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of Child Neurology
Oral Pharmacotherapy of Childhood Movement Disorders
Terence S. Edgar
J Child Neurol 2003 18: S40 originally published online 1 January 2003
DOI: 10.1177/08830738030180010601
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Special Article
Oral Pharmacotherapy of
Childhood Movement Disorders
Terence S. Edgar, MD
ABSTRACT
Movement disorders, a common problem in children with neurologic impairment, are receiving increasing clinical attention. The differences in movement disorders between adults and children are striking; presentation is frequently insidious
and may be characterized by mild hypotonia. The clinical manifestations of extrapyramidal disorders are profoundly influenced by the age of onset. The conditions reviewed in this article are expressed clinically by the occurrence of abnormalities
of movement and posture, often in association with disturbances of muscle tone. This article reviews empiric drug use
and recommendations for childhood movement disorders. (J Child Neurol 2003;18:S40–S49).
This review considers the pharmacologic management of
childhood disorders manifest clinically by alterations in
muscle tone and the presence of abnormal movements.
Because abnormal movements are difficult to define, it is
frequently simpler to describe various types of abnormal
movements and analyze their characteristics.1 Nevertheless, the definition of terms is a particularly important starting point.
Movement disorders may be divided into four major categories: (1) dyskinesias (dystonia, chorea and ballism, tics,
myoclonus, and tremor), (2) hypokinetic-rigid syndromes
(parkinsonism), (3) ataxia, and (4) spasticity. A defect in the
speed and accuracy of voluntary actions is common to all
categories (Table 1).
Movement disorders caused by nonprogressive lesions
in the developing brain are common among children.
Extrapyramidal or dyskinetic cerebral palsy is second only
to spastic cerebral palsy in frequency of occurrence and is
ahead of the ataxic forms. Its incidence is 0.21 in 1000 new-
Received March 17, 2003. Received revised May 7, 2003. Accepted for publication May 13, 2003.
From the Department of Pediatric Neurology, Medical University of South
Carolina, Charleston, SC.
Address correspondence to Dr Terence S. Edgar, Department of Pediatric
Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street,
Suite 309, Charleston, SC 29425. Tel: 843-792-3224; fax: 843-792-8626; e-mail:
[email protected].
born infants,2 and it constitutes 10 to 15% of all cases of cerebral palsy.3
Spasticity is characterized by a velocity-dependent
increase in the tonic stretch reflex. It presents as part of a
symptom complex that may or may not be associated with
motor movements. Early identification of the child who
will later develop spasticity or extrapyramidal symptoms is
made difficult by the evolution of the early lesion in cerebral palsy. This frequently presents in an insidiously asymptomatic manner that may be characterized by mild hypotonia.
Movement abnormalities are typically bilateral but may be
asymmetric, and half to three quarters of cases have a low
normal IQ or better.4 Associated neurologic abnormalities
in extrapyramidal cerebral palsy include dysarthria (in two
thirds), drooling, strabismus (one third), seizures (one quarter), sensorineural hearing loss, and spasticity.
EVALUATION OF ABNORMAL MOVEMENTS
The determination of whether the present signs and symptoms are part of a static condition or are associated with
loss of previously acquired skills (degenerative disorder)
is critical to evaluating movement disorders in children.
Many unusual movements, especially in younger children,
may be transient and do not necessarily represent pathologic disorders.5
Once it has been decided that abnormal movements are
present, the category of the involuntary movement (such as
a dyskinesia, hypokinesia, or ataxia) must be determined.
This is the second question. Separating seizures from a dyskinetic movement disorder can be confusing because both
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Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
Table 1.
Childhood Movement Disorders
Type
Spasticity
Chorea
Ballism
Athetosis
Dystonia
Myoclonus
Tremor
Tics
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Description
A constellation of clinical findings characterized by increased tone, hyperactive reflexes, weakness, and poor coordination
Involuntary, irregular, purposeless, nonrhythmic, abrupt, rapid, and unsustained movements
Very large-amplitude choreic movements of the proximal parts of the limbs
Slow, writhing, continuous, involuntary movements often associated with sustained contractions that produce abnormal
posturing
Characterized by simultaneous co-contraction of agonist and antagonist muscles producing patterned, twisting movements
Myoclonic jerks are sudden, brief, shocklike, involuntary movements caused by muscular contractions (positive myoclonus)
or inhibitions (negative myoclonus), usually arising from the central nervous system
A rhythmic, mechanical oscillation of at least one functional body region
Abnormal motor movements (motor tics) or abnormal sounds (phonic tics)
attacks are paroxysmal, they may have a preceding sensory
phenomenon, and they are responsive to anticonvulsants.
The third question is to determine the etiology of the
abnormal, involuntary movements. Is the disorder hereditary,
sporadic, or symptomatic to some known neurologic disorder? As a general rule, the etiology can be ascertained on the
basis of history and judiciously selected laboratory tests.
The final question is how to best treat the movement
disorder (Table 2).
