Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Article (PDF Available)inNeurology 74(4):336-43 · January 2010with190 Reads
DOI: 10.1212/WNL.0b013e3181cbcd2f · Source: PubMed
Abstract
To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy. A multidisciplinary panel systematically reviewed relevant literature from 1966 to July 2008. For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported. Recommendations: For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment (Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment, with caution regarding toxicity (Level B), and tizanidine may be considered (Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).
Practice Parameter: Pharmacologic treatment of
spasticity in children and adolescents with
cerebral palsy (an evidence-based review)
Report of the Quality Standards Subcommittee of the American Academy of
Neurology and the Practice Committee of the Child Neurology Society
M.R. Delgado, MD,
FRCPC, FAAN
D. Hirtz, MD, FAAN
M. Aisen, MD, FAAN
S. Ashwal, MD, FAAN
D.L. Fehlings, MD,
MSc, FRCPC
J. McLaughlin, MD
L.A. Morrison, MD
M.W. Shrader, MD
A. Tilton, MD, FAAN
J. Vargus-Adams, MD,
MS
ABSTRACT
Objective: To evaluate published evidence of efficacy and safety of pharmacologic treatments for
childhood spasticity due to cerebral palsy.
Methods: A multidisciplinary panel systematically reviewed relevant literature from 1966 to July
2008.
Results: For localized/segmental spasticity, botulinum toxin type A is established as an effective
treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence
regarding functional improvement. Botulinum toxin type A was found to be generally safe in chil-
dren with cerebral palsy; however, the Food and Drug Administration is presently investigating
isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria
are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized
spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on
its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there
are insufficient data on its effect on function and its side-effect profile. There were insufficient
data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently
reported.
Recommendations: For localized/segmental spasticity that warrants treatment, botulinum toxin
type A should be offered as an effective and generally safe treatment (Level A). There are insuffi-
cient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For
generalized spasticity that warrants treatment, diazepam should be considered for short-term
treatment (Level B), and tizanidine may be considered (Level C). There are insufficient data to
support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).
Neurology
®
2010;74:336–343
GLOSSARY
AAN American Academy of Neurology; AE adverse event; AS Ashworth scale; BoNT-A botulinum toxin type A;
BoNT-B botulinum toxin type B; CP cerebral palsy; FDA Food and Drug Administration; GAS Goal Attainment Scale;
GMFM Gross Motor Function Measure; ITB intrathecal baclofen; MAS Modified Ashworth scale; OT occupational
therapy; PT physiotherapy; QUEST Quality of Upper Extremity Skills Test; TS Tardieu scale.
The prevalence of cerebral palsy (CP) was recently
reported to be 3.6 cases per 1,000 in 8-year-old chil-
dren,
1
with very little variation among Western na-
tions.
2
More than 10,000 babies born in the United
States each year will be affected by CP.
3
CP is the
most common cause of spasticity in children, and the
majority of children with CP are affected by spasticity.
4
The Taskforce on Childhood Motor Disorders defines
spasticity as “hypertonia in which one or both of the
following signs are present: 1) resistance to externally
imposed movement increases with increasing speed of
stretch and varies with the direction of joint movement;
2) resistance to externally imposed movement rises rap-
idly above a threshold speed of joint angle.”
5
Supplemental data at
www.neurology.org
Address correspondence and
reprint requests to American
Academy of Neurology, 1080
Montreal Avenue, St. Paul, MN
55116
guidelines@aan.com
From the University of Texas Southwestern Medical Center (M.R.D.), Dallas; National Institute of Neurological Disorders and Stroke (D.H.),
Bethesda, MD; United Cerebral Palsy Research Foundation (M.A.); Loma Linda University (S.A.), Loma Linda, CA; Bloorview Kids Rehab (D.L.F.),
Toronto, Canada; University of Washington (J.M.), Seattle; University of New Mexico (L.A.M.), Albuquerque; The Core Institute (M.W.S.), Sun
City West, AZ; Louisiana State University (A.T.), New Orleans; and Cincinnati Children’s Hospital (J.V.-A.), Cincinnati, OH.
Appendices e-1 through e-4, tables e-1 through e-3, and references e1 through e19 are available on the Neurology
®
Web site at www.neurology.org.
Approved by the Quality Standards Subcommittee on February 7, 2009; by the AAN Practice Committee on April 10, 2009; by the CNS Practice
Committee on December 7, 2009; by the AAN Board of Directors on October 19, 2009; and by the CNS Board of Directors on December 11, 2009.
Disclosure: Author disclosures are provided at the end of the article.
SPECIAL ARTICLE
336 Copyright © 2010 by AAN Enterprises, Inc.
Spasticity is one component of the multifaceted
motor disability of CP and may not be the main
factor interfering with function, participation, or ac-
tivity.
6
Alleviation of spasticity may not always be
desirable; some patients may experience a decline in
function with spasticity reduction.
7
The decision to
use antispasticity medications requires careful assess-
ment of the patient’s other impairments (e.g., weak-
ness, movement disorders) and proper selection and
use of the treatment. Reasons to treat spasticity in-
clude reducing pain and muscle spasms, facilitating
brace use, improving posture, minimizing contrac-
tures and deformity, facilitating mobility and dexter-
ity, and improving patient ease of care as well as
hygiene/self-care.
8
Several tools such as the Ashworth scale (AS)
9
and
the Modified Ashworth scale (MAS)
10
have been
used in clinical trials, with the assumption that they
measure spasticity. These scales measure a broader set
of neural and musculoskeletal factors of non-
velocity-dependent hypertonia in addition to spastic-
ity itself.
11
A tool that is more consistent with the
proposed definition of spasticity above is the Tardieu
scale (TS).
