The American Journal of Sports
Medicine
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Intramuscular Pressure Before and After Botulinum Toxin in Chronic Exertional Compartment
Syndrome of the Leg: A Preliminary Study
Marie-Eve Isner-Horobeti, Stéphane Pascal Dufour, Cyril Blaes and Jehan Lecocq
Am J Sports Med 2013 41: 2558 originally published online August 22, 2013
DOI: 10.1177/0363546513499183
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Intramuscular Pressure Before and After
Botulinum Toxin in Chronic Exertional
Compartment Syndrome of the Leg
A Preliminary Study
Marie-Eve Isner-Horobeti,*yz§ MD, PhD, Stéphane Pascal Dufour,§ll PhD,
Cyril Blaes,y MD, and Jehan Lecocq,z§ MD
Investigation performed at Strasbourg University, Department of Physical Medicine
and Rehabilitation, Strasbourg, France
Background: Botulinum toxin A (BoNT-A) is used in the treatment of muscle hypertrophy but has never been used in chronic
exertional compartment syndrome (CECS). The objective diagnostic criterion in this condition is an abnormally elevated intramuscular pressure (IMP) in the compartment. In this study, the IMP was measured 1 minute (P1) and 5 minutes (P5) after the exercise
was stopped before and after BoNT-A injection.
Hypothesis: Botulinum toxin A reduces the IMP (P1 and P5) and eliminates the pain associated with CECS.
Study Design: Case series; Level of evidence, 4.
Methods: Botulinum toxin A was injected into the muscles of moderately trained patients with an anterior or anterolateral exertional compartment syndrome of the leg. The BoNT-A dose (mean 6 SD) ranged from 76 6 7 to 108 6 10 U per muscle, depending on which of the 5 muscles in the 2 compartments were injected. The primary end point was IMP (P1, P5). Secondary end
points were exertional pain, muscle strength, and safety. Follow-up was conducted up to 9 months.
Results: A total of 25 anterior compartments and 17 lateral compartments were injected in 16 patients. The time interval (mean 6
SD) between the BoNT-A injection and after BoNT-A injection IMP measurement was 4.4 6 1.6 months (range, 3-9 months). In the
anterior compartment, P1 and P5 fell by 63% 6 17% (P \ .00001) and 59% 6 24% (P \ .0001), respectively; in the lateral compartment, P1 and P5 fell by 68% 6 21% (P \ .001) and 63% 6 21% (P \ .01), respectively. Exertional pain and muscle strength
were monitored, based on the Medical Research Council score. The exertional pain was completely eliminated in 15 patients
(94%). In 5 patients (31%), the strength of the injected muscles remained normal. In 11 patients (69%), strength decreased
from 4.5 (out of 5) to 3.5 (P \ .01), although without functional consequences. In the conditions of this study, BoNT-A showed
a good safety profile in patients with CECS.
Conclusion: In this case series, BoNT-A reduced the IMP and eliminated exertional pain in anterior or anterolateral CECS of the
leg for up to 9 months after the intervention. The mode of action of BoNT-A is still unclear. A randomized controlled study should
be carried out to determine whether BoNT-A can be used as a medical alternative to surgical treatment.
Keywords: exertional compartment syndrome; botulinum toxin; leg pain; intramuscular pressure
objective diagnostic criterion: an abnormally high intramuscular pressure (IMP) after exercise within the affected compartment.50,55 The pathophysiological process of CECS is
poorly understood and probably multifactorial. One of the
hypotheses is a discrepancy between the tissue delimiting
the compartment and its muscle content, resulting in an
excessive IMP. This discrepancy may be due to a hypertrophy of the muscles within the compartment.28,47 However,
other plausible pathophysiological mechanisms are also
suggested for CECS, including a decreased compartment
syndrome size due to a thickened, unelastic fascia,4,31
a supernumerary muscle, or a vascular anatomic or functional abnormality.13,14 The pain could be explained by
A muscle compartment is a closed space bound by fascia and
bone. The leg includes 4 compartments: the anterior compartment, the lateral compartment, the superficial posterior
compartment, and the deep posterior compartment. Chronic
exertional compartment syndrome (CECS) is characterized
by 2 criteria. The first one is a subjective clinical criterion:
pain in the involved compartment triggered by a specific
exercise and disappearing when the exercise is stopped.
The second one is a paraclinical criterion and the only
The American Journal of Sports Medicine, Vol. 41, No. 11
DOI: 10.1177/0363546513499183
Ó 2013 The Author(s)
2558
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Vol. 41, No. 11, 2013
Compartment Syndrome and Botulinum Toxin
muscle ischemia33 or by the stimulation of nociceptors
located in the muscles as well as in the fascia.
