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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 atten-
tion. 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 influ-
enced 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:S40S49).

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 Neverthe-
less, the definition of terms is a particularly important start-
ing point.
Movement disorders may be divided into four major cat-
egories: (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 pub-
lication 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:
terencee@prevea.com.
born infants,2 and it constitutes 10 to 15% of all cases of cere-
bral 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 cere-
bral palsy. This frequently presents in an insidiously asymp-
tomatic 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 quar-
ter), sensorineural hearing loss, and spasticity.
EVALUATION OF ABNORMAL MOVEMENTS
The determination of whether the present signs and symp-
toms 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 patho-
logic 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 dys-
kinetic movement disorder can be confusing because both

S40
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 Oral Pharmacotherapy of Childhood Movement Disorders / Edgar S41

Table 1. Childhood Movement Disorders

Type Description
Spasticity A constellation of clinical findings characterized by increased tone, hyperactive reflexes, weakness, and poor coordination
Chorea Involuntary, irregular, purposeless, nonrhythmic, abrupt, rapid, and unsustained movements
Ballism Very large-amplitude choreic movements of the proximal parts of the limbs
Athetosis Slow, writhing, continuous, involuntary movements often associated with sustained contractions that produce abnormal
posturing
Dystonia Characterized by simultaneous co-contraction of agonist and antagonist muscles producing patterned, twisting movements
Myoclonus 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
Tremor A rhythmic, mechanical oscillation of at least one functional body region
Tics 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 disor-
der? 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 con-
nected 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
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 gan-
glia and is composed of the caudate nucleus and the puta-
men. It receives topographically organized, glutaminergic
excitatory input from the cerebral cortex. Cortical associ-
ation areas project to the caudate nucleus, whereas senso-
rimotor areas preferentially project to the putamen.7 The
striatum also receives dopaminergic input from the sub-
stantia 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 func-
tionally opposed pathways (Figures 1 and 2), both using

-aminobutyric acid (GABA) as their neurotransmitter. The
direct pathway originates in the striatum and projects

Table 2. Drugs Used in the Medical Treatment of Childhood Movement Disorders

Drug Chorea/Ballism Dystonia/Athetosis Myoclonus Tremor Tics Spasticity
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      

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S42 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 exci-
tatory 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 pal-
lidus are inhibited, and the ventrolateral thalamus is released (disin-
hibited) from the tonic inhibition it received from the substantia nigra
pars reticulata and the medial globus pallidus. The thalamus is there-
fore 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 pal-
lidus 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 thal-
amus. GABA is the inhibitory neurotransmitter in this con-
nection by which information is relayed to the cerebral
cortex. Fibers originating from the putamen terminate in the
premotor and supplementary motor cortices, whereas cau-
date-originating fibers terminate in the prefrontal cortex. Pal-
lidal 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, sub-
stance P, somatostatin, and cholecystokinin, serve as neu-
romodulators. 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
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Figure 2. The indirect motor circuit through the basal ganglia. Acti-
vated pathways are shown in solid lines, and inhibited pathways are
shown with dashed lines. A plus or a minus sign indicates the exci-
tatory 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 lat-
eral globus pallidus (LGP). The lateral globus pallidus is inhibited, so
the subthalamic nucleus (STN) is disinhibited. The excitatory sub-
thalamic nucleus drives the substantia nigra pars reticulata (SNR)
and medial globus pallidus (MGP) to inhibit the thalamus. The sub-
thalamic nucleus can also be activated directly by the cortex. This path-
way 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 symp-
tomatic treatment of movement disorders act through
attenuation of dopaminergic transmission or enhance-
ment of GABA transmission.
HYPERKINESIAS
Chorea and Ballism
Definitions
Chorea refers to involuntary, irregular, purposeless, non-
rhythmic, abrupt, rapid, and unsustained movements that
seem to flow from one part of the body to another. A char-
acteristic feature of chorea is that movements are unpre-
dictable 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 flail-
ing 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 pal-
lidal neurons liberates excessive thalamocortical drive to pre-
motor 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.
 Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
Excessive inhibition of this indirect pathway leads to inac-
tivation 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 gen-
eral, mild chorea should not require any treatment because
the consequences of therapy may be worse than any short-
term relief. There is no consensus on the optimal manage-
ment of autoimmune chorea, but both corticosteroids10 and
intravenous immunoglobulins have been used. Cortico-
steroids appear to be effective in the treatment of chorea
associated with heart transplantation.11 Nonspecific sup-
pression of chorea can be attained with benzodiazepines (eg,
clonazepam 0.56 mg/day); however, drugs with anti-
cholinergic 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 mon-
itoring for unwanted side effects is mandatory. Patients with
prolonged QT intervals are at risk for drug-induced ven-
tricular 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 produc-
ing 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 dysto-
nia 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, con-
tinuous, involuntary movements, often associated with sus-
tained 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 choreoatheto-
sis is used.
Pathophysiology
Although most lesions causing dystonia are in the lentiform
nucleus, particularly the putamen, it is difficult to produce
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S43
dystonia in primates by lesions or by pharmacologic manip-
ulation of the basal ganglia. The dopamine system is thought
to be intimately involved in the pathophysiology of dysto-
nia based on the observations that (1) dopa-responsive dys-
tonia is a levodopa pathway disorder, (2) levodopa deficiency
produces dystonia in parkinsonism, (3) levodopa excess may
produce dystonia in Parkinsons disease and dyskinesias in
dystonia, (4) dopamine receptorblocking agents produce
dystonia, and (5) dopamine-depleting agents (tetrabenazine,
reserpine) may ameliorate dystonic symptoms. However,
despite evidence implicating involvement of the dopamin-
ergic system, studies have not revealed a common neuro-
chemical 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
receptorblocking 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 receptorblocking agents may
be relieved by the intravenous administration of diphen-
hydramine. An intravenous anticholinergic agent or benzo-
diazepine can also be used.
A trial of levodopa is indicated in all patients with limb-
onset dystonia. Patients diagnosed with cerebral palsy and
idiopathic torsion dystonia may, in fact, have dopa-respon-
sive 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 lev-
odopa, 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. Fur-
thermore, 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 tetra-
benazine 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
S44 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 anticholiner-
gic agent with progressively increasing doses of a benzo-
diazepine.21 Benzodiazepines bind to the GABAA receptor-ion
channel complex, increasing chloride entry into the cell
and thus enhancing GABA-mediated inhibition. The pri-
mary side effect is sedation, which is controlled by modi-
fying 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 ben-
efit 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 kine-
siogenic, carbamazepine if nocturnal, or acetazolamide if
nonkinesiogenic.2325
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 evi-
dence 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 hyper-
innervation of the striatum.26
Treatment
Most patients with mild tics can avoid the use of medica-
tions. 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 ini-
tiated 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
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agitation, a rebound increase in tics, tachycardia, and pro-
fuse sweating can be associated with the abrupt discontin-
uation of clonidine. Clonazepam (0.55 mg/day) is sometimes
beneficial in the treatment of clonic tics.
The dopamine receptorblocking drugs (neuroleptic
agents) are the most effective drugs used to treat tics. How-
ever, acute dystonic reactions and tardive syndromes may
complicate their use. Haloperidol is effective in approxi-
mately 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 bed-
time and should be increased by 1 mg every 5 to 7 days to
a maximum of 8 mg/day.30 Pimozide may cause a prolonga-
tion of the QT interval on the electrocardiogram. Flu-
phenazine 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 dopamine-
and 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, thiori-
dazine, baclofen, and buspirone, may be effective in sup-
pressing tics. However, the response to these medications
is less predictable. The efficacy of the dopamine agonist per-
golide in the treatment of tics is probably on the basis of
presynaptic inhibition at low dosages.34 Tetrabenazine, a
monoamine-depleting and dopamine receptorblocking
drug, is a powerful antitic drug but, unfortunately, is not avail-
able in the United States.35
Myoclonus
Definition
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 mech-
anisms of which are unclear. Many epilepsy syndromes of
infancy and childhood feature myoclonus as a prominent
symptom.
 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 myoclo-
nias and generalized seizures in patients with Unverricht-
Lundborg disease. 39 Brainstem myoclonus and spinal
myoclonus seem to respond best to clonazepam. Tetra-
benazine and baclofen may occasionally be of some bene-
fit. 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 nor-
mal 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. Primidones
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 dou-
ble-blind, placebo-controlled, crossover study of 24 patients.