FUNCTIONAL ORGANIZATION
OF THE BASAL GANGLIA
The basal ganglia consists of a set of four intimately connected structures6: (1) the striatum; (2) the globus pallidus,
with its medial and lateral segments; (3) the substantia
nigra, which is divided into the pars compacta and pars
reticularis; and (4) the subthalamic nucleus. These structures
Table 2.
Drug
Baclofen
Carbamazepine
Clonazepam
Clonidine
Dantrolene
Diazepam
Fluphenazine
Haloperidol
Levetiracetam
Levodopa/carbidopa
Lorazepam
Pergolide
Phenobarbital
Pimozide
Piracetam
Primidone
Propranolol
Reserpine
Risperidone
Tetrabenazine
Tizanidine
Trihexyphenidyl
Topiramate
Valproate
Zonisamide
are connected to each other by multiple reciprocal loops and
to the cortex and thalamus by parallel circuits. The medial
globus pallidus and the substantia nigra pars reticularis
represent the final output structures of the basal ganglia.
The striatum is the major receiving area of the basal ganglia and is composed of the caudate nucleus and the putamen. It receives topographically organized, glutaminergic
excitatory input from the cerebral cortex. Cortical association areas project to the caudate nucleus, whereas sensorimotor areas preferentially project to the putamen.7 The
striatum also receives dopaminergic input from the substantia nigra pars compacta and mainly excitatory input
from the centromedian and parafascicular nuclei of the
thalamus.
The output from the striatum gives rise to two functionally opposed pathways (Figures 1 and 2), both using
-aminobutyric acid (GABA) as their neurotransmitter. The
direct pathway originates in the striatum and projects
Drugs Used in the Medical Treatment of Childhood Movement Disorders
Chorea/Ballism
Dystonia/Athetosis
Myoclonus
Tremor
Tics
Spasticity
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Journal of Child Neurology / Volume 18, Supplement 1, September 2003
Figure 1. Direct motor circuit through the basal ganglia. Activated
pathways are shown with solid lines, and inhibited pathways are
shown with dashed lines. A plus or a minus sign indicates the excitatory or inhibitory nature of the neurotransmitter of the pathway. In
this pathway, excitatory cortical output stimulates the striatal
-aminobutyric acid (GABA)/substance P neurons that project to the
substantia nigra pars reticulata (SNR) and the medial globus pallidus
(MGP). The substantia nigra pars reticulata and the medial globus pallidus are inhibited, and the ventrolateral thalamus is released (disinhibited) from the tonic inhibition it received from the substantia nigra
pars reticulata and the medial globus pallidus. The thalamus is therefore free to provide excitatory feedback to the cortex. The pathways
are used to sustain an ongoing pattern of motor behavior. Glu =
glutamate.
directly to the medial segment of the globus pallidus and the
substantia nigra pars reticularis, inhibiting these nuclei.
The indirect pathway consists of the GABAergic neurons that
project to the lateral segment of the globus pallidus.
Inhibitory neurons from the globus pallidus synapse on
neurons of the subthalamic nucleus, which then provides
excitatory (presumably glutaminergic) input to the final
output structures of the basal ganglia (the medial globus pallidus and the substantia nigra pars reticularis).
The major output from the medial segment of the globus
pallidus and the substantia nigra pars reticularis is to the thalamus. GABA is the inhibitory neurotransmitter in this connection by which information is relayed to the cerebral
cortex. Fibers originating from the putamen terminate in the
premotor and supplementary motor cortices, whereas caudate-originating fibers terminate in the prefrontal cortex. Pallidal output inhibits the excitatory thalamocortical loop.
The pallidum, in turn, is inhibited by the neostriatum, thus
disinihibiting thalamocortical activity.
The key neurotransmitters in the basal ganglia are
dopamine, acetylcholine, GABA, and glutamate. Many
other substances, such as enkephalin, dynorphin, substance P, somatostatin, and cholecystokinin, serve as neuromodulators. Dopamine is highly concentrated in the
substantia nigra and is released in the postsynaptic area
of the striatum from axons originating in the substantia
nigra. The GABA-containing striatal neurons that form the
indirect pathway preferentially express dopamine type 2
receptors and are inhibited by dopamine, with a net
inhibitory effect on the thalamus.8 Neurons of the direct
pathway tend to express dopamine type 1 receptors and
Figure 2. The indirect motor circuit through the basal ganglia. Activated pathways are shown in solid lines, and inhibited pathways are
shown with dashed lines. A plus or a minus sign indicates the excitatory or inhibitory nature of the neurotransmitter of the pathway. In
this pathway, excitatory cortical output stimulates the striatal enkephalin
(ENK) and -aminobutyric acid (GABA) neurons that project to the lateral globus pallidus (LGP). The lateral globus pallidus is inhibited, so
the subthalamic nucleus (STN) is disinhibited. The excitatory subthalamic nucleus drives the substantia nigra pars reticulata (SNR)
and medial globus pallidus (MGP) to inhibit the thalamus. The subthalamic nucleus can also be activated directly by the cortex. This pathway is used to suppress inappropriate motor behavior. Glu = glutamate;
SNC = substantia nigra pars compacta.
are excited by dopamine, with a net facilitatory effect on
the thalamus. Glutamate, an excitatory neurotransmitter,
is primarily involved in pathways leading from the cerebral
cortex to the striatum. Most of the drugs used in the symptomatic treatment of movement disorders act through
attenuation of dopaminergic transmission or enhancement of GABA transmission.