The only curative treatment available for CECS, and
considered the gold standard, is a surgical fasciotomy or
fasciectomy12,23 to release the tension on the compartment’s boundary. However, the postoperative recurrence
rate varies from around 3% to 17% and may reach 35%
in partial fasciectomy.19,37,48,56 Therefore, a less invasive
alternative may be of interest.
Given the proposed role of muscle hypertrophy within
the compartment, botulinum toxin A (BoNT-A) could help
in the management of CECS by reducing the volume of
the compartment content. BoNT-A showed favorable and
promising results in the treatment of masseter hypertrophy1,25 and gastrocnemius hypertrophy.21,29 Likewise, its
use for analgesic purposes in painful hypertrophy of the
calf muscles8 and painful muscle contractures associated
with myofascial syndromes has been described.49 The similarity between the symptoms of these conditions led us to
examine the effects of BoNT-A in CECS.
Although any muscle compartment can be affected, CECS
most commonly involves the anterior and lateral compartments of the leg. These 2 compartments are subcutaneous
and are more readily accessible and safe for exploration. Consequently, our study focused on CECS involving the anterior
and anterolateral compartments of the leg. A first case series
conducted in 2008 in 7 patients with anterior or anterolateral
CECS of the leg showed that BoNT-A injections helped
reduce muscle pain in the affected compartments.27 However, the effects of BoNT-A on IMP have never been investigated in CECS. Therefore, we hypothesized that
intramuscular injections of BoNT-A may reduce IMP and
relieve pain. Our objective was to test the effect of BoNT-A
injection on the only objective criteria able to confirm the
diagnosis of CECS, that is, the IMP and associated pain.
MATERIALS AND METHODS
Population
Clinical files from a population of patients seen between
January 2010 and June 2012 at a physical and rehabilitation medicine department were retrospectively analyzed.
During this period, 148 patients were seen in consultation for leg pain. We retained complete clinical and paraclinical data in patients’ files according to 3 criteria.
First, CECS had to be suggested clinically in the anterior
or anterolateral compartment by the presence of leg pain,
triggered by physical or sport activity, irrespective of the
patients’ age or sex. Second, patients had to be injected
by BoNT-A in the involved compartment. These patients
had to be BoNT-A naı̈ve and to have given their written
2559
TABLE 1
Population Characteristics (N = 16)a
Age, y
Sex, male/female, No.
Height, cm
Weight, kg
Body mass index, kg/m2
Time to diagnosis, mo
Anterior compartment
Anterolateral compartment
Unilateral involvement
Bilateral involvement
23 6 5 (18-36)
13/3
173 6 8 (156-185)
77 6 14 (48-105)
25 6 3 (20-31)
40 6 60 (4-240)
31% (n = 5)
69% (n = 11)
37% (n = 6)
63% (n = 10)
a
Data given as mean 6 standard deviation (range) unless otherwise noted.
consent to receive the proposed intramuscular injection.
The third criterion was the assessment of IMP before and
after BoNT-A injection.
In these patients, the CECS could be unilateral or bilateral. The definitive diagnosis was based on an elevated IMP
measured in the involved compartments after running, based
on the criteria suggested by Pedowitz et al38: IMP at the first
minute after exercise (P1) greater than 30 mm Hg and/or IMP
at the fifth minute (P5) greater than 20 mm Hg. Other exertional leg pain causes were ruled out by a clinical examination
(general, orthopaedic, neurological, and functional) and paraclinical examination (full blood examination, leg radiographs,
bone scintigraphy, lumbar scan, and dynamic echo-Doppler of
the lower limbs). Those with abnormal findings in the abovementioned examinations (periostitis, stress fracture, herniated disk, vascular compression) were excluded from the
analysis.
Using these inclusion criteria, we identified 16 patients,
consisting of 11 recreational runners and 5 military runners. These runners had all been running regularly for
more than 1 year and had a training volume of at least
5 hours per week. Patients had undergone treatment (eg,
rest, stretching, ice, nonsteroidal anti-inflammatory drugs,
analgesics) that proved unsuccessful for their persistent
muscle leg pain and forced them to reduce or stop their
usual physical activity. All members of this group were
examined by the same physician. The following data
were collected: age, sex, weight, height, body mass index,
and time to diagnosis (Table 1).
Evaluation and Follow-up
Clinical data and IMP were obtained just after the initial
running test and before BoNT-A injection.
After BoNT-A injection, IMP measurement was
assessed only once after ~4.4 6 1.6 months (range, 3-9
*Address correspondence to Marie-Eve Isner-Horobeti, MD, PhD, Institut Universitaire de Réadaptation Clémenceau (IURC)–Strasbourg, 45 boulevard
Clémenceau, F-67000 Strasbourg, France (e-mail: marieeve.isner@gmail.com).
y
Physical and Rehabilitation Medicine Department, Strasbourg University, University Institute of Rehabilitation Clémenceau, Strasbourg, France.
z
Physiology Institute, Strasbourg University, Medicine Faculty and Hospital, University Hospital, Strasbourg, France.