The most common adverse effects were appetite suppres-
sion/weight loss and paresthesias.45
HYPOKINETIC-RIGID SYNDROMES
Definition
Akinesia, bradykinesia, and hypokinesia literally mean
absence, slowness, and decreased amplitude of movement,
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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 pas-
sive 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. Rigid-
ity can be smooth (lead pipe) or jerky (cogwheel). Lead pipe
rigidity can be caused by a number of central nervous sys-
tem lesions, including those involving the corpus striatum
(hypoxia, vasculitis, neuroleptic malignant syndrome), mid-
brain (decorticate rigidity), medulla (decerebrate rigidity),
and spinal cord (tetanus). Cogwheeling occurs owing to the
superimposition of a tremor rhythm and is thus more com-
mon in the nigral lesions of parkinsonism.
Pathophysiology
Parkinsonian syndromes, the most common cause of paucity
of movement, are rarely observed in the childhood popu-
lation. The core pathology of Parkinsons disease is destruc-
tion 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-tetra-
hydropyridine (MPTP) to primates has provided a remark-
ably accurate model of Parkinsons 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 subthal-
amus. Subthalamic neuronal activity is increased in MPTP-
treated 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 tar-
gets, with resulting decreased cortical activation.
Treatment
All of the classic parkinsonian symptoms respond to levo-
dopa replacement therapy, although tremor may benefit
less than the akinesia and rigidity. A detailed review of the
management of Parkinsons 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 inabil-
ity to walk on tandem (heel to toe). Dyssynergia refers to
a decomposition of movement instead of a smooth, con-
tinuous movement; it is associated with a tendency to miss
a target and worsens when approaching the target. Dys-
synergia is frequently accompanied by dysmetria (the mis-
S46 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 benefi-
cial clinical effects of amantidine (200 mg/day) in Friedreichs
ataxia and olivopontocerebellar atrophy.48,49 Other medica-
tions reported to have some benefit include thyrotropin-
releasing 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 excita-
tion or a loss of inhibition. Loss of excitatory drive to an effec-
tor neuron causes a decrease in the frequency of firing,
with the resultant loss or reduction in function (eg, weak-
ness). 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 equi-
librium and motor control.
Several treatment options are available to manage spas-
ticity, and more than one option can be used. A comple-
mentary 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 med-
ications, 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 dis-
appointing. With the possible exception of baclofen,
diazepam, and dantrolene, there is little evidence that oral
medications can meaningfully reduce tone. The nonselec-
tive 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 Ren-
shaw 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
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barrier is very poor, with more than 90% of the absorbed drug
remaining in the systemic circulation. Oral baclofen is par-
ticularly 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 signifi-
cantly 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 initiat-
ing 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 baclofens 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 mono-
and polysynaptic inhibition in the reticular formation.
Diazepam is useful in spinal cord injury, demyelinating
myelopathy, and cerebral palsy,52 but the sedation and cog-
nitive 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 chil-
dren, the use of diazepam in combination with dantrolene
was more effective than when used separately for spastic-
ity 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-adren-
