utensils. The tremor had been
of Parkinson disease.
present for many years and perhaps even as early as her midtwenties, but
she felt it had begun to worsen considerably during the past 4 years. Her h Neck tremor should
mother had had a similar tremor, as did one of her brothers. Although she not occur in patients
did not notice it herself, her husband told her that for the past year, he with enhanced
had sometimes noticed a head tremor when he sat across from her in a physiologic tremor.
restaurant. On examination, the tremor was noticeable when she
performed the finger-nose-finger maneuver and worsened considerably as
she approached her nose. There was some postural tremor as well, but it
was less severe than the kinetic tremor. There was an occasional horizontal
head tremor, which was not present while she lay down. She was treated
with propranolol but could not tolerate more than 80 mg/d without
becoming bradycardic (ie, heart rate of less than 60 beats/min). This dose
resulted in a 20% reduction in her arm tremor.
Comment. This case illustrates the progressive and often familial nature
of essential tremor, highlights the fact that the central defining clinical
feature of essential tremor is kinetic tremor, and exemplifies the presence
of head tremor in some cases, particularly in women.

are all indicators that the likely diagno-
sis is emerging PD rather than essential
tremor. Reemergent tremor is a pos-
tural tremor that commences after a
brief latency of several seconds, rather
than immediately, and is a feature of PD.
Flexed posturing of the hand during
arm extension is an additional marker
of parkinsonism. Dystonia in the arm is
characterized by dystonic posturing
(eg, spooning of the fingers, referring
to the tendency during arm extension
to flex the wrist and hyperextend the
metacarpophalangeal and phalangeal
joints) (Supplemental Digital Content
6-1, links.lww.com/CONT/A180) or the
presence of a tremor that is neither
rhythmic nor oscillatory. The possibility
of neck dystonia should be assessed and
is characterized by head tilt or rotation
with head tremor, hypertrophy of the
sternocleidomastoid muscle, the pres-
ence of a tremor null point, or a sensory
trick by history (ie, a maneuver such as
touching the chin that lessens the
tremor). Absence of cerebellar speech
(ie, either scanning or dysarthric) and
absence of nystagmus distinguishes
Continuum (Minneap Minn) 2016;22(4):11431158
essential tremor from the spinocere-
bellar ataxias. Hyperthyroidism can be
assessed by clinical history (eg, diar-
rhea, weight loss, or heat intoler-
ance) as can the use of medications
(eg, lithium, valproate) or other sub-
stances (eg, caffeine, tobacco) that
produce or exacerbate tremor. A dif-
ficult differential is between a mild
case of essential tremor and an indi-
vidual with enhanced physiologic
tremor, although the presence of neck
tremor should exclude the latter.
Computerized tremor analysis, with
inertial loading (ie, placing a weight
on the hand), can assist with this
differential. In patients with a tremor
of central origin (eg, essential tremor),
the primary tremor frequency should
not change with inertial loading. Other
features that support the essential
tremor diagnosis are the presence of
essential tremor in one or more first-
degree relatives. Reduction in tremor
with ethanol use is often used as a
diagnostic marker; however, this is not
very specific and of limited utility.
Patients with most tremor disorders
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 Diagnosing Tremor
KEY POINT
h With enhanced often experience a reduction in tremor
physiologic tremor, no following ethanol consumption.
