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Tremor in Childhood
Stephanie Keller, MD,* and Leon S. Dure, MD†
Tremor in childhood is not commonly described in the literature; but it is also likely
underappreciated. The etiology of childhood tremor encompasses a wide variety of pathologic processes. Tremor may occur in isolation, or in association with other neurologic
findings or systemic disorders. This article aims to provide an overview of tremorogenic
mechanisms with respect to neuroanatomy and neurophysiology, particularly as they relate
to children. Classification of tremors, diagnostic entities in childhood, and treatment will
also be discussed. With improved recognition and characterization of childhood tremors,
we may gain a better understanding of the pathophysiology of the disease and determine
more age-appropriate treatment strategies.
Semin Pediatr Neurol 16:60 –70 © 2009 Published by Elsevier Inc.
Tremor
T
remor is a rhythmic oscillatory movement resulting from
the action of antagonist muscles, affecting one or more
limbs. Such oscillations may be the result of normal or accentuated muscular and postural processes; but more often, visible tremor is a sign of a pathologic process. Although not
commonly described in childhood,1,2 tremor is likely underappreciated, especially in the context of childhood neurologic
diseases. Children with tremor comprise 10%-20% of those
with pediatric movement disorders.3 The etiology of tremor
in childhood encompasses a wide variety of pathologic processes. Tremor may occur in isolation or in association with
other neurologic findings or systemic disorders. The goal of
this article is to provide an overview of tremorogenic mechanisms with respect to neuroanatomy and neurophysiology,
particularly as they relate to children. Classification of tremors, diagnostic entities in childhood, and treatment will also
be discussed.
Neurophysiology of Tremor
Maintenance of body position or of a limb in space requires a
balance between agonist and antagonist muscles, with a
*Department of Pediatrics, Division of Child Neurology, University of
Alabama at Birmingham, The Children’s Hospital of Alabama, Birmingham, AL.
†Department of Pediatrics, Division of Child Neurology, University of
Alabama at Birmingham, The Children’s Hospital of Alabama, Birmingham, AL.
Address reprint requests to: Stephanie Keller, MD, Department of Pediatrics,
Division of Child Neurology, University of Alabama at Birmingham, The
Children’s Hospital of Alabama, 1600 7th Ave. South, CHB 314, Birmingham, AL 35233. E-mail: [email protected]
60
1071-9091/09/$-see front matter © 2009 Published by Elsevier Inc.
doi:10.1016/j.spen.2009.03.007
steady flow of information both to and from the particular
muscle groups of interest. Similar processes occur during the
execution of both skilled and reflexive movements. Sensory
afferents provide proprioceptive input, as well as ongoing
information relating to muscle stretch. These sensory pathways are integrated with higher levels of the motor system to
allow for accurate and precise execution of motor activities.
Disruption or disturbance of movement can be the result of
abnormalities affecting hind-brain, midbrain, and forebrain
structures. Therefore, it is important to examine all levels of
the neuraxis to obtain a complete understanding of the anatomic and physiological origins of tremor.
Oscillatory activities of antagonistic muscles may be produced by peripheral and/or centrally mediated processes.4-6
There is an inherent instability when a limb is maintained
against gravity. This instability may be exaggerated by cardiac
activity and is exquisitely sensitive to the weight of the limb.7
Using sensitive methods of detection, oscillatory behavior
with a frequency of 20 Hz can be detected in the finger, with
correspondingly lower frequencies in the hand, forearm, and
shoulder.8 To underscore the peripheral origin of this activity, it has been shown that the tremor frequency will decrease
with loading of the limb. Such a phenomenon is the chief
characteristic of physiological tremor.
Reflex activity involved in maintenance of posture may also
give rise to tremor.9 Muscle stretch receptors provide information regarding muscle length and tension, allowing for fine adjustments of posture or limb position. Under certain conditions,
an increase in reflex gain may result in a perturbation manifesting as tremor. Such augmentation appears under the influence
of epinephrine and excess thyroid hormone.
Tremor can also result from the action of groups of neurons that manifest rhythmic discharges. The thalamus, infe-
Tremor in childhood
rior olive, and parts of the basal ganglia may each produce
rhythmic activity.10,11 There is also a central oscillator causing orthostatic tremor, but the location of this region is currently unknown. Rhythmic generators in the central nervous
system that produce tremor typically are unaffected by loading of the affected limb.
