Abstract
Background: Although botulinum toxin A is frequently used to augment
serial casting in the treatment of soft-tissue contractures in children with
cerebral palsy, its effectiveness for this purpose has not been evaluated. The
purpose of the present study was to determine whether botulinum toxin A
injection increases the efficacy of serial casting.
Methods: A prospective, randomized trial was undertaken to compare
serial casting only with serial casting combined with botulinum toxin A
(Botox) injection for the treatment of ankle equinus contractures in
twenty-three children with cerebral palsy. Range-of-motion testing, spasticity
assessment, and computerized gait analysis were performed as long as twelve
months after treatment.
Results: There was no difference between the groups with regard to
the duration of casting required to correct the equinus contracture. Both
groups maintained a significant improvement in passive ankle dorsiflexion
throughout the follow-up period, although the group managed with casting and
Botox had a significant loss of dorsiflexion when the values at six, nine, and
twelve months were compared with the value at three months. Peak dorsiflexion
during the stance and swing phases was significantly improved in both groups
at three months but only in the group managed with casting alone at twelve
months. Plantar flexor spasticity was significantly decreased at three months
in both groups, but it was significantly decreased at six, nine, and twelve
months only in the group managed with casting alone. Spasticity was
significantly greater in the group managed with casting and Botox than it was
in the group managed with casting only at six, nine, and twelve months.
Conclusions: The present study demonstrates the efficacy of serial
casting in the treatment of equinus contractures in children with cerebral
palsy who are able to walk. Contrary to our hypothesis, the addition of
botulinum toxin A to a serial casting regimen led to earlier recurrence of
spasticity, contracture, and equinus during gait. The results of the present
study suggest that botulinum toxin combined with serial casting for the
treatment of fixed contractures will lead to a recurrence of plantar flexor
spasticity and equinus contracture by six months in this patient population.
While previous research has indicated that the injection of botulinum toxin A
is superior to casting for the treatment of dynamic equinus, the present study
suggests that serial casting alone is preferable for the treatment of fixed
equinus contractures in children with cerebral palsy.
Level of Evidence: Therapeutic study, Level I-1a
(randomized controlled trial [significant difference]). See Instructions to
Authors for a complete description of levels of evidence.
Botulinum toxin A has been used for the treatment of spasticity in children
with cerebral palsy since 1990. When injected intramuscularly, botulinum toxin
A effectively denervates a muscle by inhibiting the release of acetylcholine
at the neuromuscular
junction1. It
decreases a spastic muscle's ability to generate forceful contractions, thus
decreasing the strength of the spastic response and allowing the muscle to
function in a more lengthened
position2. The
clinical effect of botulinum toxin A lasts for three to six months.
Since botulinum toxin A works to decrease the force of muscle contraction
or spasticity, it is commonly used to treat dynamic abnormalities rather than
fixed contractures in children with cerebral
palsy3-5.
Botulinum toxin A is also commonly used in conjunction with serial casting for
the treatment of fixed contractures, although the efficacy of these combined
treatments has not been documented in the literature. Anecdotal evidence
suggests that the addition of botulinum toxin A to a serial casting regimen
appears to enhance the speed of resolution of contracture and may delay the
recurrence of contracture. Although there have been a few reports in the
literature in which casting was compared with the injection of botulinum toxin
A for the treatment of dynamic
equinus6,7,
we are aware of no studies that have examined the impact of botulinum toxin A
on serial casting for the treatment of fixed equinus contractures.
Serial casting involves immobilization of a muscle in a lengthened position
for a prolonged period of time, thereby gradually increasing the extensibility
of the muscle and surrounding soft-tissue structures. The mechanism by which
this process occurs has been theorized to be an increase in both the length
and the number of sarcomeres in the target
muscle8.
Children with cerebral palsy often have a combination of fixed contracture
and spasticity in the triceps
surae9. Spasticity
can make it difficult for some children to tolerate immobilization in serial
casts. By combining the injection of botulinum toxin A for the reduction of
spasticity with serial casting for the treatment of an underlying contracture,
it may be possible to decrease the length of time that a child must be treated
with immobilization in a cast. Additionally, the range of motion and the
amount of functional improvement that are achieved may be greater and may be
maintained for a longer period of time than is the case with serial casting
alone.