intentional component The tremor of essential tremor may
occurs on the be severe enough to result in embar-
finger-nose- rassment and functional disability, and
finger maneuver. these are the main motivations for
treatment.9 Beta-blockers (especially
propranolol) and primidone, alone or
in combination, are the most effective
pharmacologic therapies, although many
patients choose to discontinue these
medications due to their limited effi-
cacy (Table 6-1). Propranolol has been
used in doses up to 320 mg/d, although
doses in excess of 100 mg/d are rarely
tolerated in the elderly, with the main
issue being slowed heart rate. Asthma
is a relative contraindication to the use
of propranolol but is not an absolute
contraindication and must be assessed
on a case-by-case basis. Primidone is
given in doses up to 750 mg/d, although
lower doses are often effective. An
acute nausea and ataxia is observed in
approximately 25% of patients who are
prescribed this medication, and pre-
loading the patient with phenobarbital
(eg, 30 mg 2 times a day for 3 days) is
one method that is used to avoid this
unwanted side effect. These drugs re-
sult in a mild to moderate reduction in
the amplitude of tremor in 30% to 70%
of patients, but they do not abolish
it unless the tremor is mild. Other
Medications and
TABLE 6-1
Dosage Ranges for
Essential Tremor
Medication Dosage Range
Propranolol 10Y320 mg/d
Primidone 25Y750 mg/d
Topiramate 25Y300 mg/d
Gabapentin 100Y1800 mg/d
Alprazolam 0.125Y3 mg/d
Clonazepam 0.5Y4 mg/d
1148 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
agents that have been used include
topiramate, gabapentin, and benzodi-
azepines (alprazolam or clonazepam)
(Table 6-1). High-frequency thalamic
stimulation (ie, deep brain stimulation
[DBS]) markedly reduces the severity
of the tremor, as does thalamotomy, in
patients with severe pharmacologically
refractory tremor.
Enhanced Physiologic Tremor
Enhanced physiologic tremor is an ac-
tion tremor of the hands that occurs
to some extent in all people.10 The pos-
tural and kinetic components are gen-
erally several Hz faster and generally
have a lower amplitude than those seen
in essential tremor,10 with the caveat
that at disease onset, patients with es-
sential tremor have a low-amplitude
tremor that may be difficult to dis-
tinguish from enhanced physiologic
tremor.11 Unlike essential tremor, no
intentional component occurs on the
finger-nose-finger maneuver. Voice and
limb tremor may be present but not
head (ie, neck) tremor. Cogwheeling
may be present, but it is not accom-
panied by rigidity. On quantitative
computerized tremor analysis, inertial
loading reveals a pattern that is con-
sistent with a peripherally generated
rather than a centrally generated tremor
(ie, a reduction in the primary tremor
frequency occurs with inertial loading).
Treatment should begin with reas-
surance that the patient does not have
essential tremor or PD. Many of the
individuals who present to a clinician
do so because they are also anxious.
Beta-blockers, at low dose (eg, pro-
pranolol up to 60 mg/d or used in
a 10 mg to 60 mg dose on an as-
needed basis), and benzodiazepines
may be effective.
Drug-Induced Action Tremor
A variety of medications may produce
or exacerbate action tremor, and the
August 2016

severity of this tremor can range from
mild to severe.10,12 These medica-
tions are inclusive of but not limited
to bronchodilators, lithium, valproic
acid, methylphenidate, prednisone,
and pseudoephedrine. A number of
features help to differentiate drug-
induced action tremor from other
forms of action tremor. First, by history,
the onset of tremor follows the use
of the putatively causative medication.
One caveat is that the onset may not
be immediate; it may occur gradually
over several months. Second, there may
be a dose-response relationship such
that higher doses of medications are
associated with greater tremor ampli-
tude. Third, discontinuing the medi-
cation should result in the complete
resolution of tremor.12 Furthermore,
while limb tremor may be present, head
tremor should not be a feature of
drug-induced action tremor. Finally,
with a stable medication dose, the
tremor should not worsen progres-
sively, in contrast to the tremor of es-
sential tremor or PD.
The mechanism that underlies these
drug-induced action tremors is not
fully known, although such tremors are
thought to represent a form of enhanced
physiologic tremor.10 In addition, some
evidence suggests that drug-induced
action tremor may also be mediated
through central mechanisms.13
The treatment of these tremors is
to remove or lower the dose of the
causative medication. When this is
not possible, beta-blockers (eg, pro-
pranolol, 10mg/d to 320 mg/d) may
be beneficial.