Finally, the coordination of goal-directed behavior is modulated by feed forward and feedback loops involving the
cerebellum.12,13 Numerous investigations have demonstrated
the disintegration of smooth purposive movements because
of either temporary or permanent lesions of cerebellar nuclei.
This type of condition would be similar to that seen in primary or secondary cerebellar disease, notably, the presence
of intention tremor.
Although it is clear that oscillatory behavior of the limbs,
head, or trunk could originate by any of these proposed
mechanisms, it is unclear whether any particular tremor is
dependent on one or a combination of causes. Although conceptualization of the neurophysiologic underpinnings is
helpful, the application of these hypotheses to childhood
tremors requires further study.
Clinical
Phenomenology of Tremor
Classification of tremor proceeds primarily from clinical features.14 Tremor may occur at rest with a limb relaxed and
supported. Rest tremor, by definition, attenuates or disappears with action. On the other hand, tremor at rest may
become more pronounced with agitation or distraction. The
paradigm of rest tremor is that observed in Parkinson disease
or Parkinsonism. Action tremor is that which occurs with
performance of a voluntary activity. Within the spectrum of
action tremor is postural tremor, in which the limb may be
stationary but held against gravity. Similarly, isometric tremor
is also seen with a stationary limb but in the context of an
exertion of force against a stationary object. Finally, kinetic
tremor is typically perceived while a limb is actually moving.
If the movement is part of a goal-directed behavior, the
tremor is termed an intention tremor; otherwise it is called a
simple kinetic tremor. There are other tremors that have been
defined, including position-specific or task-specific tremors. An
example of task-specific tremor would be primary writing
tremor, although this may also be considered part of the
spectrum of dystonia. Similarly, tremor that occurs in the
context of generalized or focal dystonia, called dystonic
tremor, represents a gray area in the interpretation of this
movement, as it could be considered a manifestation of dystonia rather than as the presence of a concomitant movement
disorder. Another discrete type of tremor is that of the
Holmes’ tremor, previously called a midbrain or rubral
tremor. This is a secondary or symptomatic tremor characterized by the combination of rest and intention tremors,
typically of a slow frequency (⬍ 4.5 Hz). It is commonly the
result of lesions affecting the brainstem, cerebellum, or thalamus. Myoclonic tremor is used to describe rhythmic or semirhythmic myoclonias that clinically appear oscillatory. An
61
example of this would be the motor disturbance seen in opsoclonus-myoclonus.15 Finally, psychogenic tremor, although
often a diagnosis of exclusion, manifests with a particular set
of features, including the following: sudden onsets and remissions; unusual combinations of rest and intention tremors
that vary in amplitude, frequency, and distribution; and historical or neurologic examination findings that suggest a
functional origin. Examples of each of these tremor types will
be discussed later in the text.
Evaluation of the
Child with Tremor
When assessing a tremor, older children and adolescents are
usually able to cooperate with a neurologic examination similar to that of adults. It is important to determine the distribution of tremor with respect to which body parts are involved, and to characterize stimuli or situations, which either
amplify or ameliorate the tremor. Finally, ascertainment of
the presence of other neurologic signs and symptoms, particularly other movement disorders, is of major importance,
as this may help identify specific disorders of which tremor is
only one component.
During clinical examination, maneuvers may be used to
elicit tremor and to illustrate any impairments of function.
Maintenance of the affected limb(s) in a particular position
will help to identify postural tremor. For example, an effective maneuver for the examination of the hands is to have the
child flex the elbows while abducting the arms, simultaneously holding the fingertips in near apposition. Asking the
child to bring the fingertips as close together as possible,
without touching, will often elicit wrist and finger tremor that
is easily observable. Simple finger-to-nose testing can elicit
action tremor in the arms and hands, as can toe-to-finger
pointing in the legs and feet. Such activities as drinking from
a full cup, eating cereal with a spoon, or threading beads on a
string are easily accomplished during the examination with a
willing child. Additionally, handwriting and drawing an
Archimedes spiral are often illustrative.
For younger children and those with cognitive impairments, some of these procedures may not be appropriate
because of lack of cooperation or failure to have achieved the
necessary motor skills. In these instances, the examiner must
endeavor to observe the child performing activities that have
been observed by the family or caregivers, as these same
behaviors are, in all likelihood, the reason for neurologic
consultation. Building towers with cubes, tracing a simple
figure with a crayon or pencil, or even drawing a path
through a maze will provide clear evidence of the presence of
a tremor, depending on the developmental level of the child.