The main objective of the present study was to determine whether better
outcomes are achieved when botulinum toxin A is added to the casting regimen
in the management of children with cerebral palsy who have plantar flexion or
equinus contractures as well as dynamic spasticity. We hypothesized that
patients who received botulinum toxin A injections in combination with serial
casting would have significantly faster resolution of contracture, greater
reduction of equinus during gait, greater reduction of spasticity, greater
improvement in gross motor function, and longer maintenance of these benefits
when compared with patients who received casting alone.
Aprospective, randomized trial was performed to compare serial casting
alone with serial casting combined with injections of botulinum toxin A for
the treatment of ankle equinus contractures in children with cerebral palsy.
Institutional review board approval was obtained prior to initiation of the
study.
Subjects
Twenty-three children with cerebral palsy participated in the study. The
study group included twelve boys and eleven girls with a mean age of 7.1
± 3.0 years (range, 4.3 to 13.8 years). Nine subjects had hemiplegia,
thirteen had diplegia, and one had quadriplegia. All subjects were able to
walk, although four subjects used a walker and one used forearm crutches.
Children were recruited from the Orthopaedic Clinic at the authors'
institution as well as from state-funded physical and occupational therapy
clinics for children with orthopaedic and neurological conditions (California
Children's Services Medical Treatment Units). The criteria for eligibility for
inclusion in the study were (1) a diagnosis of cerebral palsy with associated
spastic diplegia, hemiplegia, or quadriplegia, (2) an age of four years or
more, (3) a plantar flexion or equinus contracture associated with a decreased
range of passive dorsiflexion of =0° with the knee extended, (4) an
ability to walk independently with or without assistive devices (i.e., walker,
crutches, or cane), and (5) no history of orthopaedic surgery or selective
dorsal rhizotomy in the preceding twelve months. Children with so-called mixed
cerebral palsy, ataxia, or athetosis were excluded from participation.
Procedures
Informed consent was obtained from the parents or guardians of all subjects
prior to enrollment. All children underwent initial assessments that were
conducted by two experienced physical therapists (S.A.R. and A.F.-B.). These
assessments included measurement of range of motion and spasticity (S.A.R.);
administration of dimensions C (crawling and kneeling), D (standing), and E
(walking, running, and jumping) of the Gross Motor Function
Measure10,11
(A.F.-B. and S.A.R.); and a complete computerized gait analysis (S.A.R.). Gait
analysis included measurement of three-dimensional bilateral joint kinematics
with use of a seven-camera VICON motion capture system and data processing
with use of VICON Clinical Manager software (Oxford, England). After initial
assessment, children were randomly assigned (with use of a random-number
generator) to one of two treatment groups: one group was to be managed with
serial casting for equinus contracture following the injection of Botox
(Allergan, Irvine, California), and the other group was to be managed with
serial casting only. All investigators, except for the study coordinator
(S.A.R.) and the physician performing the Botox injections (R.M.K.), were
blinded with regard to the subjects' group assignments.
In the group that was managed with casting combined with Botox, Botox
injections were given by a single physician who was one of the principal
investigators (R.M.K.). Botox was injected into the affected gastrocnemius
muscle or muscles of all of the subjects in this group. Botox was also
injected bilaterally into the soleus in one subject and into the medial
hamstrings in two others. A dosage of 8 units per kilogram of body weight was
used (with a maximum dose of 400 units per subject), with the toxin divided
between the various injection sites. Botox injection was followed by serial
casting for equinus contracture, which was initiated one to three weeks after
the injection. In the group that was managed with casting only, serial casting
was started immediately after the initial assessment. Subjects in both groups
who had tight hamstrings and a potential to crouch were supplied with knee
immobilizers for nighttime use.
Serial casting for equinus contracture was performed by a physical
therapist and a physical therapy aide who were experienced with the technique.
The same therapist and aide performed the casting for all children. Short-leg
fiberglass walking casts were applied and changed every two weeks until
=5° of dorsiflexion was reached with the knee extended. Casts were
applied with the ankle in neutral supination-pronation and in maximum passive
dorsiflexion. Casts were lined with stockinette and Webril, and polycushion
was applied over osseous prominences. Support for the longitudinal arch was
incorporated into the cast, and an extension was added for support under the
toes. When necessary, posting was added under the hindfoot (when the ankle was
plantar flexed) or the forefoot (when the ankle was dorsiflexed) to allow the
patient to walk without hyperextension or excessive flexion of the knee. The
children used cast shoes during walking. Children with hemiplegia were managed
with casting on the affected side only, whereas those with diplegia and
quadriplegia were managed with bilateral casting (except in the case of one
child with asymmetric diplegia, who was managed with unilateral casting
because of a unilateral contracture). Once casting was complete, the subjects
were given new bivalved fiberglass splints, positioned in maximum passive
dorsiflexion, for nighttime use. The subjects were provided with ankle-foot
orthoses for daytime wear upon completion of serial casting. The type of
ankle-foot orthosis was determined by the treating physician and physical
therapist and therefore varied among the subjects. All orthoses were
fabricated by the same certified orthotist.