HYPERKINESIAS
Chorea and Ballism
Definitions
Chorea refers to involuntary, irregular, purposeless, nonrhythmic, abrupt, rapid, and unsustained movements that
seem to flow from one part of the body to another. A characteristic feature of chorea is that movements are unpredictable in timing, direction, and distribution (ie, random).
Ballism refers to very large-amplitude choreic movements
of the proximal parts of the limbs, causing flinging and flailing limb movements.
Pathophysiology
Lesions of the subthalamic nucleus in humans or primates
produce contralateral hemichorea.9 This is interpreted as
attributable to the loss of excitatory glutamate input into the
medial globus pallidus. The resulting underactivity of pallidal neurons liberates excessive thalamocortical drive to premotor cortical regions to cause chorea. The dyskinesia
observed in parkinsonism is attributed to inhibition by
dopamine (perhaps via D2 receptors) of striatal neurons
projecting to the lateral pallidum via the indirect pathway.
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Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
Excessive inhibition of this indirect pathway leads to inactivation of the subthalamus, resulting in chorea and ballism.
Management
Only a few cases of chorea are due to etiologically treatable
conditions (drugs, hyperthyroidism, and infections). In general, mild chorea should not require any treatment because
the consequences of therapy may be worse than any shortterm relief. There is no consensus on the optimal management of autoimmune chorea, but both corticosteroids10 and
intravenous immunoglobulins have been used. Corticosteroids appear to be effective in the treatment of chorea
associated with heart transplantation.11 Nonspecific suppression of chorea can be attained with benzodiazepines (eg,
clonazepam 0.5–6 mg/day); however, drugs with anticholinergic properties may exacerbate symptoms.
Most choreas can be reduced by dopamine-blocking or
dopamine-depleting medications; the choice depends on the
severity of symptoms and concomitant disease. The more
potent agents of treatment are the dopamine antagonists; the
more specific the D2 antagonism, the greater the chorea
suppression. Haloperidol 0.5 to 20 mg/day and pimozide 1 to
10 mg/day are the most specific. Dose ranges are broad,
and initiation of low-dose therapy at bedtime, with gradual
titration to beneficial levels, is recommended. Careful monitoring for unwanted side effects is mandatory. Patients with
prolonged Q–T intervals are at risk for drug-induced ventricular arrhythmias. With severe, disabling chorea, dopamine
depletion should be considered with reserpine 0.1 to 0.3
mg/day in divided doses or tetrabenazine 12.5 to 100 mg/day
in divided doses.12 Whereas some studies have suggested that
sodium valproate may be effective in the treatment of chorea,
other reports have been less conclusive.13,14
Dystonia and Athetosis
Definition
Dystonic movements are characterized by simultaneous
co-contraction of agonist and antagonist muscles producing patterned, twisting movements that are sustained at
the peak of movement and often result in abnormal postures.
The speed of the movement varies widely from slow
(athetoid dystonia) to shocklike (myoclonic dystonia).
Whereas primary dystonia often begins as an action dystonia and may persist as the kinetic (clonic) form, symptomatic
dystonia often presents as fixed postures (tonic form).
Athetosis is used to describe a class of slow, writhing, continuous, involuntary movements, often associated with sustained contractions that produce abnormal posturing. In this
regard, athetosis blends with dystonia. However, the speed
of these involuntary movements can sometimes be faster,
blending with those of chorea, and the term choreoathetosis is used.
Pathophysiology
Although most lesions causing dystonia are in the lentiform
nucleus, particularly the putamen, it is difficult to produce
S43
dystonia in primates by lesions or by pharmacologic manipulation of the basal ganglia. The dopamine system is thought
to be intimately involved in the pathophysiology of dystonia based on the observations that (1) dopa-responsive dystonia is a levodopa pathway disorder, (2) levodopa deficiency
produces dystonia in parkinsonism, (3) levodopa excess may
produce dystonia in Parkinson’s disease and dyskinesias in
dystonia, (4) dopamine receptor–blocking agents produce
dystonia, and (5) dopamine-depleting agents (tetrabenazine,
reserpine) may ameliorate dystonic symptoms. However,
despite evidence implicating involvement of the dopaminergic system, studies have not revealed a common neurochemical substrate. Although presumed to be a primary
motor disorder, the motor signs of dystonia may, in fact,
reflect aberrant sensory input.15
Pharmacologic Therapies
Acute drug-induced dystonias can be caused by dopamine
receptor–blocking agents, including antipsychotic and
antiemetic agents, anticonvulsants, and quinine-related
drugs. Decreasing the offending agent may treat dystonic
reactions associated with anticonvulsant therapy. Dystonia
induced by acute dopamine receptor–blocking agents may
be relieved by the intravenous administration of diphenhydramine. An intravenous anticholinergic agent or benzodiazepine can also be used.