If, for some reason, a child’s tremor is not adequately observed, the clinician can have the family record a video of the
child at home or play setting, performing the activities in
which the tremor is most obvious.
As part of the formal characterization of childhood tremor,
the examiner must assess the presence or absence of rest,
postural, and kinetic components. Furthermore, kinetic tremor
S. Keller and L.S. Dure
62
should be determined to be of either an action or intention type.
Finally, an attempt should be made to ascertain the frequency
and amplitude of tremor. Conventional terms for frequency
include slow (⬍4 Hz), intermediate (4-7 Hz), and fast (⬎7
Hz) tremors.14 Amplitude (large, intermediate, or small)
tends to vary inversely with frequency.6 There is also a developmental component to consider, as physiological tremor
frequencies have been shown to vary proportionally with age.
At the age of 2, the frequency is approximately 3 Hz and
increases by about 0.25 Hz per year.16,17 Precise characterization of frequency should rely on more quantitative methods,
such as surface electromyography. However, in practice,
clinical approximation of tremor frequency is often adequate
for characterization.
Etiology of Childhood Tremor
There is a wide range of conditions that may include tremor
as part of the clinical phenotype. Table 1 shows a list of some
of the scenarios in which tremor can appear. The following
sections will examine the more common clinical entities.
Essential Tremor
Considered the most common movement disorder in
adults,18-22 childhood essential tremor (ET) has not engendered a significant amount of published clinical articles. With
the exception of the reports of Paulson23 and Louis et al,24 few
reports in the literature have addressed the pediatric presentation of ET. This is somewhat remarkable, considering that 50%
of individuals diagnosed with ET report an onset during childhood.25 This can probably be explained by a minimal impact of
the tremor on function until adulthood. However, ET is not
uncommon in a pediatric movement disorder clinic,3 and familiarity with this entity is of value to neurologists caring for children.
ET was characterized as a hereditary action tremor by
Dana.26 In the 19th century, the descriptor “essential” was
applied to any condition that was felt to be idiopathic or
intrinsic to an individual. Because ET was typically an isolated condition with only an occasional tendency to progress,
and was determined to segregate in families, it was also described as benign familial tremor. ET is inherited in an autosomal dominant fashion, but with variability of expression
within families. However, the penetrance is believed to approach 100% after age 60.27 The genetics of ET remain elusive but at least 3 different loci have been identified for familial ET, which are EMT1, EMT2, and a locus on 6p23.28 The
EMT1 locus located at 3q13 was identified in a large Icelandic
pedigree.29 Within this locus, the DRD3 gene codes for dopamine D3 receptor. A Ser9Gly variant of this gene has been
found to be associated with an increased risk of ET.28 The
ETM2 locus on chromosome 2p22-25 has also been identified in multiple studies of familial and sporadic ET in American and North American patients.30-31
Large epidemiologic studies of ET have been reported,21,25,32-34
with some refinement of the clinical features as well as variant
presentations.35-37 Consensus diagnostic criteria have been
Table 1 Etiologies of Tremor
Benign
Physiological
Shuddering attacks
Jitteriness
Spasmus nutans
Hereditary
Essential tremor
Fragile X premutation
Strokes or Brain Lesions
Thalamus, midbrain, or cerebellum
Peripheral neuropathies
Mitochondrial encephalopathies
Metabolic
Hypomagnesemia
Hypocalcemia
Hypoglycemia
B12 deficiency
Inborn errors of metabolism
Endocrine
Hyperthyroidism
Hyperadrenergic states
Drugs, Toxins
Valproate
Phenytoin
Carbamazepine
Lamictal
Gabapentin
Lithium
Tricyclic antidepressants
Bronchodilators
Caffeine
Amphetamines
Thyroxine
Neuroleptics
Cyclosporin
Amiodarone
Serotonin reuptake inhibitors
Cocaine
Mercury
Toluene
Thallium
Manganese
Arsenic
Lead
Nicotine
Ethanol
Cyanide
Psychogenic
adopted, and consist of the following: (1) a monosymptomatic disorder characterized as tremor alone, typically with a
frequency of 4-11 Hz, and (2) distribution most commonly
in the hands and arms or head alone. The presence of tremor
in other body parts is consistent with ET, but only with
concomitant arm/hand or head involvement. Exclusionary
criteria include1 presence of other neurologic findings suggestive of another process; (2) an atypical course, or one that
is relatively static or slowly progressive; (3) a history of exposure to tremorogenic drugs or toxins; and (4) tremor that is
Tremor in childhood
orthostatic or occupational, or isolated to the tongue, chin,
voice, or leg. Other features of ET that aid in the diagnosis
include ethanol responsiveness and a positive family history.