Passive dorsiflexion was measured in degrees and was recorded by the same
physical therapist at the time of each cast change with use of a standard
goniometer. Plantar flexor spasticity was also recorded by the same therapist
at the time of each cast change and was rated with use of the modified
Ashworth scale12.
According to this system, a muscle's resistance to passive stretch is rated on
a scale of 0 to 4, with 0 indicating no spasticity and 4 indicating rigidity
in flexion or extension. An additional grade of 5 was added to the scale to
indicate a fixed contracture that prohibited the assessment of underlying
spasticity.
Reassessments were conducted at three, six, nine, and twelve months after
the start of treatment. These assessments included repeat range-of-motion and
spasticity measurements, with all measurements being made by the same
investigator (S.A.R.). Administration of dimensions C, D, and E of the Gross
Motor Function Measure was also conducted at these time-points. The Gross
Motor Function Measure tests were conducted by two physical therapists (S.A.R.
and A.F.-B.) who were experienced with the use of this system. Computerized
gait analysis was repeated at the three and twelve-month time-points.
Subjects who were receiving physical therapy continued their regular
regimen throughout the course of the study. The treating physical therapists
completed a treatment log for each subject in order to document the total
number of hours of therapy and the activities performed at each session.
Parent-reported compliance with brace wear also was recorded for each
child.
Statistical Methods
The demographic characteristics and baseline measures in the two groups
were compared with use of the nonparametric Mann-Whitney rank-sum test and
Fisher's exact test. As the two groups had similar proportions of subjects
with unilateral and bilateral involvement, the statistical analyses were
performed with each casted limb being considered as a unit.
The outcome measures included the duration of casting required for
contracture resolution; differences in passive dorsiflexion, spasticity, and
peak dorsiflexion during the stance and swing phases for each limb; and Gross
Motor Function Measure scores. The Mann-Whitney rank-sum test was used to
compare these outcome measures between the two groups. We also studied the
change in these outcome measures over time. The nonparametric Wilcoxon and
Friedman tests for matched data were used to test for significance within each
group. The level of significance was set at p < 0.05.
The groups did not differ in terms of age, gender, walking ability, type of
cerebral palsy, or amount of physical therapy received
(Table I). Three children
(including one in the casting-plus-Botox group and two in the casting-only
group) had undergone previous multiple-level orthopaedic surgical procedures
that had included bilateral gastrocnemius recession. In all three cases, the
previous procedures had been performed at least four years (4.0, 4.6, and 6.4
years, respectively) before enrollment in the present study. These subjects
were included in the statistical analyses because the number of these subjects
was small and because of the length of time since the procedures had been
performed. None of the children in the present study had undergone previous
selective dorsal rhizotomy.
The groups did not differ with respect to any of the baseline measures
(Table II). There were no
complications related to either the serial casting or the Botox injections.
Five of eleven subjects in the casting-plus-Botox group and five of twelve in
the casting-only group received physical therapy during the course of the
study. Two subjects in each group showed poor compliance or noncompliance with
orthotic wear after casting. The data on these subjects were included in all
statistical analyses. All other subjects were fully compliant. One subject in
each group withdrew from the study after the six-month assessment and
underwent surgical lengthening of the triceps surae. An additional subject
from the casting-only group withdrew from the study after six months and
underwent bilateral lengthening of the Achilles tendon at the recommendation
of her physician, although no recurrent contracture had been detected at the
time of the six-month assessment.
The duration of casting did not differ between the two groups (p = 0.76).
The mean duration of casting was 6.0 ± 3.1 weeks in the
casting-plus-Botox group and 5.5 ± 1.5 weeks in the casting-only group.
The duration of casting also was similar when the equinus contractures were
defined as mild (=10°) and severe (>10°); specifically, the mean
duration of casting for subjects with mild contractures was 5.2 ± 2.7
weeks in the casting-plus-Botox group and 5.5 ± 1.7 weeks in the
castingonly group, and the mean duration of casting for subjects with severe
contractures was 6.4 ± 3.4 weeks in the casting-plus-Botox group and
5.5 ± 1.4 weeks in the casting-only group.