12
The TS accounts for the joint angle
measure of the spastic phenomenon at different ve-
locities of joint movement.
Over the last 20 years, several pharmacologic an-
tispasticity treatments have been adapted for use in
patients with CP. These include oral medications
like benzodiazepines, dantrolene, baclofen, and tiza-
nidine; neuromuscular blocking agents such as botu-
linum toxins A and B (BoNT-A and BoNT-B);
chemical denervation using phenol and alcohol; and
intrathecal baclofen (ITB).
13
Oral medications and
ITB are used when a generalized antispasticity effect
is desired. Chemical denervation agents are used to
treat localized (one extremity) or segmental (lower
body, hemibody) spasticity. The mechanisms of ac-
tion and pharmacology of these drugs are described
in other publications.
14,15
This article reviews and evaluates published evi-
dence of the efficacy and safety of these medications
in children and adolescents affected by spasticity due
to CP.
DESCRIPTION OF THE ANALYTIC PROCESS
The American Academy of Neurology (AAN) con-
vened a multidisciplinary author panel consisting of
5 pediatric neurologists, 2 developmental pediatricians,
1 pediatric physiatrist, 1 pediatric orthopedist, and 1
adult neurologist. Literature searches of MEDLINE
and EMBASE were conducted for relevant articles
published from 1966 to July 2008 using the follow-
ing key text and index words: cerebral palsy, static
encephalopathy, spasticity, hypertonia, children, and
infantile. Key text and index words for the intervention
included diazepam, Valium, tizanidine, Zanaflex, dan-
trolene, Dantrium, baclofen, Lioresal, intrathecal ba-
clofen, phenol, alcohol, botulinum toxin A, Botox,
Dysport, BTX-A, BoNT-A, botulinum toxin B,
BoNT-B, BTX-B, Myobloc, and Neurobloc.
The inclusion criteria were all foreign languages
with English abstracts, human subjects, peer re-
viewed, patients 19 years of age or younger with CP,
and more than 9 patients studied. Citations of review
articles from 2000 to 2008 were checked for addi-
tional pertinent references.
A total of 978 abstracts were initially found. From
these, 528 were identified as potentially pertinent
and reviewed in full. Finally, 218 articles were se-
lected that fulfilled the inclusion/exclusion criteria.
Each article was reviewed, abstracted, and classi-
fied by at least 2 authors. Disagreements were re-
solved by reaching consensus among the reviewers,
the first author, and at least 2 other authors. The
AANs 4-tiered classification scheme for therapeutic
evidence was used to classify articles (appendix e-3 on
the Neurology
®
Web site at www.neurology.org), and
the strength of the recommendation was linked
to the evidence (appendix e-4).
ANALYSIS OF EVIDENCE Treatment of localized
or segmental spasticity.
There were no publications
on phenol, alcohol, or BoNT-B that met criteria for
review.
A total of 148 studies using BoNT-A to reduce
spasticity in children with CP met eligibility criteria.
Fifteen studies were Class I and 5 were Class II (table
e-1). Five of these studies assessed the effect of
BoNT-A in the upper extremity
16–20
; the rest assessed
only the lower extremity. A total of 573 children re-
ceived BoNT-A in the Class I and II studies. The
majority of the studies included children as young as
2 years of age. Spasticity was measured using the AS
or the MAS in 13 of the 20 studies. The BoNT-A
doses used are indicated in table e-1.
Spasticity reduction. Spasticity reduction was re-
ported in all but 3 studies.
20–22
In one study, spastic-
ity was significantly reduced by electromechanical
measure but not by AS.
23
Spasticity was reduced at 2
weeks (p 0.0001),
24
4 weeks (p 0.001),
25
and 3
months (p 0.01)
16
after treatment.
One Class I study provided information regard-
ing the degree of spasticity improvement. This study
compared the effect of BoNT-A lower extremity
treatment combined with physiotherapy (PT) vs PT
alone and reported a mean increase in score on the
MAS (increased tone) after 6 months (approximately
half of an MAS point) in the control group, whereas
the BoNT-A group showed a mean decrease in MAS
Neurology 74 January 26, 2010 337
score (decreased tone) 6 months after injection (ap-
proximately 1 MAS point) (p 0.05).
26
Lower extremity functional improvement. A Class I
dose-comparison parallel study found a significant
dose-effect correlation in gait kinetics and kinematics
using 3-dimensional gait analysis.
27
The high-dose
group showed greater ankle dorsiflexion in stance
(p 0.001) and swing (p 0.05) at 4 weeks than at
baseline; these differences were not seen in the low-
dose group. The high-dose group also showed a
longer effect than the low-dose group, demonstrating
increased ankle dorsiflexion during stance at 12
weeks compared to baseline (p 0.01). A Class I
study
28
(n 40; spastic diparesis and hemiparesis)
reported significant functional lower extremity im-
provement by the Gross Motor Function Measure
(GMFM) walking dimension 12 weeks after
BoNT-A treatment in the lower extremities. Of pa-
tients treated with BoNT-A, 37% (7/19) (mean im-
provement 9.7%) showed improvement compared
with 7% (1/15) in the placebo group (p 0.04). A
Class II study that measured functional improve-
ment by the Goal Attainment Scale (GAS) reported
that 11 of 33 (33%) functional ability goals were
achieved by 7 of 11 children with CP after BoNT-A
treatment in the lower extremities (p 0.001).
29
Gait improvement was reported by using the Physi-
cian Rating Scale in a Class I study.
28
The mean im-
provement change was twice as great in the treated
group as in the placebo group 12 weeks after treat-
ment (p 0.02).