In over half of adult ET patients, they report a significant
improvement in symptoms after a moderate intake of alcohol. Obviously, this is a feature that is seldom observed in
children, but pertinent family history of ethanol responsiveness may be elicited.
Studies to examine the pathophysiology of ET indicate the
cerebellum as the likely anatomic site of the disorder. Although gross brain pathology in ET is normal,38,39 in vivo
imaging has been performed in a number of studies. Functional magnetic resonance imaging (fMRI) has shown increased neuronal activity in cerebellum, red nucleus, and
globus pallidus contralateral to the affected limb in ET.40
Similarly, positron emission tomography41,42 in patients with
ET show an increase in activity in the cerebellum with intention or action tremor, and further increases in the thalamus
and basal ganglia with postural tremor compared to those in
controls. Finally, two studies of magnetic resonance spectroscopy have been reported in ET,13,43 both demonstrating altered neuronal metabolism in the cerebellum.
There is some controversy regarding ET, in that some authors consider the disorder to be monosymptomatic44,45
whereas others emphasize the possibility of comorbid features.46 ET usually manifests as an action tremor but has been
described with associated rest tremor in almost 20% of
adults.36 Other conditions described with ET include buccofacial dyskinesias and myoclonus,47 and other tremors may
be misdiagnosed as ET.48 To better clarify this issue, the
Committee for the Classification of Tremor has purposed the
entity of indeterminate ET, or a tremor with the typical appearance of ET but in the context of some other neurologic
disorder or syndrome. This type of tremor may be quite
common in children, but the relative frequency compared to
that of ET is not known.
In childhood, the usual presentation of ET is that of a
postural and action tremor of insidious onset and prolonged
duration. The frequency of the tremor has been reported to
vary with age and limb position,49 but the tremor is typically
between 5 and 9 Hz. The distribution is overwhelmingly
centered on the hands, with a minority manifesting head
tremor on examination. Voice tremor was not reported in
either of the 2 series of patients with childhood ET. If a
careful history is obtained, family members may recall tremor
from infancy, although this type of retrospection is of uncertain reliability. In terms of age of onset, the series of Louis
et al24 reported ET to begin at 6.8 years, but this is solely
reliant on parental history. Of note, however, is that referral
for evaluation seems to cluster around 2 epochs of childhood.
Some children present to the neurologist in the latter half of
the first decade, and in all cases this is because of the perception of the tremor by a parent, teacher, or the child’s physician. In these cases, the children are seldom disabled or otherwise adversely affected by the tremor. Although the young
child with ET will characteristically manifest a tremor when
drinking from a full cup or will have poor handwriting, it is
63
unusual for the complaint to include impairments in other
activities.
Another group of children present in their teens, and in
these patients, the chief complaint often centers on similar
activities to that of younger children, but the perceived impairment is considerably greater. In these patients, they often
relate a longstanding history of tremor but indicate that the
tremor is more obvious in social or occupational settings.
Notably, the tremor severity parallels emotional state, so it is
more apparent when the child is nervous, upset, or anxious.
It is difficult to gauge whether the progression of tremor is
truly a worsening or a subjective perception of deterioration.
This is of importance from various perspectives. Foremost
among these is that a progressive tremor may actually indicate the likelihood of some other diagnosis than that of ET, as
in adult-onset ET the course of progression is quite long.
Another issue is whether childhood ET is a manifestation of
genetic anticipation, an issue of some relevance to what is
known about trinucleotide repeat disorders. In published
studies, there is no indication of genetic anticipation in ET,
but few studies have addressed this issue. Finally, a common
concern among families who have a child with ET is the
long-term prognosis. Although it may be presumed that duration of tremor would correlate with ultimate severity and
disability, this has not been thoroughly studied.
The differential diagnosis of ET in childhood is not particularly lengthy, especially if consensus criteria are met. When
confronted with a child exhibiting a postural or action tremor
that primarily involves the hands and head, of long duration
and minimal impairment, with no other concomitant neurologic findings, the likelihood of other disorders becomes low.