With the numbers available, there were no significant differences between
the two groups with regard to the magnitude of improvement in any of the
outcome measures during the casting period. At the three-month evaluation,
both groups had significant improvement in passive and dynamic dorsiflexion as
well as decreased spasticity (Table
III).
Both groups maintained a significant increase in passive dorsiflexion when
the values at six, nine, and twelve months were compared with the baseline
value. However, the casting-plus-Botox group had a significant decrease in
passive dorsiflexion when the values at six, nine, and twelve months were
compared with the value at three months. Post hoc analysis indicated that the
change occurred between the three and six-month time-points. There were no
significant differences between the groups with regard to passive dorsiflexion
at any time-point (Fig. 1).
Peak dorsiflexion during the stance and swing phases decreased
significantly between three and twelve months in the casting-plus-Botox group.
The casting-only group maintained improved dorsiflexion during the stance and
swing phases at twelve months. With the numbers available, the differences
between the groups at twelve months were not significant (Figs.
2 and
3).
The significant reduction in plantar flexor spasticity at three months was
lost over time in the casting-plus-Botox group. Post hoc analysis suggested
that the change occurred between the three and six-month time-points, although
the difference was not significant because of the small sample size. The
significant reduction in spasticity from baseline was maintained in the
casting-only group at six, nine, and twelve months. Plantar flexor spasticity
was significantly greater in the casting-plus-Botox group than in the
casting-only group at six, nine, and twelve months
(Fig. 4).
The Gross Motor Function Measure scores did not change significantly in
either group during the first three months
(Table III), but they did
increase significantly after the first three months, such that the change from
baseline was significant starting at the six-month time-point in both groups
(Fig. 5). With the numbers
available, the amount of change did not differ significantly between the two
groups.
Although botulinum toxin A is widely used to augment serial casting in the
treatment of fixed contractures in children with cerebral palsy, the present
study is the first to evaluate its effectiveness when used for this purpose.
The addition of botulinum toxin A did not decrease the duration of serial
casting in the present study. It also had no effect on contracture correction,
improvement in dorsiflexion during gait, or decrease in plantar flexor
spasticity immediately after treatment. Both groups experienced significant
short-term improvements, regardless of the degree of contracture that had been
present before treatment. Because casts were changed and measurements were
taken at two-week intervals, it is possible that one group may have
experienced an earlier resolution of contracture during the last two-week
interval that we were unable to detect. However, even if such a difference
existed, it would not have reduced the total number of cast changes
needed.
Contrary to our hypothesis, the addition of botulinum toxin A to a serial
casting regimen appeared to lead to earlier recurrence of spasticity,
contracture, and equinus during gait in the present study. The casting-only
group experienced a significant benefit in the form of improved passive and
dynamic dorsiflexion and decreased plantar flexor spasticity, which lasted for
a longer period of time than was the case in the casting-plus-Botox group. The
difference in response between the two groups was not related to age, the
amount of physical therapy received, or compliance with bracing. Despite the
earlier recurrence of equinus in the casting-plus-Botox group, both groups
showed significant improvement in gross motor function that was maintained
over the twelve-month period.
Our findings differ from those of previous studies that demonstrated
improved, longer-lasting results in association with injections of botulinum
toxin A than in association with serial casting
alone6,7.
However, those studies examined shorter-term effects (twelve and twenty-four
weeks, respectively) than did the present study. The discrepancy between the
results of the current study and those of previous reports cannot be explained
by differences in the dosage of Botox. The dosage used in the current study (8
U/kg) was equal to or greater than those used in the studies by Flett et
al.7 and Corry et
al.6 (4 to 8 U/kg
and 6 to 8 U/kg, respectively). The response to botulinum toxin A is thought
to be
dosage-dependent13,14,
and the response therefore would have been expected to be greater and of
longer duration in the current study. However, previous studies regarding
botulinum toxin A and serial casting excluded patients with fixed
contractures, with serial casting being used only for spasticity
reduction3,4.
There may have been differences in architecture or structure between muscles
with and without contracture that accounted for the different responses
observed.
In the current study, equinus contracture partially recurred and spasticity
and dynamic equinus returned almost to baseline levels between three and
twelve months in the casting-plus-Botox group whereas all variables were
improved at all time-points in the casting-only group. This finding suggests
that serial casting was effective for reducing the fixed portion of the
equinus for all subjects, whereas recurrent spasticity led to earlier
recurrence of dynamic and static equinus in the casting-plus-Botox group.