A trial of levodopa is indicated in all patients with limbonset dystonia. Patients diagnosed with cerebral palsy and
idiopathic torsion dystonia may, in fact, have dopa-responsive dystonia. Small doses are used (100 mg two to three
times daily) in association with carbidopa. Generally,
responses are quite rapid, but some patients may require
higher doses and prolonged therapy before a response is
observed.
In most situations in which there is no response to levodopa, various agents can be used on a trial-and-error basis.
Open-label and double-blind studies have substantiated the
beneficial effect of anticholinergic agents in children and
adults with focal, segmental, and generalized dystonia.16,17
Initiation of trihexyphenidyl at 2 to 4 mg/day can by increased
by 2.5 mg every other week to a maximal dosage as high as
60 mg/day in children. Side effects (dry mouth, constipation,
blurred vision, urinary retention, anorexia, confusion, and
psychosis) are frequently avoided with a slow titration. Furthermore, pilocarpine eye drops or oral physostigmine can
be used to minimize side effects. Response rates as high as
60% have been reported.18
If there is a limited response to the anticholinergic
agent, consider combination with pimozide. Pimozide, a
potent dopamine antagonist, should be initiated at 1 mg/day
and can be gradually titrated weekly to a maximum dosage
of 6 to 12 mg/day. Experience with the atypical neuroleptic
agents is limited. The dopamine-depleting agents tetrabenazine and reserpine may be effective in the treatment of
primary and secondary dystonia.19 Marsden et al proposed
triple therapy (“Marsden cocktail”), comprising a dopamine
depletor, a dopamine-blocking agent (pimozide), and an
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Journal of Child Neurology / Volume 18, Supplement 1, September 2003
anticholinergic agent (trihexyphenidyl) in cases of severe
dystonia.20
An alternative approach is combining an anticholinergic agent with progressively increasing doses of a benzodiazepine.21 Benzodiazepines bind to the GABAA receptor-ion
channel complex, increasing chloride entry into the cell
and thus enhancing GABA-mediated inhibition. The primary side effect is sedation, which is controlled by modifying the dose. There are no double-blind studies exploring
the clinical utility of benzodiazepines in dystonia.
Oral baclofen is a GABAB agonist that stimulates the
metabotropic GABAB autoreceptor. The mechanism of benefit in dystonia is not known. Dosage ranges for oral baclofen
are from 40 to 180 mg/day. The main side effects are lethargy,
dry mouth, and dizziness. Rapid decreases in the dose of oral
baclofen may produce psychosis and seizures.22
Paroxysmal dystonias are preferentially treated with
the anticonvulsant carbamazepine or phenytoin if kinesiogenic, carbamazepine if nocturnal, or acetazolamide if
nonkinesiogenic.23–25
Tics and Tourette Syndrome
Definition
Tics consist of abnormal motor movements (motor tics) or
abnormal sounds (phonic tics). When both types of tics are
present for a period of more than 1 year, the designation of
Tourette syndrome is commonly applied.
Pathophysiology
The anatomic localization and biochemical nature of tics and
Tourette syndrome are unknown. There is compelling evidence to support the view that overactivity of striatal
dopamine contributes to tic disorders. Dopamine receptor
antagonists suppress tics, whereas dopaminergic agents
such as amphetamines may exacerbate them. A postmortem
study of the brains of patients with Tourette syndrome
revealed an increased density of presynaptic dopamine
nerve terminals, which was attributed to dopamine hyperinnervation of the striatum.26
agitation, a rebound increase in tics, tachycardia, and profuse sweating can be associated with the abrupt discontinuation of clonidine. Clonazepam (0.5–5 mg/day) is sometimes
beneficial in the treatment of clonic tics.
The dopamine receptor–blocking drugs (neuroleptic
agents) are the most effective drugs used to treat tics. However, acute dystonic reactions and tardive syndromes may
complicate their use. Haloperidol is effective in approximately 80% of cases.29 Start administration at 0.25 mg/day
and increase by 0.25 to 0.5 mg increments every week,
according to response, to a maximum of 5 to 10 mg/day. The
long-term risk of tardive dyskinesias prevents the chronic
use of haloperidol in children except as a last resort.
Pimozide has a more selective antidopaminergic action
with fewer side effects. The initial dosage is 1 mg/day at bedtime and should be increased by 1 mg every 5 to 7 days to
a maximum of 8 mg/day.30 Pimozide may cause a prolongation of the Q–T interval on the electrocardiogram. Fluphenazine is preferred over haloperidol and pimozide
because it has a lower incidence of sedation and other side
effects. The initial dosage is 1 mg/day at bedtime and should
be increased by 1 mg every 5 to 7 days to a maximum of
15 mg/day.31 Risperidone, a neuroleptic with both dopamineand serotonin-blocking properties, has been shown to be
effective in reducing tic frequency and intensity in some
patients.32,33
A variety of medications, including calcium channel
blockers (verapamil, nifedipine), carbamazepine, thioridazine, baclofen, and buspirone, may be effective in suppressing tics. However, the response to these medications
is less predictable. The efficacy of the dopamine agonist pergolide in the treatment of tics is probably on the basis of
presynaptic inhibition at low dosages.34 Tetrabenazine, a
monoamine-depleting and dopamine receptor–blocking
drug, is a powerful antitic drug but, unfortunately, is not available in the United States.35
Myoclonus
Definition
Treatment
Most patients with mild tics can avoid the use of medications. The mere presence of tics is not a sufficient reason
for drug treatment. If pharmacologic treatment is used,
complete suppression of tics is seldom attainable without
the risk of intolerable side effects, and complete symptomatic
eradication is therefore not the goal. All medications are initiated at the lowest possible dose and are gradually increased
until sufficient benefit is obtained or intolerable side effects
supervene.