By definition, historical information regarding exposure to
tremorogenic agents, such as anticonvulsants and ␤-adrenergic agonists should be obtained, and the presence of signs
of hyperthyroidism should be determined. Wilson disease
(see later in text) has been reported to present initially with
tremor, but rest tremor is more typical. In short, an otherwise
normal child or adolescent with hand tremor as the sole
manifestation is probably suffering from ET.
However, there are no published studies of treatment of
childhood ET. Keeping in mind that younger children typically have minimal impairment, it should not be a common
practice to consider pharmacologic intervention in preadolescents. Rather, specific remedies or adaptations should be
sought to address the particular problems experienced by
these children. As mentioned above, handwriting and some
fine motor tasks are impaired. Interventions such as weighting of the wrists50 or an evaluation by an occupational therapist to apply adaptive strategies for fine motor problems can
be quite beneficial.
On the other hand, adolescents who present with ET have
usually accommodated to their condition for some years; and
by the time they present to a neurologist, a common interest
is the desire to minimize the tremor. This often necessitates
medication therapy, and it is appropriate to approach treatment similar to that in adults. First-line medications have
included primidone and propranolol, both of which have
demonstrated efficacy in studies performed on adults.51-54
64
Because of problems with primidone availability, propranolol or other ␤ blockers have been considered the first-line
therapy for childhood ET. In adolescents, dosage guidelines
would be identical to those for adults. A starting dose of 30
mg once a day, then changing to 30 mg twice a day, is often
helpful in ameliorating hand tremor. Care should be taken to
ascertain whether a patient suffers from reactive airway disease, as ␤ blockers are contraindicated. Many childhood ET
patients will respond to doses in the 60-80 mg range, and
long-acting preparations (Inderal, LA) are taken once per day
to promote compliance. Other ␤ blockers (atenolol, timolol,
etc.) can be tried, as they have proved to be successful in
some cases.
Occasionally, because of lack of efficacy, side effects, or
both, other therapeutic options may be necessary. In instances of episodic aggravation of ET when, for example,
there is a particular situation that provokes tremor, shortterm treatment with a benzodiazepine, such as clonazepam
or lorazepam, can be quite helpful. Adolescents who can
identify such stressful situations make good candidates for
this approach. Finally, evidence from controlled clinical trials
using topiramate in ET indicates efficacy, but no studies have
been performed in children.55-57 Topiramate is in widespread
use for childhood epilepsy, so concern about its suitability in
pediatric patients is not much of an issue. This author has
used topiramate successfully in children with ET, but comprehensive studies are needed.
Newer therapies are on the horizon for ET, but so far they
have been used primarily in adults. These include stereotaxic
ablations, most commonly in ventralis intermediate nucleus
of the thalamus,58-60 as well as deep brain stimulation,61,62
and botulinum A toxin injections.63 These methods have all
been shown to be quite effective, with excellent long-term
results for ablations and deep brain stimulation.64-66 A pilot
study of vagus nerve stimulation has been reported, with no
consistent effect on ET.67 The applicability of these studies to
childhood ET, however, is likely to be low, as few children
manifest a significant enough disability to require surgical
therapy.
In summary, ET in childhood has many of the same features of adult-onset ET. Indeed, the clinical phenotype and
response to therapy are identical. It is not known, however,
what the prevalence of childhood ET is, nor is it known
whether childhood onset ET is a particularly severe form of
ET. These questions will require inclusion of children in epidemiologic ET studies.
Tremor in Association
With Other Conditions
According to consensus guidelines, indeterminate ET is
tremor that has the clinical appearance of ET but is not an
isolated neurologic finding, or occurring in the context of
another neurologic disorder. The most obvious example of
this entity has been described in carriers of the Fragile X
(FRAX) premutation, caused by an expansion of untranslated
CGG trinucleotide repeats.68-72 The clinical presentation of
S. Keller and L.S. Dure
tremor is usually in adulthood, consisting primarily of an
action or intention tremor. Because FRAX premutations are
common in the general population, it has been postulated
that some cases of ET are actually caused by CGG expansions.