In contrast, 3 Class I placebo-controlled studies—
(n 64),
22
(n 125),
30
and (n 52)
31
using the
same BoNT-A preparation at slightly higher dose (30
U/kg vs 25 U/kg) and the same outcome measure
(GMFM) failed to demonstrate a significant func-
tional improvement, despite significant improve-
ments in ankle dorsiflexion
30
4 weeks after injections
and initial foot contact
31
16 weeks after injections.
Upper extremity functional improvement. The effect of
BoNT-A treatment on upper extremity function in
children with hemiplegic CP was measured using the
Quality of Upper Extremity Skills Test (QUEST) in
4 Class I studies.
17–20
One study (n 42),
18
which
compared the effect of a single low-dose, high-
concentration BoNT-A treatment plus occupational
therapy (OT) to OT alone, found upper extremity
functional improvement at 1 month (p 0.001)
and 3 months (p 0.001) but not at 6 months after
treatment. A larger proportion of treatment group
subjects showed more than 20% change above base-
line QUEST scores compared with the control group
at 1 month (67% vs 19%; p 0.004) and 3 months
(71% vs 33%; p 0.03) but not at 6 months. Appli-
cation of BoNT-A in this study was guided by elec-
trical stimulation. In another Class I study (n
29),
17
BoNT-A was injected into upper extremity
muscles using anatomic knowledge only to guide in-
jection location. The study used the same BoNT-A
formulation and similar doses, demonstrating an im-
provement in QUEST scores at 1 month ( p 0.05)
but not at 3 or 6 months after treatment. In a small
Class II study (n 14)
16
in which BoNT-A was in-
jected using anatomic knowledge only to guide injec-
tion location, despite an increase in maximum active
elbow and thumb extension (p 0.02 and p 0.03)
and a reduction of tone in the wrist and elbow (p
0.003 and p 0.01) 2 weeks after BoNT-A treat-
ment, only a modest improvement in hand function
was reported by the grasp-and-release score measure
at 12 weeks (p 0.01). However, no improvement
was noted in fine motor function, assessed by the
ability to pick up coins, and in some cases this ability
deteriorated temporarily. A Class I study (n 80)
demonstrated a much higher functional benefit when
BoNT-A was used in combination with OT than
when used alone.
19
Adverse events. Specific adverse events (AEs) were
reported in 17 studies (table e-1). All were transient
and did not require hospitalization. The most com-
mon AEs were localized pain, excessive weakness, un-
steadiness and increased falls, and fatigue. Urinary
incontinence was reported in 5 patients and dyspha-
gia in 2 patients. No deaths were reported.
Conclusions. For children with CP, BoNT-A is es-
tablished as an effective treatment to reduce spastic-
ity in the upper and lower extremities (Class I and II
evidence), but there is conflicting evidence regarding
functional improvement. The available evidence sug-
gests that BoNT-A is generally safe in children with
CP. However, severe generalized weakness may occur.
Recommendations.
1. For localized/segmental spasticity in the upper
and lower extremities of children with CP that
warrants treatment, BoNT-A should be offered as
an effective and generally safe treatment (Level
A). There is insufficient evidence to support or
refute the use of BoNT-A to improve motor func-
tion in this population (Level U).
2. There is insufficient evidence to support or refute
the use of BoNT-B, phenol, and alcohol injec-
tions as a treatment for spasticity in children with
spastic CP (Level U).
Clinical context. At the time of this writing, the Food
and Drug Administration (FDA) has not approved
BoNT-A for the treatment of spasticity in children.
BoNT-A is approved for the treatment of spasticity
in children and adults in Canada and several other
countries. Different formulations are not bioequiva-
338 Neurology 74 January 26, 2010
lent and may have different therapeutic efficacy and
safety profiles.
32,33
The AAN recently published an evidence-based
review on the safety and efficacy of BoNT for the
treatment of adult and childhood spasticity.
34
A Level A
recommendation was given for the use of BoNT-A as a
treatment of spasticity in the lower extremities (equinus
and hip adductor spasticity) and a Level B recommen-
dation was given for the treatment of spasticity in the
upper extremities of children with CP.
It is common practice to use BoNT-A in combi-
nation with serial casting, orthoses, and PT and
OT.
19
Typically, there is a 3- to 4-month clinical
response requiring repeated injections. Some experts
recommend using the smallest dose of BoNT-A and
avoiding injecting more frequently than every 3
months to minimize the risk of antibody resistance.
35
On the basis of postmarketing reports from its
Adverse Event Reporting System, the FDA released
on February 8, 2008, an “early communication” de-
scribing a “relative handful of systemic reactions” af-
ter BoNT injection (A or B) for limb spasticity
associated with CP. At the time of this writing, the
FDA has not completed the review of reported seri-
ous AEs related to BoNT, and has made the follow-
ing recommendations: 1) understand that potency
determinations expressed in “Units” or “U” differ
among the BoNT products; clinical doses expressed
in units are not comparable from one botulinum
product to the next; 2) be alert to the potential for
systemic effects following administration of BoNT
such as dysphagia, dysphonia, weakness, dyspnea, or
respiratory distress; 3) understand that these effects
have been reported as early as 1 day and as late as
several weeks after treatment; 4) provide patients and
caregivers with the information they need to be able
to identify the signs and symptoms of systemic effects
after receiving an injection of BoNT; 5) tell patients
they should receive immediate medical attention if they
have worsening or unexpected difficulty swallowing or
talking, trouble breathing, or muscle weakness.
Treatment of generalized spasticity. Seventy studies
using oral antispasticity medications and ITB were
identified, and 20 met selection criteria: 4 used diaz-
epam,
36–39
5 used dantrolene,
40
,e1-e4
1 used both,
e5
3
used oral baclofen,
7
,e6,e7
1 used tizanidine,
e8
and 6
used ITB.
e9-e14
Diazepam. Regarding diazepam treatment, we
identified 1 Class I study,
36
2 Class II studies,
37
,e5
1
Class III study,
38
and 1 Class IV study
39
(table e-2).