2-Adrenergic receptor agonists such as clonidine or
guanfacine provide effective treatment.27,28 The initial dosage
of clonidine is 0.05 mg/day and should be increased by
0.05 mg every week to a maximum of 0.3 mg/day in three
divided doses. Side effects include sedation, insomnia, and
dryness of mouth. A withdrawal syndrome characterized by
Myoclonic jerks are sudden, brief, shocklike, involuntary
movements caused by muscular contractions (positive
myoclonus) or inhibitions (negative myoclonus), usually
arising from the central nervous system.
Pathophysiology
Myoclonus occurs as a result of excessive discharge from
a group of neurons with subsequent spread through the
neural axis. The clinical features of myoclonus and results
of electrophysiologic investigations enable differentiation
into three major categories: cortical, subcortical (brain
stem), and spinal myoclonus. Myoclonus is a nonspecific sign
of a number of nervous system disorders, the detailed mechanisms of which are unclear. Many epilepsy syndromes of
infancy and childhood feature myoclonus as a prominent
symptom.
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Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
Treatment
Epileptic myoclonus and cortical myoclonus respond best
to drugs such as sodium valproate and clonazepam, often
used in combination.36 In patients with severe myoclonus,
start with sodium valproate (250 mg/day to 4200 mg/day) and
then add clonazepam (4 mg/day to 10 mg/day). If there is no
significant improvement, consider adding piracetam (8 g/day
to 24 g/day).37 Levetiracetam has been reported to alleviate
posthypoxic and postencephalitic myoclonus.38 Zonisamide
appears to be effective in reducing the amount of myoclonias and generalized seizures in patients with UnverrichtLundborg disease. 39 Brainstem myoclonus and spinal
myoclonus seem to respond best to clonazepam. Tetrabenazine and baclofen may occasionally be of some benefit. Essential myoclonus occasionally improves with
primidone, propranolol, or an anticholinergic agent.40,41
Tremor
Definition
A practical definition of a tremor is a rhythmic, mechanical
oscillation of at least one functional body region. One should
keep in mind that any movement is accompanied by a normal physiologic tremor; this physiologic tremor is assumed
to be necessary for fast movements.
Pathophysiology
A detailed description of our present knowledge of tremor
is beyond the scope of this article. For a comprehensive
review, see Elble.42 Various classification schemes for tremor
exist based on anatomic distribution, etiology (idiopathic
or symptomatic), or circumstance of occurrence (resting,
postural, or action tremor).
Treatment
The antitremor drugs exert their ameliorating effects by
reducing tremor amplitude without any effect on tremor
frequency. Currently, popular drugs for the treatment of
tremor include primidone, -adrenergic blockers, and
benzodiazepines.
The antitremor effect of primidone has been confirmed
by several open-label and placebo-controlled studies.43 Start
treatment at a very low dosage of 25 mg/day and titrate up
gradually over several weeks until an optimal therapeutic
dosage is achieved. Dosages above 250 mg/day are rarely
required. The principal side effects are nausea, vomiting, and
sedation over the first few days of treatment. Primidone’s
antitremor effect is attributed to the parent compound
rather than its metabolites.44 In addition, the efficacy of
topiramate (400 mg/day or maximum tolerated dose) in
treating essential tremor was recently demonstrated in a double-blind, placebo-controlled, crossover study of 24 patients.
The most common adverse effects were appetite suppression/weight loss and paresthesias.45
HYPOKINETIC-RIGID SYNDROMES
Definition
Akinesia, bradykinesia, and hypokinesia literally mean
absence, slowness, and decreased amplitude of movement,
S45
respectively. The three terms can be grouped together for
convenience and referred to under the term hypokinesia.
Rigidity is characterized as increased muscle tone to passive motion. It is distinguished from spasticity in that it is
present equally in all directions of passive movement, equally
in flexors and extensors, throughout the range of motion,
and it does not exhibit the clasp-knife phenomenon. Rigidity can be smooth (lead pipe) or jerky (cogwheel). Lead pipe
rigidity can be caused by a number of central nervous system lesions, including those involving the corpus striatum
(hypoxia, vasculitis, neuroleptic malignant syndrome), midbrain (decorticate rigidity), medulla (decerebrate rigidity),
and spinal cord (tetanus). Cogwheeling occurs owing to the
superimposition of a tremor rhythm and is thus more common in the nigral lesions of parkinsonism.