ergic receptors. It reduces aspartate and glutamate release
from the presynaptic nerve terminals of the spinal interneu-
rons 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 admin-
istered 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 mus-
cle fiber rather than the spinal cord. Dantrolene uncouples
electrical excitation from contraction by inhibiting the
release of calcium from the sarcoplasmic reticulum. It is use-
ful for symptomatic relief, especially of clonus, in all types
of upper motoneuron insults. Because it may significantly

Table 3. Drug Treatment Guidelines in Childhood Movement Disorders
Generic Name Dose Forms
Baclofen Lioresal tablets: 10 mg, 20 mg
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
Clonazepam Klonopin tablets: 0.5, 1, and 2 mg
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 q57 d
Clorazepate Tranxene tablets: 3.75, 7.5, 11.25,
22.5, and 15 mg
Capsules: 3.75, 7.5, and 15 mg
Dantrolene Dantrium capsule: 25, 50, and 100 mg
Diazepam Valium tablets: 2, 5, and 10 mg
Solutions: 1 mg/mL, 5 mg/mL
Fluphenzaine Oral suspension 5 mg/mL
1, 2.5, 5, and 10 mg tablets
Gabapentin Neurontin
Capsules: 100, 300, and 400 mg
Tablets: 600 and 800 mg
Suspension: 250 mg/5 mL
Haloperidol Haldol oral suspension 2 mg/mL
0.5, 1, 2, 5, and10 mg tablets
Levodopa/carbidopa Sinemet 25/100 (25 mg carbidopa,
100 mg levodopa)
Lorazepam Ativan 0.5, 1, and 2 mg tablets,
2 mg/mL oral solution
Pimozide Oral 1 and 2 mg tablets
Piracetam (unavail- 400, 800, 1000, and 1200 mg tablets
able in the United
States)
Primidone Mysoline 250 mg/5 mL suspension,
50 and 250 mg capsules
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Oral Pharmacotherapy of Childhood Movement Disorders / Edgar S47
Usual Dosages Mechanisms of Action
Child < 2 yr: 2.5 mg PO q8h, maximum GABA agonist that inhibits transmis-
20 mg/d sion of reflexes at the spinal cord
Child 27 yr: 5 mg PO q8h, maximum level
40 mg/d
Child > 8 yr: 5 mg PO q8h, maximum
60 mg/d
Dose titration at 7-d intervals to
effective dose
Child: initial: 510 mg/kg/d  bid Modulates sodium channels
Maintenance: 1025 mg/kg/d  bid, qid
Adult: 4002400 mg/d  bid, qid
Initial dose: 100200 mg hs for 57 d
then increase by 200 mg/d every 57 d
0.010.3 mg/kg/d  bid or tid Facilitates the actions of GABA
Start at 0.05 mg/d and increase by Centrally acting 2-adrenergic agonist
0.05 mg every week, to a maximum that increases presynaptic
of 0.3 mg/d tid inhibition of motoneurons
Adult: 7.5 mg PO  bid; increase by Facilitates the action of GABA
7.5 mg at weekly intervals to maxi-
mum of 90 mg/d given in individual
doses
Child 912 yr: 3.75 mg PO  bid; increase
by 3.75 mg at weekly intervals not to
exceed 60 mg/d in divided doses
Adult: 25 mg PO qid; increase q47 d Interferes with calcium ion release
to maximum of 400 mg  4 doses/d from sarcoplasmic reticulum of
skeletal muscles
Child > 5 yr: 0.5 mg/kg PO  bid;
increase q47 d to maximum of
12 mg/kg  4 doses/d
Adults: 210 mg PO  bid to qid Facilitates the actions of GABA
Child: 0.050.1 mg/kg PO  bid to qid
(maximum of 0.8 mg/kg/d)
Start at 1 mg/d and increase by 1 mg Dopamine receptor antagonist
each week
Usual maintenance dose is 46 mg
(maximum is 10 mg/d)
Adult: 9003600 mg PO  tid to Unknown
qid
Child: up to 60 mg/kg/d  tid to qid
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
12 tablets bid, qid Dopamine precursor, indirect receptor
agonist
Child: 0.010.1 mg/kg/d bid, qid Benzodiazepine receptor agonist
Adult: 110 mg/d bid, qid
Start at 1 mg/d and increase by 1 mg Dopamine receptor antagonist
each week; maintenance dose is
24 mg/d bid, tid; maximum dose
is 10 mg/d
Dose range is 4.8 to 24 mg/d tid Unknown mechanism of action
Child: 1025 mg/kg/d bid or tid Modulates GABA
Adult: Initial dose 125 mg/d qhs for
35 d, then increase by 125 mg/d
( bid to tid) every 35 d
Continued on next page
S48 Journal of Child Neurology / Volume 18, Supplement 1, September 2003
Table 3 (continued). Drug Treatment Guidelines in Childhood Movement Disorders