The doses and regimens used varied from 0.5 mg a
day to 5 mg TID. The Class I study (n 180) ran-
domized children with spastic CP weighing less than
15 kg to receive 1 of 2 doses of diazepam (0.5–1 mg
vs 1–2 mg) or placebo at bedtime. Improvements 3
weeks after treatment included a dose-dependent re-
duction of tone (p 0.001 as measured by the
MAS), increased passive range-of-motion angles
(p 0.001), and an increase in spontaneous move-
ments (p 0.001); no functional outcome measures
were reported. No daytime drowsiness was noted.
One Class II study
e5
compared the antispastic effect
of diazepam at a dose as high as 12 mg a day vs
dantrolene and placebo and found a subjective re-
duction of spasticity, which was even more notice-
able when diazepam and dantrolene were combined.
Although teachers and parents reported a subjective
improvement in activities of daily living, no stan-
dardized outcome measures were used. The other
Class II study
37
did not evaluate the antispasticity
effects of diazepam but mentioned improved behav-
ior and coordination (12/16 subjects improved on
active drug vs 2/16 on placebo).
Conclusions. Diazepam is probably effective for the
short-term treatment of spasticity in children with
CP (1 Class I study and 1 Class II study). None of
the studies formally addressed whether diazepam im-
proved motor function. Ataxia and drowsiness were
identified in the side-effect profile of most studies.
Recommendations. Diazepam should be considered as
a short-term antispasticity treatment in children with
CP (Level B). There is insufficient evidence to sup-
port or refute the use of diazepam to improve motor
function in this population (Level U).
Clinical context. The incidence of AEs associated with
diazepam, such as drowsiness, sedation, hypersalivation,
and weakness, are important limiting factors for long-
term use. Experts caution that the prolonged use of this
medication can produce physical dependence and rec-
ommend against abrupt discontinuation.
13
Dantrolene. One Class I,
40
2 Class II,
e1,e2
and 2
Class IV
e3,e4
studies met the selection criteria (table
e-2). The Class I study and 1 of the Class II
e1
studies
found conflicting results using a similar dose of 4 –12
mg/kg/day. The Class I study found no spasticity
improvement, no functional gain, and strength re-
duction (p 0.013). The Class II study,
e1
which
used a within-subject crossover design, found spastic-
ity improvement (not graded) with changes in the
neurologic examination (tone, tendon reflexes, clo-
nus) (p 0.01). Although there was no change in
gross motor function, activities of daily living (in-
cluding coordination in dressing and eating, control
of limbs in spontaneous play, stamina, freedom of
movement, and facilitation of therapy) improved
during the treatment period compared to baseline
(p 0.02). Improvement in reflexes (p 0.005)
and reduced scissoring (p 0.05) were reported in
the other Class II study.
e2
AEs were found in 30% to
Neurology 74 January 26, 2010 339
60% of the patients and included fatigue, irritability,
drowsiness, anorexia, and gastrointestinal symptoms
(e.g., vomiting and diarrhea). Four of 9 children who
continued taking dantrolene after the study was com-
pleted developed or had exacerbations of seizures.
e1
Conclusions. There is conflicting evidence regarding
the effectiveness of dantrolene in reducing spasticity
in children with CP. Dantrolene frequently causes
side effects such as weakness, drowsiness, and irrita-
bility in children with spastic CP.
Recommendation. There is insufficient evidence to
support or refute the use of dantrolene for the treat-
ment of spasticity in children with CP (Level U).
Clinical context. On the basis of the author panel’s
experience, dantrolene is rarely used in clinical practice
to reduce spasticity in children with CP. This may be
due to the lack of evidence in the literature to support
its efficacy and the general concern regarding its poten-
tial frequent and/or serious AEs. Although dantrolene
has been associated with hepatotoxicity,
e15
none of
the studies reviewed reported this AE in children,
perhaps due to the small number of subjects included
in these investigations.
Baclofen (oral). Two Class II studies
7
,e7
and 1 Class
IV study
e6
met selection criteria (table e-2). The Class II
studies showed conflicting results. A double-blind cross-
over trial in 20 children 2–16 years old receiving a dose
of 10 60 mg/day found a reduction in spasticity by
means of the AS (p 0.001).
7
After 28 days of treat-
ment, 14 patients improved at least 1 level and 5 im-
proved more than 1 level. Only 2 patients improved
while taking placebo. Spasticity improvement was dem-
onstrated by increased passive range of motion, seen in
11 patients (p 0.001). Ten patients who were able to
walk without assistance prior to treatment showed no
significant functional improvement. Furthermore, one
patient who relied on the spastic “crutch” to ambulate
showed walking impairment after treatment as the un-
derlying weakness was manifested. The other Class II
study,
e7
a double-blind placebo crossover trial (n 15)
using a similar dose and age group, was powered to de-
tect a difference as measured by the GAS but not for
other measures. Although improvement on the GAS
was reported (p 0.05), there was no improvement in
spasticity (modified TS) or functional benefit measured
using the Pediatric Evaluation of Disability Inventory at
12 weeks. The first study found AEs in 25% of patients
taking the medication, and no AEs were noticed in
those taking placebo. Side effects included somnolence
or sedation (20%) and hypotonia (15%) that resolved
after drug discontinuation. The second study did not
find a significant difference in AEs between groups.
Conclusions. There is conflicting Class II evidence
regarding the effectiveness of oral baclofen in re-
ducing spasticity and improving function in chil-
dren with CP. Systemic toxicity was found in
some patients.