Return of muscle function after the injection of botulinum toxin A occurs
through extensive sprouting from nerve terminals. Axonal sprouting peaks at
approximately eight weeks after the injection of botulinum toxin
A15. At that time,
function in the original terminals returns whereas function in the sprouts
declines, with the full process being completed by about twelve weeks after
the injection. There is evidence from animal studies that polyneuronal
innervation (contact of a given muscle fiber with axon terminals from several
motor neurons, similar to that seen during prenatal development) occurs in
response to nerve
injury14,16.
A process of synapse elimination follows in which axons decrease their
connections over time until each endplate is eventually innervated by a single
axon. It is unclear how long polyneuronal innervation persists, with one study
showing that it was present for as long as two years in
frogs14. It has
been suggested that the rate of synapse elimination may be dependent on use or
disuse of the
connections17.
Therefore, immobilization of a muscle recovering from denervation (as during
serial casting) may delay synapse elimination and prolong polyneuronal
innervation. There has been extensive research related to neuronal recovery
after physical
injury14,16-19
but very little research related to recovery from chemical denervation as
occurs after the injection of botulinum toxin A. Serial casting for the
treatment of fixed contractures is known to result in an increase in the
number of sarcomeres in series for a given
muscle20. The
effect of changes in muscle architecture caused by serial casting combined
with changes in the structure, organization, and function of the recovering
neuromuscular junction after the injection of botulinum toxin A have not been
studied. These factors may have been related to the earlier recurrence of
spasticity as well as static and dynamic equinus in the casting-plus-Botox
group in the current study. Additional study is needed to elucidate these
mechanisms.
The current study included patients in whom the plantar flexor spasticity
was mild to moderate, with an average grade of 2.3 on the modified Ashworth
scale (which included a grade of 5 for fixed contractures). Casts were applied
with great attention to positioning and with adequate padding and were
monitored closely by the physical therapist. Therefore, all subjects tolerated
serial casting well, without skin irritation or breakdown. Patients with more
severe spasticity or dystonia, however, may not tolerate serial casting
because of skin problems. Despite the findings of the current study, such
patients may benefit from botulinum toxin A injections combined with serial
casting to maximize tolerance of the casting procedure itself. This benefit
may outweigh the risk of early recurrence of spasticity in these cases.
The small sample size was a limitation of this study. However, the data
were sufficient to show some important differences between and within the
groups over time. Even when significance was not reached, a trend of loss of
improvement was seen for all measures of static and dynamic equinus and
plantar flexor spasticity in the casting-plus-Botox group. Another limitation
was the lack of establishment of reliability for the range of motion,
spasticity, and Gross Motor Function Measure assessments. We did not perform
formal reliability testing, but all range-of-motion and spasticity
measurements were performed with use of a consistent technique by the same
physical therapist, who had more than fifteen years of experience. The Gross
Motor Function Measure tests were performed by two experienced physical
therapists (S.A.R. and A.F.-B.) with use of standardized procedures for
testing and
scoring11.
In summary, the use of botulinum toxin A to facilitate serial casting in
the treatment of fixed equinus contractures may hasten a recurrence of
contracture, spasticity, and equinus during gait. The mechanism behind these
findings is unclear. The effects of the higher doses of Botox currently
favored by many practitioners on recurrent equinus are also unknown. There is
a great need for further research into the response to botulinum toxin A
injection at the level of the neuromuscular junction. The use of botulinum
toxin A with serial casting for the treatment of fixed contractures may be
more appropriate for patients with severe spasticity or mixed hypertonia who
do not tolerate casting well, in whom such treatment may minimize skin
problems. Previous research has indicated that the injection of botulinum
toxin A is superior to casting for the treatment of dynamic equinus. However,
the results of the current study suggest that serial casting alone is
preferable for the treatment of fixed equinus contractures in patients with
cerebral palsy. ?
Note: The authors thank Los Angeles County California Children's
Services for providing valuable assistance with this project. They also thank
Cheré Dryden, MA, PT, and Clement Chan for their services with serial
casting and Linda Chan, PhD, for assistance with the statistical analyses.
Aoki KR, Guyer B. Botulinum toxin
type A and other botulinum toxin serotypes: a comparative review of
biochemical and pharmacological actions. Eur J Neurol.2001;8 Suppl 5:
21-9.821
2001
[PubMed][CrossRef]
Cosgrove AP, Graham HK. Botulinum
toxin A prevents the development of contractures in the hereditary spastic
mouse. Dev Med Child Neurol.1994;
36: 379-85.36379
1994
[PubMed][CrossRef]
Sutherland DH, Kaufman KR, Wyatt MP,
Chambers HG. Injection of botulinum A toxin into the gastrocnemius muscle
of patients with cerebral palsy: a 3-dimensional motion analysis study.