Interestingly, another X-linked mental retardation syndrome
with action tremor has been reported,73 additionally characterized by short stature, hypogonadism, muscle wasting, and
localizing to Xq24-q25. Other genetic conditions in which
tremor has been described include 47, XYY syndrome74-77
and mutations of the MECP-2 gene.78,79 An ET-like tremor
has also been described in a patient with X-linked CharcotMarie-Tooth disease.28 One family has been reported with
hemiplegic migraine, nystagmus, and tremor with onset in
childhood, and is presumed to be a form of multisystem
degeneration.80 Another family has also been described with
a distal amyotrophy, akin to Charcot-Marie-Tooth disease,
progressive ataxia, and tremor.81 Whether either of these
families represents a distinct nosologic entity is unclear.
Action and/or postural tremor have been described as part
of the presentation of a variety of illnesses affecting all parts
of the neuraxis. As an example, Dawood and Moosa82 studied
hand tremor in spinal muscular atrophy, correlating their
clinical observations with an “ECG tremor.” They describe a
coarse tremor corresponding to the presence of muscle potentials on limb leads of the electrocardiogram. This may
actually represent polyminimyoclonus, but further study is
needed. Peripheral nerve injury may cause tremor in the
context of complex regional pain syndrome,83,84 and it has
been described as both a postural and a rest tremor. Tremor
because of stroke occurs in childhood,85-87 similar to what
has been described in adults. In children, cysts in the thalamus and pineal gland have also been reported to present with
tremor.88,89 Mitochondrial encephalopathies can at times
manifest as movement disorders. Macaya et al90 reported 22
of 34 patients with Leigh syndrome who had evidence of a
movement disorder. Although dystonia and rigidity were the
most common, 2 of these patients exhibited tremor. Frequent
traumatic brain injury is a cause of tremor, particularly in the
convalescent stages up to 18 months after the event.91 Fortunately, it has been reported to resolve spontaneously in approximately half of patients.
Tremor as a component of other movement disorders has
been described in numerous conditions. Juvenile onset occurs in fewer than 10% of patients with Huntington disease
and is the consequence of a marked expansion of a CAG
trinucleotide repeat motif in the translated 5= end of the
huntingtin gene. The clinical phenotype of this condition differs from the adult-onset variety, in that there is a preponderance of parkinsonism and rigidity.92,93 Tremor, when it occurs in this context, is most often during rest. On the other
hand, one family with benign hereditary chorea has been
reported in association with intention tremor.94 Primary parkinsonism, juvenile Parkinson disease, is rare in childhood
and usually presents with dystonia, bradykinesia, and rigidity. In contrast to the adult form of the disease, it rarely
involves tremor.95 Another basal ganglia disorder that may
present with a prominent tremor is that of Wilson disease, or
hepatolenticular degeneration. In children, this disorder of
Tremor in childhood
copper metabolism presents primarily as a disturbance of
hepatic function, although there are rare reports of isolated neurologic symptoms.96 Intention tremor as an initial finding of Wilson disease was seen in 1 patient in the
study by Slovis et al. 97 Tongue tremor with dysarthria has
also been reported.97,98 Dystonia is another movement disorder that has been reported in association with tremor. In the
so-called dystonic tremor, most patients suffer from cervical
dystonia. Large series by Jankovic99 and Rondot100 indicate a
prevalence of tremor of 71% and 21%, respectively. In Jankovic’s series, however, most of the tremors involved the head
and neck, whereas 27% had tremor identical to ET. The
possible link between focal or segmental dystonia and tremor
has also been illustrated by one report of torsion dystonia and
writing tremor in a family,101 and by the phenomenon of
task-specific tremor coexisting with task-specific dystonia.102
As is obvious from the previous discussion, the topic of
secondary tremors and indeterminate ET is somewhat broad,
especially given the lack of detail with respect to the types of
tremor that occur in various disease states. Therefore, a discussion of a treatment algorithm is problematic. In some
cases that this author has observed, a secondary tremor or
indeterminate ET may resolve on its own or be of minimal
severity, not requiring treatment. More commonly, though,
empiric trials of agents used to treat tremor, such as primidone, propranolol, clonazepam, and topiramate, have been
ineffective in ameliorating the condition. This is an area that
is poorly understood, and greater efforts are needed to develop effective therapeutic strategies for these children. In
cases of severe, disabling tremor secondary to trauma, surgical therapy has been beneficial,103 but moderate gains are
offset by significant morbidity.