Generic Name Dose Forms
Propranolol Inderal 10, 20, 40, 60, and 80 mg
tablets
Inderal LA 60, 80, 120, and 160 mg
tablets
Reserpine 0.1 and 0.25 mg tablets
Tetrabenazine
(unavailable in
the United States)
Tiagabine Gabatril 4, 12, 16, and 20 mg tablets
Tizanidine Zanaflex 2 and 4 mg tablets
Trihexyphenidyl 2 mg/5 mL elixir, 2 and 5 mg tablets Initial dose is 22.5 mg/d; increase by
Valproate Depakene 250 mg/5 mL oral solution, Initial: 510 mg/kg/d ( bid to qid)
250 mg capsules
Depakote 125 mg sprinkles. 125, 250, Maintenance: 1560 mg/kg/d
and 500 mg tablets
Depakote ER 500 mg tablets
Zonisamide Zonegran 100 mg capsules
= 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 dantro-
lene has been associated with hepatotoxicity in 1.8% of
patients, with fatal hepatitis in 0.3%.58 Baseline liver func-
tion 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 mech-
anism of action is unknown. In trials of subjects with mul-
tiple sclerosis, gabapentin reduced Ashworth Scale scores
and improved comfort when compared with the placebo.59
SUMMARY
Neurologic disorders characterized by a disturbance of
muscle tone, a paucity of voluntary movements, or an excess
of involuntary movements are receiving increasing clinical
attention. However, treatment of many disorders remains
less than optimal, and there continues to be a scarcity of good
clinical drug trials in childhood movement disorders. The
cognitive and neuropsychologic impact is largely unknown.
Abnormal motor movements are easily recognized, difficult
to define, and a challenge to treat.
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Usual Dosages Mechanisms of Action
Start at 0.51 mg/kg/d tid; increase -Blocker
every 5 d to a maintenance dose of
26 mg/kg/d or 35 kg: 1020 mg
3/d tid; > 35 kg: 2040 mg 3/d tid
0.13 mg/d bid Presynaptic depletion of catecholamine
and serotonin stores
12.5100 mg/d Irreversible catecholamine granular
storage depletor and dopamine
receptor blocker
Adult: 3256 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
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 0.30.5 mg/kg/d
qid
Anticholinergic
22.5 mg every other week to a
maximal dose as high as 60 mg/d
Enhances action of GABA
(7504000 mg/d) ( bid to qid)
Initial: 24 mg/kg/d ( qd to bid) Multiple mechanisms of action
Maintenance: 412 mg/kg/d ( qd to bid)
References
1. Jankovic J: Phenomenology and classification of tics. Neurol
Clin North Am 1997;15:267275.
2. Hagberg G, Zetterstrom R: Decreasing perinatal mortality. Increase
in cerebral palsy morbidity. Acta Paediatr Scand 1989;78:664670.
3. Aicardi J, Bax M: Cerebral palsy, in Aicardi J (ed): Diseases of the
Nervous System in Childhood, 2nd ed. London, MacKeith Press,
1998, 210239.
4. Polani PE: The natural history of choreoathetoid cerebral palsy.
Guy Hosp Rep 1959;108132.
5. Burke RE, Fahn S, Gold AP: Delayed-onset dystonia in patients
with static encephalopathy. J Neurol Neurosurg Psychiatry
1980;43:93104.
6. Young AB, Penney JB: Biochemical and functional organization
of the basal ganglia, in Jankovic J, Tolosa E (eds): Parkinsons Dis-
ease and Movement Disorders, 3rd ed. Baltimore, Williams and
Wilkins, 1998, 113.
7. Cavada C, Goldman-Rakic PS: Topographic segregation of cortico-
striatal projection from posterior parietal subdivisions in the
macaque monkey. Neuroscience 1991;42:683696.
8. Alexander GE, Crutcher MD: Functional architecture of basal
ganglia circuits: Neural substrates of parallel processing. Trends
Neurosci 1990;13:266271.
9. Carpenter MB, Whittier JR, Mettler FA: Analysis of choreoid
hyperkinesias in the rhesus monkey. Surgical and pharmacolog-
ical analysis of hyperkinesias resulting from lesions in the sub-
thalamic nucleus of Lys. J Comp Neurol 1950;92:293332.
10. Green LN: Corticosteroids in the treatment of Syndenhams chorea.
Arch Neurol 1978;3553.
11. Blunt SB, Brooks DJ, Kennard C: Steroid-responsive chorea in
childhood following cardiac transplantation. Mov Disord 1994;9:
112113.