Pathophysiology
Parkinsonian syndromes, the most common cause of paucity
of movement, are rarely observed in the childhood population. The core pathology of Parkinson’s disease is destruction of the pigmented neurons in the pars compacta of the
substantia nigra. As a result, there is degeneration of the
nigrostriatal dopaminergic system and profound depletion
of the striatal dopaminergic content. Administration of the
selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to primates has provided a remarkably accurate model of Parkinson’s disease.46 MPTP destroys
the dopaminergic striatal system, with lesser effects on the
noradrenergic neurons. Metabolic studies of parkinsonian
monkeys treated with MPTP revealed increased activity of
GABA projection neurons from the striatum to the lateral
globus pallidus and consequent decreased activity of GABA
projections from the lateral globus pallidus to the subthalamus. Subthalamic neuronal activity is increased in MPTPtreated primates, and lesions of the subthalamic nucleus in
such animals considerably reduce contralateral tremor,
rigidity, and akinesia.47 The net effect is increased neuronal
firing of pallidal GABA neurons projecting to thalamic targets, with resulting decreased cortical activation.
Treatment
All of the classic parkinsonian symptoms respond to levodopa replacement therapy, although tremor may benefit
less than the akinesia and rigidity. A detailed review of the
management of Parkinson’s disease is beyond the scope of
this article.
ATAXIA
Definition
The cardinal clinical features of cerebellar disease are
ataxia, dyssynergia, and dysmetria. Ataxia of gait is typified
by unsteadiness with a wide base, body sway, and an inability to walk on tandem (heel to toe). Dyssynergia refers to
a decomposition of movement instead of a smooth, continuous movement; it is associated with a tendency to miss
a target and worsens when approaching the target. Dyssynergia is frequently accompanied by dysmetria (the mis-
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Journal of Child Neurology / Volume 18, Supplement 1, September 2003
judging of distance), with its characteristic overshooting and
undershooting of a target.
Treatment
Double-blind and open-label studies have reported beneficial clinical effects of amantidine (200 mg/day) in Friedreich’s
ataxia and olivopontocerebellar atrophy.48,49 Other medications reported to have some benefit include thyrotropinreleasing hormone, 5-hydroxytryptophan, physostigmine,
and clonazepam. However, the long-term efficacy of these
medications has been uniformly disappointing.
TREATMENT OPTIONS IN
SPASTICITY MANAGEMENT
Spasticity is a stretch-related response, characterized by a
velocity-dependent, increased resistance to passive stretch.
Our clinical observations reflect a dysregulation of motoneuron activity, either a failure of appropriate excitation or a loss of inhibition. Loss of excitatory drive to an effector neuron causes a decrease in the frequency of firing,
with the resultant loss or reduction in function (eg, weakness). Loss of inhibitory drive to an effector neuron causes
an increase in firing frequency and the appearance of a
new response (eg, increased muscle tone). The resulting
abnormalities of tone may be beneficial and compensate to
some extent for associated weakness and disruptions in equilibrium and motor control.
Several treatment options are available to manage spasticity, and more than one option can be used. A complementary approach to the treatment of spasticity is
encouraged and may include physical, pharmacologic, and
surgical interventions. It is not uncommon to use physical
and occupational therapies in combination with oral medications, botulinum toxin injections, intrathecal baclofen
therapy, and timed orthopedic interventions. A rational
approach to therapy can be developed on the basis of the
proposed pathophysiology and receptor-neurotransmitter
interactions. Realistic and clearly defined goals should be
established prior to the initiation of treatment.
Oral medications may be of benefit in the treatment of
painful spasms, disrupted sleep, and dystonia, but their use
in the management of generalized spasticity has been disappointing. With the possible exception of baclofen,
diazepam, and dantrolene, there is little evidence that oral
medications can meaningfully reduce tone. The nonselective action is seen in all muscle groups and centrally, with
frequent cognitive side effects. A detailed description of
drugs is found in Table 3.
Baclofen
Baclofen is a structural analogue of GABA. It enhances Renshaw cell activity and appears to block the polysynaptic
and monosynaptic afferents in the spinal cord by binding to
GABAB receptors. Its mechanism of action may be as a direct
inhibitory neurotransmitter or through hyperpolarization of
the afferent nerve terminals. Penetration of the blood-brain
barrier is very poor, with more than 90% of the absorbed drug
remaining in the systemic circulation. Oral baclofen is particularly useful for symptomatic problems, such as flexor
spasms, stiffness, and pain in patients with spinal cord injury
and demyelinating myelopathies. In a double-blind, crossover
trial of children 2 to 16 years of age with successive 4-week
treatment periods, baclofen (up to 60 mg/day) was significantly more effective than placebo in reducing spasticity and
allowing active and passive limb movements.50 Sedation
appears to be dose related and can be minimized by initiating treatment at a low dose and gradually titrating upward.
Along with sedation, it may cause impairment of cognitive
function, dizziness, weakness, and ataxia. There is some
controversy regarding baclofen’s effect on seizure activity.51
Benzodiazepines
Benzodiazepines exert their antispasmodic action through
GABAA receptors. In the spinal cord, diazepam appears to
increase presynaptic afferent inhibition and depress monoand polysynaptic inhibition in the reticular formation.