Dystonic Tremor
A variety of tremors may occur in pa-
tients who have been diagnosed with
dystonia, and a particularly challeng-
ing differential is that of essential
tremor versus dystonia with dystonic
tremor.14Y16 The tremors in patients
Continuum (Minneap Minn) 2016;22(4):11431158
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
who have been diagnosed with dystonia h While limb tremor may
may occur both in limbs that exhibit be present, head tremor
dystonic postures or movements as should not be a feature
well as limbs that do not exhibit these. of drug-induced
Furthermore, the tremor may occur in action tremor.
limbs that appear to be at rest as well h The tremor in dystonia is
as those that are active (ie, during sus- often neither rhythmic
tained posture or during movement). nor oscillatory.
What complicates matters is that, as
noted previously, patients with long-
standing and clinically advanced essen-
tial tremor may develop mild dystonic
posturing of the hand during arm ex-
tension. Hence, considerable debate
exists as to where dystonia as a disease
ends and where essential tremor as a
disease begins and vice versa. With all
this in mind, when considering a par-
ticular patient, several issues should be
taken into consideration. First, what are
the features of the tremor itself? Sec-
ond, does the patient exhibit dystonic
postures or movements? On closer in-
spection, the tremor itself in patients
with dystonia may be neither rhythmic
(ie, it is not regularly recurrent) nor
oscillatory (ie, it does not rotate around
a central plane); these features distin-
guish the tremor from that of essential
tremor. In terms of the second ques-
tion, patients with dystonia may have
a variety of sustained postures or twist-
ing movements involving the orbicu-
laris muscles, neck, and other muscles,
which do not occur in essential tremor.
Some patients with dystonia only have
these postures and movements in their
hands. These patients exhibit one or
more of a variety of dystonic postures
during arm extension (eg, spooning of
the hands as defined previously [Sup-
plemental Digital Content 6-2, links.
lww.com/CONT/A181], difficulty
maintaining both hands strictly parallel
while outstretched in a karate-chop posi-
tion, thumb flexion during arm ex-
tension, or other dystonic postures).
These should not occur in essential
tremor unless the disease is advanced;
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 Diagnosing Tremor

KEY POINT
h Voice tremor in patients furthermore, they should be of mild
with dystonia is often severity relative to the tremor itself.
associated with Tremor in the neck or voice is
voice breaks. another issue worth discussing. Patients
with neck dystonia (ie, torticollis) may
also have neck tremor (Case 6-2).17
This tremor is generally neither strictly
rhythmic nor oscillatory and may be
accompanied by twisting or tilting of
the neck, jerklike or sustained neck
deviation, hypertrophy of neck mus-
cles, or a symptom of pulling sensations
or pain in the neck. These features do
not occur in essential tremor. Also, in
contrast to the head tremor of essential
tremor, which generally resolves when
the patient lies down, dystonic head
tremor often persists while the patient
is recumbent.18 Voice tremor may also
be present in patients with vocal cord
dystonia (ie, spasmodic dysphonia), but
in contrast to the voice tremor of es-
sential tremor, is often associated with
voice breaks or strangulated speech.
The treatment of dystonic tremor
includes the use of medications used
to treat dystonia (ie, trihexyphenidyl
up to 10 mg/d in adults, baclofen up
to 60 mg/d), benzodiazepines, or
beta-blockers. For dystonic neck
tremor, other options include IM botu-
linum toxin injections, selective dener-
vation, or DBS.
Primary Writing Tremor
Primary writing tremor is a task-specific,
kinetic hand tremor that occurs pri-
marily or only during writing and does
not occur or is milder during other
tasks that involve the use of the
hands.10,19 The current definition of
primary writing tremor excludes pa-
tients who have dystonic postures with
hand tremor while writing (ie, dystonic
writing tremor).10 Primary writing tremor
has a similar frequency to that seen in
patients with essential tremor (ie, 4 Hz
to 8 Hz) and is relieved by ethanol con-
sumption in 30% to 50% of cases.19 The
mechanisms that underlie primary writ-
ing tremor are unclear, and it is debated
whether the condition represents a
variant of essential tremor or a variant
of dystonia, and in some families all
three conditions may be present.20
Tremor in patients with essential tremor

Case 6-2
A 43-year-old woman presented for a neurologic consultation because of
neck pain with tremor. She stated that her neck pain had begun about
5 years previously, mainly on the left side. For the past 3 years, she had felt
a pulling sensation and increased pain in the neck region. She also
described that her head had been turning to one side and sometimes it
even felt shaky. She had not noticed any hand tremor. On examination,
there was a mild postural tremor of the left arm with a little bit of spooning
of the hand on that side. No tremor occured during the finger-nose-finger
maneuver. Her left sternocleidomastoid muscle was slightly hypertrophic,
and her head tended to preferentially turn to the right and shake
intermittently. The shakiness was irregular. This head tremor persisted even
when she lay down on the examining table. She was treated with IM
botulinum toxin injections to several neck muscles, which helped diminish all
of her symptoms, although they did not resolve completely.