Recommendation. There is insufficient evidence to
support or refute the use of oral baclofen for the
treatment of spasticity or to improve motor function
in children with CP (Level U).
Clinical context. Baclofen is widely used in clinical
practice to treat spasticity in children with CP. Ex-
perts recommend starting baclofen at the lowest pos-
sible dose (5–10 mg/day divided into 3 doses a day)
7
to minimize AEs like drowsiness and sedation. The
dose is gradually tapered until discontinuing because
abrupt discontinuation may cause withdrawal symp-
toms, including increased spasticity, hallucinations,
confusion, hyperthermia, and seizures.
13
Tizanidine. One small Class II
e8
placebo-
controlled parallel study treated 10 children with a
mean age of 4.1 years (range 2–15) with tizanidine
0.05 mg/kg/day and 30 children with placebo for 6
months (table e-2). A reduction in spasticity (p
0.0001) was found beginning 2 weeks after initiating
treatment and was sustained throughout the trial.
Postural and reflex improvement was also reported
(p 0.0001). No functional assessments were done.
No side effects were found, and liver enzymes remained
normal throughout the duration of the study.
Conclusions. Tizanidine is possibly effective to treat
spasticity in children with CP. No toxicity was found
in this small study.
Recommendations. Tizanidine may be considered for
the treatment of spasticity in children with CP (Level
C). There is insufficient evidence to support or refute
the use of tizanidine to improve motor function in
this population (Level U).
Clinical context. Tizanidine’s antispasticity effect has
been demonstrated in adults with multiple sclerosis
and spinal cord injury.
e16
Little information is avail
-
able to assist practitioners with the effective use of
this drug to treat spasticity in children. Because tiza-
nidine is extensively metabolized by the liver, hepatic
impairment may have a significant effect on its
pharmacokinetics. AEs related to tizanidine use in
adults include hypotension, sedation, asthenia, dry
mouth, dizziness, hallucinations, and hepatotoxic-
ity. Their incidence in pediatric patients has not
been studied.
Intrathecal baclofen pump. One Class III study
e9
and
5 Class IV studies
e10-e14
assessing ITB met inclusion
criteria (table e-3). All studies reported reduced spas-
ticity in children with CP.
Occasional headache, vomiting, lethargy, disori-
entation, agitation, irritability, and meningitis were
reported in 2 of the Class IV studies.
e10,e14
CSF leaks
(17%), seromas (29%), catheter malfunction (43%),
340 Neurology 74 January 26, 2010
and wound infection (39%) were reported more
frequently.
Conclusions. Data are inadequate concerning the use
of continuous ITB as an antispasticity treatment in
children with CP. CSF leaks, seromas, catheter-
related complications, and wound infection occur
frequently, and other, milder complications occur
less frequently.
Recommendation. There is insufficient evidence to
support or refute the use of continuous ITB for
the treatment of spasticity in children with CP
(Level U).
Clinical context. In 1996, ITB received FDA ap-
proval to treat spasticity of cerebral origin. A major
factor in the lack of Class I and II evidence may be
the difficulty of performing a randomized control
trial or crossover trial in subjects with ITB pumps.
Catheter-related complications, pump pocket collec-
tions, and wound infections remain a concern, and
ongoing efforts aim to reduce their incidence. One
retrospective study of the safety of ITB in children
(n 200) found that 11% had CSF leakage, 7% had
catheter-related problems, and 5.5% developed
infections.
e17
RECOMMENDATIONS FOR FUTURE RESEARCH
1. The AS has been used by most spasticity studies.
It measures muscle resistance to passive move-
ment but fails to describe the velocity of the
stretching movement and therefore is inadequate
to measure spasticity and distinguish it from
other types of hypertonia (e.g., dystonia). Stan-
dardized and validated spasticity scales and clini-
cally relevant measures sensitive enough to detect
change should be used to qualify and quantify
spasticity according to its current definition (e.g.,
Tardieu Spasticity Scale).
2. None of the oral medications used to treat spas-
ticity in children has been adequately tested for
safety and efficacy. There are minimal or no data
regarding the pharmacokinetics or appropriate
dosing parameters to treat children. These critical
questions deserve serious research efforts.
3. The effects of both spasticity and the treatment
of spasticity on activity and participation as de-
fined by the International Classification of
Function, Disability and Health of the World
Health Organization need to be studied in chil-
dren with CP.
e18
4. Although there is sufficient evidence to recom-
mend BoNT-A as an effective antispasticity treat-
ment in children with CP, its beneficial effects on
function, ease of caregiving, activity, and partici-
pation need to be established. More data about
safety and long-term effects are also needed.
5. The efficacy and safety of BoNT-B, phenol, and
alcohol chemodenervation as treatments for spas-
ticity in children with CP need to be determined.
6. The efficacy and safety of oral baclofen and the
long-term continuous intrathecal pump adminis-
tration of this medication need to be determined
in children with CP.