Head Tremors in Childhood
The subject of oscillatory movements of the head in childhood requires a separate discussion, as there are several entities presenting in childhood. Head nodding is a relatively
slow head movement in a “yes-yes” direction seen during
infancy, and is often first noticed in the first few months of life
as head control is attained. The frequency of this movement is
usually about 2 Hz, and reflects the mechanical and viscoelastic properties of the head and neck.104 Nodding may be
pathologic in the context of weakness and an inability to
maintain the head in a stable position, such as that seen in
myopathic states,105 or it can be a compensatory phenomenon in relation to congenital nystagmus.104,106,107
Spasmus nutans is another disorder of infancy, typically
described as the triad of head tremor (usually in a “no-no”
direction), head tilt, and nystagmus.108-109 The head tremor is
of a variable frequency, and may be vertical, horizontal, or a
combination of both. The nystagmus is asymmetric, and
(similar to head movement) may be horizontal, vertical, or
rotatory. It has been postulated that the head tremor in spasmus nutans is a compensatory response to the nystagmus to
aid visual fixation.110-112 Similarly, abnormal head movements have been described in congenital nystagmus,106,113
but this entity is distinct from spasmus nutans, as the former
65
is usually present from birth, while the latter appears at approximately 4-12 months of age. The constellation of findings in spasmus nutans is certainly indicative of a process
involving posterior fossa structures or at least a central process. Indeed, both infra- and supratentorial lesions have been
described in children presenting with spasmus nutans, and
cranial imaging studies are warranted.114-118 However, in the
absence of a discernible lesion, spasmus nutans resolves
within months in most cases.
Finally, some mention is necessary of the bobble-head doll
syndrome. This head movement is usually in a “yes-yes” direction, with a higher frequency and lower amplitude than
head nodding, and may be intermittent. First described as a
clinical concomitant of an intraventricular tumor,119 later reports indicate that the findings may also be seen in the context of hydrocephalus as well as other supratentorial lesions.120-126 Because of the association with tumors of the
central nervous system, there may be other associated findings, including gait abnormalities, incoordination, oculomotor disturbances, and even behavioral changes.127 Should
there be an effective treatment of the underlying cause, the
head tremor usually resolves.124,128,126
Tremor Related to Drugs
There is a long list of agents that can produce tremor as a side
effect.5 Drugs that modify dopaminergic neurotransmission,
such as neuroleptics, typically produce a parkinsonian rest
tremor. Action or postural tremors can also be caused by
medication exposure, and there are numerous drugs that are
frequently used in childhood, which should be taken into
consideration. Anticonvulsants are commonly prescribed in
childhood epilepsy, and valproic acid has been reported to
cause an action tremor in 15% of patients.129 Other antiepileptics associated with childhood tremor include phenytoin,
14% and carbamazepine, 1%. Lamotrigine overdose has been
reported to manifest in part with a generalized tremor of short
duration.130 Adult studies indicate that tremor occurs in 9% of
patients taking tiagabine and 12.5% of those taking gabapentin.
Seldom, though, is anticonvulsant-induced tremor a cause for
cessation of the medication, nor is it a significant contributor
to disability.
Another common childhood condition is reactive airways
disease, commonly treated with ␤-adrenergic agents, corticosteroids, or a combination of the two agents. ␤-adrenergic
agents are particularly prone to cause tremor,131-133 but corticosteroids are rarely reported to be associated with clinically significant tremor.134
Finally, bone marrow and solid organ transplantation have
become more common in the pediatric age group, resulting
in a population that is chronically immunocompromised.
Although there are few studies characterizing the neurologic
complications of pediatric cancer patients,135 tremor has
been described in approximately 1%. Solid tumors in brain
can cause tremor136 but are rare. In the context of a pediatric
oncology patient, the cause of tremor is usually attributed to
cyclosporin or FK-506, both of which are used regularly in
pediatric transplant medicine.137-139
S. Keller and L.S. Dure
66
Metabolic and
Toxic Causes of Tremor
Nutritional deficiency has long been known to present with
tremor, particularly vitamin B12. Periodic case reports of
infants diagnosed with B12 deficiency describe an action
tremor that appears after treatment of the deficiency has begun.140,141 In developed countries, an infant with megaloblastic
anemia typically suffers from an isolated lack of B12; but in
underdeveloped nations, the context is one of a more pervasive
nutritional impairment. “Infantile tremor syndrome,” reported
primarily in India, is described as a fine “shivering” of high
frequency, and a predominantly generalized distribution.142-149
The clinical context is one of the concomitant nutritional deficiencies, and later authors have considered the condition to be a
manifestation of B12 deficiency and perhaps other vitamins
or minerals.150,151 An apparently similar entity, “kwashi
shakes” has also been described in Africa and the Caribbean
in children who have undergone correction of severe malnutrition.152,153
Metabolic disorders may present with a variety of neurologic symptoms, including movement disorders and tremor.