Comment. This case illustrates a number of key features of dystonic
head (neck) tremor, including the fact that the tremor is often irregular
and that it often persists in the recumbent position. Furthermore, it may
be accompanied by pain or pulling sensations.

1150 www.ContinuumJournal.com August 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


may be present to a differing degree
during various activities; sometimes
tremor may be most prominent during
writing, which is a further challenge
when attempting to arrive at the correct
diagnosis (ie, essential tremor versus
primary writing tremor).21 This obser-
vation about essential tremor also raises
the question as to whether primary writ-
ing tremor is an overdiagnosed entity.
Treatment of primary writing tremor
includes the use of propranolol, pri-
midone, or anticholinergic medications
(see the previous sections on essential
tremor and dystonic tremor) as well as
the use of writing and hand orthotic
devices. Local IM injections of botuli-
num toxin have exhibited some benefit
as well.22
Orthostatic Tremor
Patients with this rare, although debil-
itating, entity often report feelings of
unsteadiness while standing.23 In addi-
tion, there is a clear complaint of
tremor while standing (ie, orthostatic
tremor) rather than while walking,
sitting, or lying down. Because of
these symptoms, patients with ortho-
static tremor typically avoid situations
that require standing still (eg, standing
in lines).24 On examination, physi-
cians may see, feel, or be able to
auscultate a rapid (14 Hz to 16 Hz)
fine tremor in the calves. The EMG
indicates the presence of a 14 Hz to
16 Hz tremor in leg (especially calf)
muscles. A slower, larger-amplitude
tremor may also be superimposed on
top of this tremor and can be more
disabling for the patients than the
faster tremor.
The treatment for orthostatic tremor
is challenging and rarely effective.23
Numerous agents have been used,
often to little avail. The most com-
monly used agents have been clonaz-
epam (0.5 mg/d to 4 mg/d), gabapentin
(300 mg/d to 1800 mg/d), and carbidopa/
Continuum (Minneap Minn) 2016;22(4):11431158
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
levodopa (levodopa doses of 100 mg/d h Orthostatic tremor may
to 1000 mg/d). A large number of be more easily felt or
other agents have also been tried, in- auscultated than seen.
cluding propranolol, primidone, phe-
h In patients with diseases
nytoin, carbamazepine, ethosuximide, of the cerebellum, it is
baclofen, and acetazolamide. DBS can important to distinguish
provide benefit.25 tremor from dysmetria.
Cerebellar Tremor
The term cerebellar tremor has clas-
sically been used to describe a tremor
that can occur in patients with spin-
ocerebellar ataxia as well as other clas-
sic disorders of the cerebellum.10 There
is some overlap in clinical phenome-
nology with that which is seen in
patients with essential tremor (ie, a
kinetic tremor with intentional com-
ponent), as the latter is increasingly
being viewed as a disorder that in-
volves cerebellar system dysfunc-
tion.6 The classic cerebellar tremor
is an action tremor and has both ki-
netic components as well as a terminal
worsening (ie, an intentional compo-
nent).26 The tremor is quite slow (3 Hz
to 4 Hz), and other cerebellar signs,
such as overshoot, may also be present
on the finger-nose-finger maneuver.