7. The few available treatments to reduce general-
ized spasticity are associated with a high incidence
of AEs and complications. There is an urgent
need for studies to establish the efficacy of the
current therapies and find additional safe and
effective treatments to help children affected by
generalized spasticity due to CP. A first step
could be to investigate medications that have
shown antispasticity effect in adult patients (e.g.,
gabapentin).
e19
DISCLOSURE
Dr. Delgado serves on the editorial board of Developmental Medicine and
Child Neurology; has received research support from Abbott, Sciele
Pharma, Inc., UCB, Allergan, Inc., the Hurst Foundation, the United
Cerebral Palsy Research & Educational Foundation, the Linda and Don
Carter Foundation, and the Crowley Carter Foundation; and estimates
that 50% of his clinical effort is spent on assessment and management of
motor disorders of childhood, which includes treating children with cere-
bral palsy with oral antispasticity medications, ITB, and botulinum toxin
injections. Dr. Hirtz reports no disclosures. Dr. Aisen serves as Medical
Director of Cerebral Palsy International Research Foundation. Dr. Ash-
wal serves on the editorial board of Pediatric Neurology; receives royalties
from publishing Pediatric Neurology: Principles and Practice (Elsevier,
2006); and receives research support from the NIH [R01 NS054001-01
(PI); 1R01NS059770-01A2 (PI)]. Dr. Fehlings has received speaker hon-
oraria and funding for travel from RX Media; receives research support
from Allergan, Inc., the Canadian Institutes of Health Research (CIHR),
Social Sciences and Humanities Research Services (SSHRS), the Bloor-
view Research Institute, and Physician Services Inc.; and estimates 50% of
her clinical effort is spent on spasticity intervention including botulinum
toxin injections and ITB. Dr. McLaughlin has received research support
from Medtronic, Inc., the NIH [NINDS NO1-HD-3–3351 (site PI), 1
U01 AR52171-01 (site PI), 1RC 1HD063838-01 (site PI)], and United
Cerebral Palsy Research & Education Foundation; and spends 10% of his
time evaluating and managing children with oral medications, baclofen
pumps, and botulinum toxin. Dr. Morrison serves on the editorial boards
of the Journal of Child Neurology and Pediatric Neurology; and estimates
that 1% of her clinical effort is spent on skin biopsy and 1% on
lumbar puncture. Dr. Shrader has received funding for travel from
Stryker; and has received research support from Stryker, Smith and
Nephew, Biomet, and VQ Orthocare. Dr. Tilton has served on a speakers’
bureau for and received speaker honoraria and funding for travel from
Medtronic, Inc.; has received research support from Allergan, Inc.; holds
patent rights on a non-neurologic application of botulinum toxin (under
consideration for licensure to her institution); and estimates 8%–10% of
her clinical effort is spent on botulinum toxin injections and 10%–15%
on intrathecal baclofen pumps. Dr. Vargus-Adams receives research sup-
port from the NIH [K23 HD049552 (PI), NICHD-2005-13-2 (Co-I),
U01 AR057940-01 (Co-I)] and the Ohio Division of Emergency Medical
Systems; her immediate family member holds financial interest in Novar-
tis, Dermik Laboratories, Inc., and Proctor & Gamble and holds equity
interest in Proctor & Gamble, Ligand, and GlucoWatch; and estimates
3% of her clinical effort is spent on intrathecal baclofen test dose and
management, 15% on botulinum toxin injections, and 2% on phenol
nerve blocks.
Neurology 74 January 26, 2010 341
DISCLAIMER
This statement is provided as an educational service of the American
Academy of Neurology. It is based on an assessment of current scientific
and clinical information. It is not intended to include all possible proper
methods of care for a particular neurologic problem or all legitimate crite-
ria for choosing to use a specific procedure. Neither is it intended to
exclude any reasonable alternative methodologies. The AAN recognizes
that specific patient care decisions are the prerogative of the patient and
the physician caring for the patient, based on all of the circumstances
involved. The clinical context section is made available in order to place
the evidence-based guideline(s) into perspective with current practice
habits and challenges. No formal practice recommendations should be
inferred.
CONFLICT OF INTEREST
The American Academy of Neurology is committed to producing inde-
pendent, critical and truthful clinical practice guidelines (CPGs). Signifi-
cant efforts are made to minimize the potential for conflicts of interest to
influence the recommendations of this CPG. To the extent possible, the
AAN keeps separate those who have a financial stake in the success or
failure of the products appraised in the CPGs and the developers of the
guidelines. Conflict of interest forms were obtained from all authors and
reviewed by an oversight committee prior to project initiation. AAN lim-
its the participation of authors with substantial conflicts of interest. The
AAN forbids commercial participation in, or funding of, guideline
projects. Drafts of the guideline have been reviewed by at least three AAN
committees, a network of neurologists, Neurology
®
peer reviewers, and
representatives from related fields. The AAN Guideline Author Conflict
of Interest Policy can be viewed at www.aan.com.
Received April 23, 2009. Accepted in final form October 9, 2009.
REFERENCES
1. Yeargin-Allsopp M, Van Naarden Braun K, Doernberg
BA, Benedict RE, Kirby RS, Durkin MS. Prevalence of
cerebral palsy in 8-year-old children in three areas of the
United States in 2002: a multisite collaboration. Pediatrics
2008;121:547–554.
2. Paneth N, Hong T, Korzeniewski S. The descriptive epi-
demiology of cerebral palsy. Clin Perinatol 2006;33:251–
267.
3. Boyle CA, Yeargin-Allsopp M, Doernberg NS, Holmgreen
P, Murphy CC, Schendel DE. Prevalence of selected de-
velopmental disabilities in children 3–10 years of age: the
Metropolitan Atlanta Developmental Disabilities Surveil-
lance Program, 1991. MMWR CDC Surveill Summ
1996;45:1–14.
4. Ronan S, Gold JT. Nonoperative management of spastic-
ity in children. Childs Nerv Syst 2007;23:943–956.
5. Sanger TD, Delgado MR, Gaebler-Spira D, Hallett M,
Mink JW. Classification and definition of disorders caus-
ing hypertonia in childhood. Pediatrics 2003;111:e89
e97.
6. Damiano DL, Quinlivan J, Owen BF, Shaffrey M, Abel
MF. Spasticity versus strength in cerebral palsy: relation-
ships among involuntary resistance, voluntary torque, and
motor function. Eur J Neurol 2001;8 suppl 5:40 49.
7. Milla PJ, Jackson AD. A controlled trial of baclofen in
children with cerebral palsy. J Int Med Res 1977;5:398
404.