Diazepam is useful in spinal cord injury, demyelinating
myelopathy, and cerebral palsy,52 but the sedation and cognitive side effects limit its use in stroke and traumatic brain
injury. It is particularly useful in children with painful spasms
that produce insomnia. In a double-blind study of 22 children, the use of diazepam in combination with dantrolene
was more effective than when used separately for spasticity in cerebral palsy.53 Clonazepam has a shorter half-life of
18 to 28 hours and has been effective in decreasing evening
spasms. Clorazepate has been of some benefit in patients
with multiple sclerosis.54
Tizanidine
Tizanidine is an imidazole derivative, related to clonidine,
with agonist action at both spinal and supraspinal 2-adrenergic receptors. It reduces aspartate and glutamate release
from the presynaptic nerve terminals of the spinal interneurons and appears to have antinocioceptive properties. It may
be particularly useful in nighttime spasms, pain, and clonus.
Sedation is a significant limiting factor in achieving adequate
dosing, which is compounded if the medication is administered with food. In an unpublished, prospective study on
22 children 3 to 12 years of age with diplegic cerebral palsy,
the author was not able to demonstrate changes in range or
tone, as measured on the Ashworth Scale (dosage range was
0.3 to 0.5 mg/kg/day as tolerated). Hepatoxicity occurs in
5% of patients, and liver enzymes should be monitored.
Dantrolene
This is a potentially underused treatment, particularly in the
nonambulatory patient. It is unique among antispasmodic
agents in that it reacts peripherally at the level of the muscle fiber rather than the spinal cord. Dantrolene uncouples
electrical excitation from contraction by inhibiting the
release of calcium from the sarcoplasmic reticulum. It is useful for symptomatic relief, especially of clonus, in all types
of upper motoneuron insults. Because it may significantly
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Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
Table 3.
Generic Name
S47
Drug Treatment Guidelines in Childhood Movement Disorders
Dose Forms
Usual Dosages
Mechanisms of Action
Baclofen
Lioresal tablets: 10 mg, 20 mg
Child < 2 yr: 2.5 mg PO q8h, maximum
20 mg/d
Child 2–7 yr: 5 mg PO q8h, maximum
40 mg/d
Child > 8 yr: 5 mg PO q8h, maximum
60 mg/d
Dose titration at 7-d intervals to
effective dose
GABA agonist that inhibits transmission of reflexes at the spinal cord
level
Carbamazepine
Carbatrol (extended release)
200 and 300 mg capsules
Tegretol 100 mg/5 mL suspension,
100 mg chewable tablets and
200 mg tablets
Tegretol XR 100, 200, and 400 mg
tablets
Child: initial: 5–10 mg/kg/d bid
Modulates sodium channels
Maintenance: 10–25 mg/kg/d bid, qid
Adult: 400–2400 mg/d bid, qid
Initial dose: 100–200 mg hs for 5–7 d
then increase by 200 mg/d every 5–7 d
Clonazepam
Klonopin tablets: 0.5, 1, and 2 mg
0.01–0.3 mg/kg/d bid or tid
Facilitates the actions of GABA
Clonidine
Catapres tablets: 0.1, 0.2, and 0.3 mg
Catapres-TTS transdermal patch:
0.1 mg/d, 0.2 mg/d, 0.3 mg/d;
change q5–7 d
Start at 0.05 mg/d and increase by
0.05 mg every week, to a maximum
of 0.3 mg/d ÷ tid
Centrally acting 2-adrenergic agonist
that increases presynaptic
inhibition of motoneurons
Clorazepate
Tranxene tablets: 3.75, 7.5, 11.25,
22.5, and 15 mg
Adult: 7.5 mg PO bid; increase by
Facilitates the action of GABA
7.5 mg at weekly intervals to maximum of 90 mg/d given in individual
doses
Child 9–12 yr: 3.75 mg PO bid; increase
by 3.75 mg at weekly intervals not to
exceed 60 mg/d in divided doses
Capsules: 3.75, 7.5, and 15 mg
Dantrolene
Dantrium capsule: 25, 50, and 100 mg
Adult: 25 mg PO qid; increase q4–7 d
to maximum of 400 mg 4 doses/d
Child > 5 yr: 0.5 mg/kg PO bid;
increase q4–7 d to maximum of
12 mg/kg 4 doses/d
Interferes with calcium ion release
from sarcoplasmic reticulum of
skeletal muscles
Diazepam
Valium tablets: 2, 5, and 10 mg
Solutions: 1 mg/mL, 5 mg/mL
Adults: 2–10 mg PO bid to qid
Child: 0.05–0.1 mg/kg PO bid to qid
(maximum of 0.8 mg/kg/d)
Facilitates the actions of GABA
Fluphenzaine
Oral suspension 5 mg/mL
1, 2.5, 5, and 10 mg tablets
Start at 1 mg/d and increase by 1 mg
each week