Moreover, the tremor may occur in
several planes (ie, X, Y, and Z axes)
during this and other maneuvers. Pa-
tients with classically defined cerebel-
lar tremor often have other cerebellar
signs, including saccadic eye movement
abnormalities, dysarthric or scanning
speech, gait ataxia, and hypotonia.10 It
is important, although often difficult,
to try to separate the tremor (ie, rhyth-
mic oscillatory movements) from prob-
lems with force and timing of motion
(ie, dysmetria), as only the former gen-
erally improves with DBS, whereas the
latter might worsen. A number of med-
ications have been used to treat cere-
bellar tremor, although efficacy is
extremely limited.27 The most effec-
tive treatment for cerebellar tremor
is thalamic DBS.27
www.ContinuumJournal.com 1151
 Diagnosing Tremor

KEY POINTS
h The presence of
entrainment, distractibility,
and suggestibility all
point to a diagnosis of
psychogenic tremor.
h Wing-beat tremor is
considered a classic
tremor in Wilson
disease, but it is not the
most common type of
tremor in that disease.
Psychogenic Tremor
This type of tremor occurs in patients
with specific psychiatric conditions,
especially conversion disorder, and
malingering.28 By history, the tremor
often has a sudden (ie, abrupt) start
with maximal tremor at onset rather
than an insidious onset followed by a
slowly progressive course. On examina-
tion, the tremor often has nonphysiologic
or unusual features (eg, may exhibit
variable frequency or change direction,
and an unusual combination of rest,
postural, and kinetic tremors may
be seen) (Case 6-3). On examination,
the clinician may see signs that are
suggestive of psychogenic tremor,
including entrainment (ability of the
examiner to alter the rhythm of the
patients tremor by having it match
the rhythm of a tremor the examiner
produces), distractibility (ability of
the examiner to stop the tremor by
asking the patient to perform certain
mental or physical tasks), and sug-
gestibility (ability of the examiner to
bring on the tremor with the power of
suggestion).29 Interestingly, on quan-
titative computerized tremor analysis,
inertial loading can result in a para-
doxical increase in tremor amplitude
rather than the expected decrease in
amplitude that should be seen with
organic tremors.30
The treatment of psychogenic trem-
or usually begins with a discussion of
the diagnosis, recognition of the pa-
tients suffering, and a referral to a
psychiatrist in order to explore the
underlying psychiatric issues.
Wilson Disease With
Associated Tremor
Patients with Wilson disease may pres-
ent with a wide range of involuntary
movements, including tremor.31,32 In-
deed, tremor ranks among the eight
major symptoms reported by patients
with Wilson disease who have neuro-
logic features.33 Tremor is usually ac-
companied by other neurologic signs,
although there are rare reports of iso-
lated tremor and even rarer reports of
isolated action tremor.34 Although the
classic tremor associated with Wilson
disease is the wing-beat tremor (pres-
ent on abduction of the shoulder and
flexion of the elbow), it is not the most
commonly observed type of tremor.32,35
Overall, the tremor phenomenology
is quite varied. Indeed, across patients,
a wide range of tremors may occur, in-
cluding kinetic tremor as well as resting
tremor, postural and intention tremors,
tremors that can be symmetric or
asymmetric, those that are low ampli-
tude and others that are high ampli-
tude, and those that are intermittent,

Case 6-3
A 27-year-old woman presented for a neurologic evaluation with a reported
tremor that had begun suddenly 2 years previously after she had fallen down
the stairs. The tremor affected her entire body and was not relieved by
anything. She had been unable to work as a waitress since the onset of the
tremor and stated that her life was falling apart. On examination, she had
a head tremor, which sometimes involved a horizontal movement and, at
other times, involved a vertical movement. At other times it was complex
and rotatory. The tremor was virtually continuous. The examination was
otherwise normal. The examiner was able to stop the tremor for a few
seconds while distracting the patient.
Comment. A number of important features of psychogenic tremor are
illustrated in this case, including its sudden onset, its often variable quality,
and the fact that it may cease when the patient is distracted.