In a study from Spain, 10%-30% of patients with phenylketonuria developed kinetic or positional tremors.154 Pyruvate
carboxylase deficiency155 and homocystinuria156 have also
been associated with tremor. In most metabolic disorders,
the tremor presents in a constellation with other symptoms
and is not the sole presenting complaint.
Various intoxications with heavy metals may cause tremor,
but usually as part of a more generalized parkinsonian presentation.5 Mercury poisoning, however, can result in a
coarse action or postural tremor,157 as can intoxication with
diethyltoluamide, commonly found in insect repellants.158
Benign Tremors of Childhood
In the immediate postpartum period, concerns are often
raised regarding excessive tremulous behavior. Usually referred to as “jitteriness,” the tremor involves the entire body,
and is state-sensitive, becoming more prominent with handling or distress. Studies examining the prevalence and
course of jitteriness indicate that as many as 44% of healthy
newborns will manifest at least a “mild” amount of tremulous
behavior.159 The long-term course, though, is relatively benign, with most patients experiencing a resolution within 2-5
months.160 Futagi161 has reported a series of 24 patients
with neonatal tremor. Although it was not clearly indicated
whether these children manifested jittery behavior, most patients had a benign outcome with the exception of those who
had sustained some type of perinatal insult.
Another benign tremor of childhood is that of shuddering
attacks.162,163 These occur during infancy or early childhood
and consist of paroxysmal fine shaking of the arms and trunk
lasting ⬍20 seconds. The clinical history is of major importance, so as to avoid overaggressive investigations. Families
who witness these events describe the children appearing as
if they are momentarily chilled. Every effort should be made
to obtain a videotape of these events, but that is often difficult
owing to the brevity of the episodes. Electrographic studies
are often uninformative, unless, of course, an event is captured on videotape.164 These events resolve spontaneously
and do not require a specific therapy.
Psychogenic Tremor
Conversion disorders are well described in pediatric patients,165 not uncommonly presenting with neurologic complaints. Tremor as a conversion symptom has been described
in adults,166-168 and rarely in childhood.169 Fortunately, psychogenic tremor is fairly easy to distinguish from other
tremor types, precisely because the clinical features of tremor
do not correspond to those seen as part of pathologic processes. No adequate information exists regarding the prevalence or typical clinical presentation of psychogenic tremor
in childhood. However, tremor of sudden onset with inconsistent amplitude, frequency, and distribution of affected
limbs or muscles should certainly raise suspicions of a conversion disorder. Unusual combinations of rest, postural,
or intention tremor are common, and in most cases
marked attenuation of tremor with distraction may be observed. The clinician who suspects a psychogenic tremor
should attempt to ascertain the presence of recent stressors, behavior changes, or other concomitants that are
often associated with this disorder.
Conclusions
Clinically, tremor in childhood has many of the same features
as in adults. In indeterminate or symptomatic tremors, the
underlying causes may be particular to childhood diseases,
but the phenomenology of tremor remains indistinct through
the lifespan. Despite these similarities, however, a great deal
remains to be ascertained regarding tremor in childhood that
could shed light not only on brain development but on disease mechanisms. For example, although there have been
investigations of physiological tremor in the young,16,170,171
recent assessments of pathologic states have focused on agerelated changes in mature individuals.6,172 Because physiological tremor frequencies change with maturation into
adulthood, the contribution of this dynamic process to the
manifestation of pathologic tremors could possibly play a
role in tremor expression and disability. Furthermore, there
may be an impact on treatment strategies as well. However,
comprehensive investigations into childhood pathologic tremors are lacking; hence, inadequate understanding and treatment
of these conditions.
In the future, a better recognition of childhood tremor will
be needed, with appropriate classifications as well. As better
identification and clarification of tremor occurs, we can begin
to develop age-appropriate management strategies and take
advantage of the progress being made in adult tremor disorders.
Tremor in childhood
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