8. Ward A. Long-term modification of spasticity. J Rehabil
Med 2003;35:6065.
9. Ashworth B. Preliminary trial of carisoprodol in multiple
sclerosis. Practitioner 1964;192:540–542.
10. Bohannon RW, Smith MB. Interrater reliability of a mod-
ified Ashworth scale of muscle spasticity. Phys Ther 1987;
67:206–207.
11. Nielsen JF, Sinkjaer T. A comparison of clinical and labo-
ratory measures of spasticity. Mult Scler 1996;1:296–301.
12. Haugh AB, Pandyan AD, Johnson GR. A systematic re-
view of the Tardieu Scale for the measurement of spastic-
ity. Disabil Rehabil 2006;28:899–907.
13. Verrotti A, Greco R, Spalice A, Chiarelli F, Iannetti P.
Pharmacotherapy of spasticity in children with cerebral
palsy. Pediatr Neurol 2006;34:1–6.
14. Gracies JM, Elovic E, McGuire J, Simpson D. Traditional
pharmacological treatments for spasticity: part I: local
treatments. Muscle Nerve 1997;6 (suppl):S61–S91.
15. Gracies JM, Nance P, Elovic E, McGuire J, Simpson DM.
Traditional pharmacological treatments for spasticity: part
II: general and regional treatments. Muscle Nerve 1997;6
(suppl):S92–S120.
16. Corry IS, Cosgrove AP, Walsh EG, McClean D, Graham
HK. Botulinum toxin A in the hemiplegic upper limb: a
double-blind trial. Dev Med Child Neurol 1997;39:185–
193.
17. Fehlings D, Rang M, Glazier J, Steele C. An evaluation of
botulinum-A toxin injections to improve upper extremity
function in children with hemiplegic cerebral palsy. J Pedi-
atr 2000;137:331–337.
18. Lowe K, Novak I, Cusick A. Low-dose/high-concentration
localized botulinum toxin A improves upper limb move-
ment and function in children with hemiplegic cerebral
palsy. Dev Med Child Neurol 2006;48:170 –175.
19. Wallen M, O’Flaherty SJ, Waugh MC. Functional out-
comes of intramuscular botulinum toxin type a and occu-
pational therapy in the upper limbs of children with
cerebral palsy: a randomized controlled trial. Arch Phys
Med Rehabil 2007;88:1–10.
20. Kawamura A, Campbell K, Lam-Damji S, Fehlings D. A
randomized controlled trial comparing botulinum toxin A
dosage in the upper extremity of children with spasticity.
Dev Med Child Neurol 2007;49:331–337.
21. Ackman JD, Russman BS, Thomas SS, et al. Comparing
botulinum toxin A with casting for treatment of dynamic
equinus in children with cerebral palsy. Dev Med Child
Neurol 2005;47:620627.
22. Moore AP, Ade-Hall RA, Smith CT, et al. Two-year
placebo-controlled trial of botulinum toxin A for leg spas-
ticity in cerebral palsy. Neurology 2008;71:122–128.
23. Bjornson K, Hays R, Graubert C, et al. Botulinum toxin
for spasticity in children with cerebral palsy: a comprehen-
sive evaluation. Pediatrics 2007;120:49–58.
24. Corry IS, Cosgrove AP, Duffy CM, McNeill S, Taylor
TC, Graham HK. Botulinum toxin A compared with
stretching casts in the treatment of spastic equinus: a ran-
domised prospective trial. J Pediatr Orthop 1998;18:304
311.
25. Mall V, Heinen F, Siebel A, et al. Treatment of adductor
spasticity with BTX-A in children with CP: a randomized,
double-blind, placebo-controlled study. Dev Med Child
Neurol 2006;48:10–13.
26. Reddihough DS, King JA, Coleman GJ, et al. Functional
outcome of botulinum toxin A injections to the lower
limbs in cerebral palsy. Dev Med Child Neurol 2002;44:
820827.
27. Polak F, Morton R, Ward C, Wallace WA, Doderlein L,
Siebel A. Double-blind comparison study of two doses of
342 Neurology 74 January 26, 2010
botulinum toxin A injected into calf muscles in children
with hemiplegic cerebral palsy. Dev Med Child Neurol
2002;44:551–555.
28. Ubhi T, Bhakta BB, Ives HL, Allgar V, Roussounis SH.
Randomised double blind placebo controlled trial of the
effect of botulinum toxin on walking in cerebral palsy.
Arch Dis Child 2000;83:481–487.
29. Steenbeek D, Meester-Delver A, Becher JG, Lankhorst GJ.
The effect of botulinum toxin type A treatment of the
lower extremity on the level of functional abilities in chil-
dren with cerebral palsy: evaluation with goal attainment
scaling. Clin Rehabil 2005;19:274–282.
30. Baker R, Jasinski M, Maciag-Tymecka I, et al. Botulinum
toxin treatment of spasticity in diplegic cerebral palsy: a
randomized, double-blind, placebo-controlled, dose-
ranging study. Dev Med Child Neurol 2002;44:666 675.
31. Kanovsky P, Bares M, Severa S, et al. Functional benefit of
botulinum toxin (Dysport) in the treatment of dynamic
equinus cerebral palsy spasticity: a prospective, multi-
center, double-blind, placebo-controlled study. Ces A Slov
Neurol Neurochir 2004;67:16–23.
32. Wenzel R, Jones D, Borrego JA. Comparing two botuli-
num toxin type A formulations using manufacturers’ prod-
uct summaries. J Clin Pharm Ther 2007;32:387– 402.