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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


while others are constant and progres-
sive.32,35 Most of the large published
case series describe the broad pano-
ply of neurologic signs, and a detailed
modern characterization of the tremor
phenomenology is lacking. According
to one series, 32% of patients exhibited
tremor at the time of their first neuro-
logic evaluation at a tertiary care cen-
ter35; in another retrospective review
of patients seen in a tertiary referral
center, 60% of patients exhibited tremor
at some point.36 Tremor most com-
monly occurs in the hands, with 82% of
patients having hand tremor, accord-
ing to one report.37 Most patients pres-
ent well before the age of 40 years, and
the laboratory workup may reveal a
low serum ceruloplasmin, an abnor-
mal brain MRI (ie, lesions in the basal
ganglia), a high 24-hour urine copper
concentration, an abnormal slit-lamp
examination (ie, presence of Kayser-
Fleischer rings), elevated liver function
tests, or abnormal liver biopsy results.33
Treatment of the underlying disease
with tetrathiomolybdate, zinc, or trien-
tine has been recommended38; little
has been written about the specific
treatment of the tremor as a neuro-
logic sign. For more information, refer
to the article Wilson Disease by
Ronald F. Pfeiffer, MD, FAAN,39 in this
issue of Continuum.
Fragile X Tremor-Ataxia
Syndrome
Fragile X tremor-ataxia syndrome
(FXTAS) is an inherited degenerative
disorder that primarily affects older men
and is associated with a wide range of
neurologic symptoms and signs.40 The
syndrome is caused by a CGG repeat
expansion in the premutation range in
the 5 noncoding region of the fragile
X mental retardation 1 (FMR1) gene.
Classically, these patients are men in
their sixties who develop some com-
bination of action tremor, cerebellar
Continuum (Minneap Minn) 2016;22(4):11431158
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
ataxia, parkinsonism, or cognitive de- h Patients with fragile X
cline.40 Tremor can be one of the ear- tremor-ataxia syndrome
liest signs,41 and it may occur in a may have a mixture
variety of activation conditions, includ- of different tremor
ing with action (ie, postural, kinetic, or phenomenologies.
intentional) or with rest. Action tremor
predominates, although the tremor has
not been described in a nuanced and
systematic manner in the published lit-
erature. While an occasional patient will
have isolated action tremor, which re-
sembles that seen in patients with essen-
tial tremor,40 many patients have mixed
tremor phenomenology and a constel-
lation of neurologic signs in addition
to tremor.42 When present, the tremor
may vary in severity from mild and
asymptomatic to severe and disabling,40
although one retrospective cohort study
reported that tremor becomes consid-
erably disabling within 13 years of on-
set of motor symptoms.41 Controlled
trials evaluating symptomatic therapies
have not been reported in FXTAS.43
However, therapies used for tremor in
essential tremor and PD have been
tried with variable success; surgical ther-
apy is very effective for essential tremor
and PD tremor and is an option for pa-
tients with FXTAS who have medication-
resistant and disabling tremor.43
Peripheral NeuropathyYRelated
Tremor
Several of the acquired and familial
neuropathies are associated with pos-
tural and kinetic tremors of the arms
of mild to moderate severity.44Y46 For
some neuropathies (eg, IgM demyelin-
ating paraproteinemic neuropathy), up
to 90% of patients are reported to have
such tremor.47 By history, patients with
this type of tremor have a coexist-
ing peripheral neuropathy in the same
limbs that are tremulous. The neurop-
athy and the tremor should be tempo-
rally linked, with tremor accompanying
or following the neuropathy. On ex-
amination, a peripheral neuropathy
www.ContinuumJournal.com 1153
 Diagnosing Tremor
KEY POINT
h Midbrain (rubral) tremor
is generally a unilateral
tremor accompanied
by rest, postural,
and kinetic/intentional
components.