Gait Posture.1996;4:
269-79.4269
1996
[CrossRef]
Cosgrove AP, Corry IS, Graham HK.
Botulinum toxin in the management of the lower limb in cerebral palsy.
Dev Med Child Neurol.1994;36:
386-96.36386
1994
[PubMed][CrossRef]
Koman LA, Mooney JF 3rd, Smith BP,
Goodman A, Mulvaney T. Management of spasticity in cerebral palsy with
botulinum-A toxin: report of a preliminary, randomized, double-blind trial.
J Pediatr Orthop.1994;14:
299-303.14299
1994
[PubMed][CrossRef]
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 randomised prospective
trial. J Pediatr Orthop.1998;18:
304-11.18304
1998
[PubMed][CrossRef]
Flett PJ, Stern LM, Waddy H, Connell
TM, Seeger JD, Gibson SK. Botulinum toxin A versus fixed cast stretching
for dynamic calf tightness in cerebral palsy. J Paediatr Child
Health.1999;35:
71-7.3571
1999
[CrossRef]
Gajdosik RL. Passive
extensibility of skeletal muscle: review of the literature with clinical
implications. Clin Biomech (Bristol, Avon).
2001;16:
87-101.1687
2001
[PubMed][CrossRef]
Graham HK. Botulinum toxin type A
management of spasticity in the context of orthopaedic surgery for children
with spastic cerebral palsy. Eur J Neurol.2001;8 Suppl 5:
30-9.830
2001
[PubMed][CrossRef]
Russell DJ, Rosenbaum PL, Cadman DT,
Gowland C, Hardy S, Jarvis S. The gross motor function measure: a means to
evaluate the effects of physical therapy. Dev Med Child
Neurol.1989;31:
341-52.31341
1989
[CrossRef]
Russell DJ, Rosenbaum PL, Avery LM,
Lane M.Gross motor function measure (GMFM-66 and GMFM-88)
user's manual. 3rd ed. London: Mac Keith; 2002. p
ix, 234.ix
2002
Bohannon RW, Smith MB. Interrater
reliability of a modified Ashworth scale of muscle spasticity. Phys
Ther.1987;67:
206-7.67206
1987
Eames NW, Baker R, Hill N, Graham K,
Taylor T, Cosgrove A. The effect of botulinum toxin A on gastrocnemius
length: magnitude and duration of response. Dev Med Child
Neurol.1999;41:
226-32.41226
1999
[CrossRef]
Werle MJ, Herrera AA. Elevated
levels of polyneuronal innervation persist for as long as two years in
reinnervated frog neuromuscular junctions. J
Neurobiol.1991;22:
97-103.2297
1991
[CrossRef]
de Paiva A, Meunier FA, Molgo J, Aoki
KR, Dolly JO. Functional repair of motor endplates after botulinum
neurotoxin type A poisoning: biphasic switch of synaptic activity between
nerve sprouts and their parent terminals. Proc Natl Acad Sci
USA. 1999;96:
3200-5.963200
1999
[CrossRef]
Barry JA, Ribchester RR.
Persistent polyneuronal innervation in partially denervated rat muscle after
reinnervation and recovery from prolonged nerve conduction block. J
Neurosci.1995;15:
6327-39.156327
1995
Costanzo EM, Barry JA, Ribchester
RR. Competition at silent synapses in reinnervated skeletal muscle.
Nat Neurosci.2000;3:
694-700.3694
2000
[PubMed][CrossRef]
Ijkema-Paassen J, Meek MF,
Gramsbergen A. Reinnervation of muscles after transection of the sciatic
nerve in adult rats. Muscle Nerve.2002;25:
891-7.25891
2002
[PubMed][CrossRef]
Waldeck RF, Murphy EH, Pinter MJ.
Properties of motor units after self-reinnervation of the cat superior oblique
muscle. J Neurophysiol.1995;
74: 2309-18.742309
1995
[PubMed]
O'Dwyer NJ, Neilson PD, Nash J.
Mechanisms of muscle growth related to muscle contracture in cerebral palsy.
Dev Med Child Neurol.1989;
31: 543-7.31543
1989
[PubMed][CrossRef]