33. Simonetta Moreau M, Cauhepe C, Magues JP, Senard JM.
A double-blind, randomized, comparative study of Dys-
port vs. Botox in primary palmar hyperhidrosis. Br J Der-
matol 2003;149:1041–1045.
34. Simpson DM, Gracies JM, Graham HK, et al. Assessment:
botulinum neurotoxin for the treatment of spasticity (an
evidence-based review): report of the Therapeutics and
Technology Assessment Subcommittee of the American
Academy of Neurology. Neurology 2008;70:1691–1698.
35. Tilton AH. Management of spasticity in children with ce-
rebral palsy. Semin Pediatr Neurol 2004;11:58 65.
36. Mathew A, Mathew MC, Thomas M, Antonisamy B. The
efficacy of diazepam in enhancing motor function in chil-
dren with spastic cerebral palsy. J Trop Pediatr 2005;51:
109–113.
37. Engle HA. The effect of diazepam (Valium) in children
with cerebral palsy: a double-blind study. Dev Med Child
Neurol 1966;8:661–667.
38. Holt KS. The use of diazepam in childhood cerebral palsy.
Report of a small study including electromyographic ob-
servations. Ann Phys Med 1964;suppl:16 –24.
39. Hiller CJ, Mason JL, Jr. Therapeutic test of diazepam (va-
lium) in cerebral palsy.JSCMedAssoc 1966;62:306
309.
40. Joynt RL, Leonard JA, Jr. Dantrolene sodium suspension
in treatment of spastic cerebral palsy. Dev Med Child
Neurol 1980;22:755–767.
Neurology 74 January 26, 2010 343
    • "Ботулинотерапия также была рекомендована экспертами Американской академии неврологии и Обществом детских неврологов США как «эффективный и в целом безопасный метод снижения локальной спастичности у детей с ДЦП». Однако признано, что данных о влиянии ботулинотерапии на улучшение моторных функций при ДЦП недоста- точно [6]. Для достижения функциональных улучшений ботулинотерапия всегда должна дополняться дальнейшим проведением реабилитационных мероприятий [7, 8]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Our aim was to analyze the dosages of Abobotulinum toxin A used for each muscle in the clinically effective and safe repeated multilevel injections in CP children, and the intervals between injections. Methods: Retrospective analysis of 229 injection sessions into 359 muscles of the upper and 361 muscles of the lower extremities in 133 children (2-18 years) with spastic CP. Analysis included only patients who were injected for the first time and demonstrated decrease of spasticity in injected muscles according to modified Ashworth and/or Tardieu scales without significant side effects 2-4 weeks after injections. Motor deficit according to GMFCS was: GMFCS I--16(12%) children, GMFCS II--26 (19.6%), GMFCS III--43 (32.3%), GMFCS IV--30 (22.6%), GMFCS V--18 (13.5%). Repeated injections (up to 5 sessions) were done in 59 children. Maximum follow-up perion was 22 months. 40 patients (30.1%) had one-sided injections, 93 (69.9%)--two-sided, 125 (94%)--multilevel injections. Results: We presented minimal and maximal dosages, interquartile ranges for each injected muscle, also "off-label" and our proposition of per-segment calculation of dosages in multilevel injections in CR. We also demonstrated the stability of intervals between repeated injections and dosages per kg in a patient. These results are compared with the official Russian and international recommendations of BTX-A treatment for children. Conclusion: We presented our experience of BTX-A dosages calculation for the spastic CP treatment which could be used as a recommendation and guide for the multilevel injections treatment according to the aims of rehabilitation, spasticity level, muscle size and motor deficit of a concrete patient.
    Full-text · Article · Mar 2015
    • "Tizanidine is possibly effective, but there are insufficient data on its effect on motor function and its side-effect profile. There are insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity has been frequently reported.[17] A survey in the USA showed 56% of the families of children with CP using Complementary and Alternative Medicine which included massage therapy and aqua therapy as the most common.[24] "
    [Show abstract] [Hide abstract] ABSTRACT: Cerebral palsy (CP) is the leading cause of childhood disability affecting cognitive function and developments in approximately 1.5 to 3 cases per 1000 live births. Based on Ayurvedic therapeutic principles, CP patients were subjected to Abhyanga (massage) with Moorchita Tila Taila (processed sesame oil) and Svedana (fomentation) with Shastikashali Pinda Sveda (fomentation with bolus of drugs prepared with boiled rice). Study group received Mustadi Rajayapana Basti (enema with herbal decoction) and Baladi Yoga (a poly-herbo-mineral formulation), while the placebo group received Godhuma Vati (tablet prepared with wheat powder) and saline water as enema. Treatment with Mustadi Rajayapana Basti and Baladi Yoga improved the activities of daily life by 8.79%, gross motor functions by 19.76%, and fine motor functions 15.05%, and mental functions like memory retention got improved by 15.43%. The placebo group showed an improvement of 0.21% in daily life activities, 2.8% in gross motor, and 2.4% in fine motor functions. Mustadi Rajayapana Basti and Baladi Yoga proved to be more supportive in improving the motor activities and gross behavioral pattern. Further clinical trials are required to evaluate and validate the maximum effect of the combination therapy in a large sample with repetition of the courses for longer duration.
    Full-text · Article · Mar 2014
    • "Специалистами Американской академии неврологии и Обществом детских неврологов США ботулинотерапия БТА была рекомендована «как эффективный и в целом безопасный метод снижения локальной спастичности у детей с ДЦП». Однако признано, что «данных о влиянии ботулинотерапии на улучшение моторных функций при ДЦП недостаточно» [4]. В связи с этим было рекомендовано продолжить всестороннее изучение результатов применения ботулинотерапии в сочетании с другими методами реабилитации и лечения детей и взрослых с ДЦП. "
    Full-text · Article · Nov 2013
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