1154 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
characterized by sensory deficits, weak-
ness, wasting (Supplemental Digital Con-
tent 6-3, links.lww.com/CONT/A182),
and diminished/absent deep tendon re-
flexes is readily apparent in the tremu-
lous limb or limbs,48,49 although the
severity of the weakness does not ne-
cessarily correlate with the severity of
the tremor.50 The tremor disappears if
neuropathic weakness progresses to
the point of paralysis. The underlying
mechanisms are likely to be diverse and
may involve central as well as peripheral
components.44 If the tremor occurs
in the setting of an immunoglobulin-
mediated disease, then immunosuppres-
sive therapies, such as corticosteroids,
IV immunoglobulin, cyclophosphamide,
or plasma exchange may be used. There
are several reports of the use of pre-
gabalin (up to 450 mg/d) for the treat-
ment of neuropathic tremor.46 The
tremor may respond to DBS.51
Midbrain (Rubral) Tremor
Midbrain tremor has also been re-
ferred to as Holmes tremor or rubral
tremor.10,52 The tremor is generally
unilateral and has three components:
tremor at rest, postural tremor, and
kinetic/intentional tremor, with the rel-
ative severity generally being such that
kinetic tremor is greater than postural
tremor, which is greater than resting
tremor (Supplemental Digital Con-
tent 6-4, links.lww.com/CONT/A183).
The tremor is often severe and dis-
abling and can render the affected
limb functionally useless. Patients may
have other neurologic signs as well,
including mild dystonia or ataxia. The
tremor may occur in a variety of clinical
settings (eg, in the setting of a brain
tumor, multiple sclerosis, or slowly
expanding vascular lesion) and, when
occurring in the setting of a stroke, the
tremor may arise after a latency of
months to years. On brain imaging, a
lesion is often but not always present in
the pontine-midbrain region, affecting
cerebellar outflow tracts and dopaminer-
gic nigrostriatal fibers.53 There are also
reports of lesions occurring elsewhere
(eg, the thalamus),54 which is one of
the motivations for referring to the
tremor as Holmes tremor rather than
rubral tremor. As the dopaminergic
system is involved in most cases,
treatment with levodopa (100 mg/d to
1000 mg/d) may be beneficial.55 In
addition, medications that are used
for the treatment of essential tremor
may be effective. DBS has proven
beneficial in some cases as well.55
RESTING TREMOR
The differential for resting tremor is
less extensive than that of kinetic
tremor. The main items are PD and
drug-induced tremor.
Parkinson Disease
The tremor in patients with PD is clas-
sically a tremor at rest. The tremor may
affect any limb but is generally asym-
metric, affecting one limb or one side
of the body (ie, arm and leg) preferen-
tially. In patients with arm tremor, the
tremor often involves distal joints
(eg, fingers and wrist) rather than the
elbow or shoulder. In addition, wrist
pronation-supination rather than
flexion-extension is more common
(Supplemental Digital Content 6-5,
links.lww.com/CONT/A184). In addi-
tion, limb postures (flexed posture of
the hand while walking or during arm
extension) is quite common, as are other
cardinal signs of parkinsonism. A con-
fusing feature of the examination can
be the presence of reemergent tremor
during arm extension or during activi-
ties (eg, pouring water). Tremor may
affect the jaw, although in contrast to
essential tremor, is more often there
when the mouth is closed and relaxed
rather than while speaking or holding
the mouth open.
August 2016

The treatment of parkinsonian
resting tremor includes the use of anti-
cholinergic agents (including aman-
tadine up to 300 mg/d), as well as
carbidopa/levodopa (levodopa dose
up to 2000 mg/d) and dopamine
agonists. Benzodiazepines play a role
as well. DBS is reserved for severe
cases in which patients are refractory
to medications.
It is important to note that although
resting tremor is one of the hallmark
features of PD, a large proportion of
patients also have postural or kinetic
tremors of the arms.56 Sometimes the
postural and kinetic tremor have a re-
emergent quality; this so-called reemer-
gent tremor surfaces after a latency of
one or several seconds, has a frequency
that is similar to that of the resting
tremor in PD, and often attains ampli-
tudes greater than that seen in patients
with essential tremor.57 This tremor is
often asymmetric and tends to increase
in severity (ie, crescendo) with sus-
tained posture or during the course of
repetitive movements during which
much of the limb is immobile (eg, while
pouring water between two cups, dur-
ing which much of the movement is
proximal rather than distal). Reemergent
tremor may at times occur in patients
who do not have resting tremor.58 The
treatment of this tremor is similar to the
treatment of the resting tremor of PD,
although it is less responsive to medi-
cations than the latter.