12. Jankovic J, Beach J: Long term effects of tetrabenazine in hyper-
kinetic movement disorders. Neurology 1997;48:358362.
 Oral Pharmacotherapy of Childhood Movement Disorders / Edgar
13. Daoud AS, Zaki M, Shakir R, et al: Effectiveness of sodium val-
proate in the treatment of Sydenhams chorea. Neurology 1990;40:
11401141.
14. Sethi KD, Patel BP: Inconsistent response to divalproex sodium
in hemichorea/hemiballism. Neurology 1990;40:16301631.
15. Hallett M, Toro C: Dystonia and the supplementary sensorimotor
area. Adv Neurol 1996;70:471476.
16. Lang AE: High dose anticholinergic therapy in adult dystonia.
Can J Neurol Sci 1986;13:4246.
17. Brans JW, Lindeboom R, Snoek JW, et al: Botulinum toxin versus
trihexphenidyl in cervical dystonia: A prospective randomized, dou-
ble-blind controlled trial. Neurology 1996;46:10661072.
18. Greene O, Shale H, Fahn S: Analysis of open-label trials in torsion
dystonia using high dosages of anticholinergics and other drugs.
Mov Disord 1988;3:4660.
19. Jankovic J: Treatment of hyperkinetic movement disorders with
tetrabenazine: A double-blind crossover study. Ann Neurol 1982;11:
4147.
20. Marsden CD, Marion MH, Quinn N: The treatment of severe dys-
tonia in children and adults. J Neurol Neurosurg Psychiatry
1984;47:11661173.
21. Weiner WJ, Lang AE (eds): Movement Disorders. A Comprehen-
sive Survey. Mount Kisko, NY, Futura, 1989.
22. Green P, Fahn S: Baclofen in the treatment of idiopathic dysto-
nia in children. Mov Disord 1992;7:4852.
23. Marsden CD: Paroxysmal choreoathetosis. Adv Neurol 1996;70:
467470.
24. Hirsch E, Sella F, Maton B, et al: Nocturnal paroxysmal dystonia:
A clinical form of focal epilepsy. Neurophysiol Clin 1994;24:
207217.
25. Biary N, Singh B, Bahou Y, et al: Posttraumatic paroxysmal noc-
turnal hemidystonia. Mov Disord 1994;9:9899.
26. Singer HS, Hahn IH, Moran TH: Abnormal dopamine uptake sites
in postmortem striatum from patients with Tourettes syndrome.
Ann Neurol 1991;30:558562.
27. Leckman JE, Detlar J, Harcherik DF, et al: Short and long-term
treatment of Tourettes syndrome with clonidine. A clinical per-
spective. Neurology 1985;35:343351.
28. Walkup JT, Scahill LD, Riddle MA: Disruptive behavior, hyperac-
tivity, and learning disabilities in children with Tourettes syndrome,
in Weiner WJ, Lang AE (eds): Advances in Neurology. Behavioural
Neurology of Movement Disorders, vol. 65. New York, Raven
Press, 1995, 259272.
29. Erenberg G, Cruse RP, Rothner AD: The natural history of Tourette
syndrome. A follow-up study. Ann Neurol 1987;22:383385.
30. Chappell PB, Leckman JF, Riddle MA: The pharmacologic treat-
ment of the tic disorders. Child Adolesc Psychiatr Clin North Am
1995;4:197216.
31. Goetz CG, Klawans HN: Fluphenazine and multifocal tic disorders.
Arch Neurol 1984;41:271272.
32. Van der Linden C, Bruggerman R, Van Woerkom TC: Serotonin-
dopamine antagonist and Gilles de la Tourettes syndrome: An open
pilot dose titration study with risperidone. Mov Disord 1994;9:
687688.
33. Sallee FR, Kurlan R, Goetz CG, et al: Ziprasidone treatment of chil-
dren and adolescents with Tourettes syndrome: A pilot study. J Am
Acad Child Adolesc Psychiatry 2000;39:292299.
34. Gilbert DL, Sethuraman G, Sine L, et al: Tourettes syndrome
improvement with pergolide in a randomized, double-blind,
crossover trial. Neurology 2000;54:13101315.