Usual maintenance dose is 4–6 mg
(maximum is 10 mg/d)
Dopamine receptor antagonist
Gabapentin
Neurontin
Capsules: 100, 300, and 400 mg
Tablets: 600 and 800 mg
Suspension: 250 mg/5 mL
Adult: 900–3600 mg PO tid to
qid
Child: up to 60 mg/kg/d tid to qid
Unknown
Haloperidol
Haldol oral suspension 2 mg/mL
0.5, 1, 2, 5, and10 mg tablets
Start at 0.5 mg qhs and increase by
Dopamine receptor antagonist
0.5 mg each week; maximum dose is
0.15 mg/kg/d ÷ bid, tid
Levodopa/carbidopa Sinemet 25/100 (25 mg carbidopa,
100 mg levodopa)
1–2 tablets bid, qid
Dopamine precursor, indirect receptor
agonist
Lorazepam
Ativan 0.5, 1, and 2 mg tablets,
2 mg/mL oral solution
Child: 0.01–0.1 mg/kg/d ÷ bid, qid
Adult: 1–10 mg/d ÷ bid, qid
Benzodiazepine receptor agonist
Pimozide
Oral 1 and 2 mg tablets
Start at 1 mg/d and increase by 1 mg
each week; maintenance dose is
2–4 mg/d ÷ bid, tid; maximum dose
is 10 mg/d
Dopamine receptor antagonist
Piracetam (unavail- 400, 800, 1000, and 1200 mg tablets
able in the United
States)
Dose range is 4.8 to 24 mg/d ÷ tid
Unknown mechanism of action
Primidone
Child: 10–25 mg/kg/d ÷ bid or tid
Adult: Initial dose 125 mg/d qhs for
3–5 d, then increase by 125 mg/d
(÷ bid to tid) every 3–5 d
Modulates GABA
Mysoline 250 mg/5 mL suspension,
50 and 250 mg capsules
Continued on next page
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S48
Journal of Child Neurology / Volume 18, Supplement 1, September 2003
Table 3 (continued).
Generic Name
Drug Treatment Guidelines in Childhood Movement Disorders
Dose Forms
Usual Dosages
Mechanisms of Action
Propranolol
Inderal 10, 20, 40, 60, and 80 mg
tablets
Inderal LA 60, 80, 120, and 160 mg
tablets
Start at 0.5–1 mg/kg/d ÷ tid; increase
every 5 d to a maintenance dose of
2–6 mg/kg/d or ≤ 35 kg: 10–20 mg
3/d ÷ tid; > 35 kg: 20–40 mg 3/d ÷ tid
-Blocker
Reserpine
0.1 and 0.25 mg tablets
0.1–3 mg/d ÷ bid
Presynaptic depletion of catecholamine
and serotonin stores
Tetrabenazine
—
(unavailable in
the United States)
12.5–100 mg/d
Irreversible catecholamine granular
storage depletor and dopamine
receptor blocker
Tiagabine
Gabatril 4, 12, 16, and 20 mg tablets
Adult: 32–56 mg/d ÷ bid to qid (start
Inhibits neuronal and glial uptake of
with 4 mg PO qid, adjust weekly)
GABA
Child: 0.1 mg/kg/d; increase to 0.5 mg/kg/d
Tizanidine
Zanaflex 2 and 4 mg tablets
Adult: initial dosing is 1 mg PO q8h prn; Centrally acting 2-adrenergic agonist
may increase to maximum of 36 mg/d
that increases presynaptic inhibition
Child: initial dosing 1 mg PO qhs for
of motoneurons
< 10 yr, 2 mg PO qhs for > 10 yr with
maintenance at 0.3–0.5 mg/kg/d
÷ qid
Trihexyphenidyl
2 mg/5 mL elixir, 2 and 5 mg tablets
Valproate
Zonisamide
Initial dose is 2–2.5 mg/d; increase by
2–2.5 mg every other week to a
maximal dose as high as 60 mg/d
Depakene 250 mg/5 mL oral solution, Initial: 5–10 mg/kg/d (÷ bid to qid)
250 mg capsules
Depakote 125 mg sprinkles. 125, 250, Maintenance: 15–60 mg/kg/d
and 500 mg tablets
(750–4000 mg/d) (÷ bid to qid)
Depakote ER 500 mg tablets
Zonegran 100 mg capsules
Anticholinergic
Enhances action of GABA
Initial: 2–4 mg/kg/d (÷ qd to bid)
Multiple mechanisms of action
Maintenance: 4–12 mg/kg/d (÷ qd to bid)
÷ = divided doses; GABA = -aminobutyric acid.
exacerbate weakness, it should be used with caution in
demyelinating myelopathies and in ambulatory patients
with cerebral palsy. In a study of 15 children on dantrolene
for 8 weeks, little improvement was found.55 However,
improvement was found in two other studies, with 28 and
23 children, respectively.56,57 Minor side effects include
fatigue, anorexia, diarrhea, and vomiting. The use of dantrolene has been associated with hepatotoxicity in 1.8% of
patients, with fatal hepatitis in 0.3%.58 Baseline liver function tests should be performed before starting dantrolene
and they should be monitored throughout treatment.
Gabapentin
Gabapentin is an anticonvulsant that is structurally similar
to GABA. It increases brain levels of GABA, but the mechanism of action is unknown. In trials of subjects with multiple sclerosis, gabapentin reduced Ashworth Scale scores
and improved comfort when compared with the placebo.59
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