Drug-Induced Resting Tremor
Several medications (eg, neuroleptic
agents) may cause resting tremor,
which is generally accompanied by
other features of parkinsonism (eg,
bradykinesia or rigidity).12 The tremor
generally resembles a typical parkinso-
nian resting tremor and may even be
asymmetric. As with other parkinso-
nian tremors, the tremor may have a
reemergent component as well. By
Continuum (Minneap Minn) 2016;22(4):11431158
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
history, there is a link between the use h In addition to the classic
of a medication and the onset of the resting tremor, a large
tremor. Unless the patient has an proportion of patients
underlying disease of the basal ganglia, with Parkinson disease
removal of the medication should re- also have postural or
sult in complete resolution of tremor, kinetic tremors of
although this may take weeks to the arms.
months. The treatment of such tremor h Drug-induced resting
first involves the removal of the causa- tremor may be either
tive drug or a reduction in dosage if unilateral or bilateral.
this is possible, although this is often
not possible in the setting of psycho-
sis. Carbidopa/levodopa, amantadine,
and anticholinergic agents may lessen
the severity of the tremor and may even
be used in combination with the tremor-
producing medication, if the latter
cannot be discontinued.
CONCLUSION
The diagnosis of tremor disorders is
challenging. The approach to tremor
involves a history and careful neuro-
logic examination, focused on the nu-
ances of clinical phenomenology. It
is important, when generating the
differential diagnosis, to first consider
whether the primary type of tremor
is an action tremor or one at rest. As is
the case with the diagnosis of many
movement disorders, arriving at the
correct diagnosis is often based on
pattern recognition.
VIDEO LEGENDS
Supplemental Digital
Content 6-1
Essential tremor. Video shows a
woman who exhibits a kinetic tremor
with an intentional component on
the finger-nose-finger maneuver. The
tremor is slightly asymmetric and is
worse on the left. A mild head tremor
as also present. When she attempts
to pour water between two cups, the
kinetic tremor results in spillage.
links.lww.com/CONT/A180
B 2016 American Academy of Neurology.
www.ContinuumJournal.com 1155
 Diagnosing Tremor
Supplemental Digital
Content 6-2
Dystonic postures with dystonic
tremor. Video shows a man who ex-
hibits mild kinetic tremor on the
finger-nose-finger maneuver. On arm
extension, the man exhibits a mild
postural tremor with dystonic postur-
ing of the hands, more so on the
left that on the right, where there is
obvious spooning.
links.lww.com/CONT/A181
B 2016 American Academy of Neurology.
Supplemental Digital
Content 6-3
Peripheral neuropathy with tremor.
Video shows a man with peripheral
neuropathy with wasting of the intrin-
sic hand muscles and some weakness
of finger extensors on arm extension.
When the man follows the examiners
finger with his finger, a mild kinetic
tremor is evident.
links.lww.com/CONT/A182
B 2016 American Academy of Neurology.
Supplemental Digital
Content 6-4
Midbrain tremor. Video shows a
woman with midbrain tremor who
exhibits some posturing of the right
arm as well as reduced right arm swing
while walking. Mild tremor is also
present while walking, although it is
not clear whether the hand is fully
at rest. While her right hand rests in
her lap, a mild tremor appears, which
has a pill-rolling quality. The patient
exhibits a flapping postural tremor
on the right, with some posturing of
that hand. On finger-nose-finger ma-
neuver (right), there is tremor with
terminal worsening. There is no tremor
on the left.
links.lww.com/CONT/A183
B 2016 American Academy of Neurology.
1156 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Supplemental Digital
Content 6-5
Parkinson disease. Video shows a
woman with Parkinson disease who
exhibits a resting tremor while stand-
ing with her hand at her side. The
tremor involves the distal joints (fin-
gers and wrist) and is characterized by
wrist pronation-supination and has a
slight pill-rolling quality at times.
links.lww.com/CONT/A184
B 2016 American Academy of Neurology.
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