35. Jankovic J, Beech J: Long-term effects of tetrabenazine in hyper-
kinetic movement disorders. Neurology 1997;48:358362.
Downloaded from jcn.sagepub.com at VANDERBILT UNIV on August 23, 2013
S49
36. Obeso JA, Artieda J, Rothwell JC, et al: The treatment of severe
action myoclonus. Brain 1989;112:765777.
37. Obeso JA, Arteida J, Quinn NP, et al: Piracetam in the treatment
of different types of myoclonus. Clin Neuropharmacol 1988;11:
529536.
38. Krauss GL, Bergin A, Kramer RE, et al: Suppression of post-
hypoxic and post-encephalitic myoclonus with levetiracetam.
Neurology 2001;56:411412.
39. Kyllerman M, Ben-Menachem E: Zonisamide for progressive
myoclonus epilepsy: Long-term observations in seven patients.
Epilepsy Res 1998;29:109114.
40. Pranzatelli MR: The pharmacology of myoclonus. Clin Neu-
ropharmacol 1995;8:99130.
41. Chokroverty S, Manocha MK, Duvoisin RC: A physiologic and
pharmacologic study in anticholinergic-responsive essential
myoclonus. Neurology 1987;37:608615.
42. Elble RJ: Central mechanisms of tremor. J Clin Neurophysiol 1996;
13:133144.
43. Koller WC, Royse VL: Efficacy of primidone in essential tremor.
Neurology 1986;36:121124.
44. Sasso E, Perucca E, Fava R, et al: Quantitative comparison of bar-
biturates in essential hand and head tremor. Mov Disord 1991;6:
304309.
45. Conner GS: A double-blind placebo-controlled trial of topiramate
treatment for essential tremor. Neurology 2002;59:132134.
46. Burns RS, Chiueh CC, Markey SP, et al: A primate model of parkin-
sonism: Selective destruction of dopaminergic neurons in the
pars compacta of the substantia nigra by N-methyl-4 phenyl-
1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 1983;80:
45464550.
47. Bergman H, Wichmann T, De Long MR: Reversal of experimental
parkinsonism by lesions of the subthalamic nucleus. Science
1990;249:14361438.
48. Botez MI, Botez-Marquard T, Elie R, et al: Amantidine hydrochlo-
ride in heredodegenerative ataxia: A double blind study. J Neu-
rol Neurosurg Psychiatry 1996;61:259264.
49. Botez MI, Young SN, Rotez T, et al: Treatment of heredo-degen-
erative ataxias with amantadine hydrochloride. Can J Neurol
Sci 1991;18:307311.
50. Milla PJ, Jackson ADM: A controlled trial of baclofen in children
with cerebral palsy. J Int Med Res 1977;5:398404.
51. Young RR, Enure M, Nance PW, et al: Current issues in spasticity
management. Neurologist 1997;3:261275.
52. Denhoff E: Cerebral palsyA pharmacologic approach. Clin
Pharmacol Ther 1964;5:947954.
53. Nogen AG: Effect of dantrolene sodium on the incidence of
seizures in children with spasticity. Childs Brain 1979;5:420425.
54. Nance PW, Young RR: Antispasmodic medications. Phys Med
Rehabil Clin North Am 1999;10:337355.
55. Ford F, Bleck EE, Aptekar RG, et al: Efficacy of dantrolene sodium
in the treatment of spastic cerebral palsy. Dev Med Child Neurol
1976;18:770783.
56. Denhoff E, Feldman S, Smith MG, et al: Treatment of spastic
cerebral-palsied children with dantrolene sodium. Dev Med Child
Neurol 1975;17:736742.
57. Halsam RHA, Walcher JR, Leitman PS, et al: Dantrolene sodium
in children with spasticity. Arch Phys Med Rehabil 1974;55:384388.
58. Gracies J-M, Nance P, Elovic E, et al: Traditional pharmacologic
treatments for spasticity part II: General and regional treatments.
Muscle Nerve 1997;20(Suppl 6):S92S120.
59. Cutter NC, Scott DD, Johnson JC, Whiteneck G: Gabapentin effect
on spasticity in muliple sclerosis. A placebo controlled random-
ized trial. Arch Phys Med Rehabil 2000;81:164169.