§
Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France.
ll
Faculty of Sports Science, Strasbourg University, Strasbourg, France.
The authors declared that they have no conflicts of interest in the authorship and publication of this contribution.
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2560 Isner-Horobeti et al
Duration of symptoms
preinjection: 40±60 mo
The American Journal of Sports Medicine
1-month
recovery
3- to 9-month
recovery: 4.4±1.6 mo
Time
Running test
IMP at 1 and 5 min after running test
BoNT-A injection
Clinical data
Figure 1. Study design: All patients had chronic exertional
compartment syndrome (CECS) for a mean (6SD) duration
of 40 6 60 months before the first visit to the medical department. During this time, all other exertional leg pain causes
were discarded. At the first visit, all patients were asked to
run on a treadmill to demonstrate the effects of the usual
pain in their lower leg muscles. Intramuscular pressure
(IMP) was measured 1 and 5 minutes after running to confirm
CECS, and lower leg muscle strength and pain were evaluated. The intramuscular botulinum toxin A (BoNT-A) injection
was given 15 minutes after the running test. Patients returned
to the department after 1 month of recovery from the BoNT-A
injection for evaluation of lower leg muscle strength, pain,
and side effects. All patients had their last visit between 3
and 9 months after BoNT-A injection; at this visit, the running
test was repeated, IMP was measured, and lower leg muscle
strength, pain, and side effects were evaluated.
months). For clinical data (ie, exertional pain, muscle
strength, and safety), a first evaluation was performed 1
month after the injection of BoNT-A and a second evaluation was performed when the IMP was assessed at
~4.4 6 1.6 months (range, 3-9 months) (Figure 1).
Running Test
To trigger their usual leg pain, all patients performed
a treadmill running test (Medical Development S2500,
Andrezieux Boutheon, France) before and 4.4 6 1.6
months after BoNT-A injection. The running speed was
increased progressively until the patient complained of
leg pain. The exercise was then stopped and the patient
was placed lying supine for immediate IMP measurements.
The running protocol after BoNT-A injection was identical
to the protocol used before the injection. Thus, each patient
was asked to run at the same speed and for the same duration in both tests.
Special Procedures and Measurements
IMP in the Lower Leg Compartments. Before the exercise test, local skin anesthesia was given (1.5 mL, 1% xylocaine) at the point where the IMP needle would be
inserted. The needle, connected to a pressure transducer
(Stryker Instruments, Mahwah, New Jersey), was inserted
immediately into the anterior or lateral compartment.22
The pressures in the compartment and in the transducer
were evened out by use of a syringe filled with 0.2 mL of
Figure 2. Intramuscular injection of botulinum toxin in the
tibialis anterior muscle under electrical stimulation guidance.
saline solution. The pressure was displayed on the transducer in mm Hg and was read about 10 seconds after saline
injection, as previously described in clinical settings.10,45
The IMP was measured continuously, but we recorded
only the values at 1 minute (P1) and 5 minutes (P5) after
the exercise. After BoNT-A injection, the IMP was measured in the same conditions and with the same procedures
as used for the initial measurements.
Clinical Data. Clinical data (ie, exertional pain, muscle
strength, and safety) were obtained before as well as 1
month and 4.4 6 1.6 months (range, 3-9 months) after
the injection of BoNT-A.
Exertional Pain. Pain was assessed as binary data (ie,
present or absent) irrespective of its intensity, and therefore a quantified visual analog scale was not necessary.
The analgesic effect of BoNT-A was thus considered as positive only if the pain had disappeared after the injection of
BoNT-A.
Muscle Strength. Muscular strength was assessed with
the semiquantitative Medical Research Council score32
(0 to 5). To aid statistical calculations, intermediate values
typically represented with the plus (1) symbol were
replaced by the decimal 0.5. The duration of muscular
strength loss was quantified in months. The functional consequences of any muscle impairment were evaluated during
the interview as a feeling of ankle instability when walking
or running, as well as the ability to walk on heels.
Safety. The potential side effects of BoNT-A (general
muscle weakness, muscular atrophy,3,17,18,30 flulike symptoms,34 breathing and swallowing difficulties, and
death9,26) were exhaustively explained to study participants before they gave their written consent to receive
the proposed intramuscular injection. After the injection,
all patients were given the option to call the examiners
at any time during the follow-up for any concerns, including occurrence of a potential side effect.
Intramuscular Injection of BoNT-A. At 15 minutes after
the initial running test, the BoNT-A injection was performed under electrical stimulation guidance, which was
used to position the needle as close as possible to the motor
endplate35 of all the muscles in the involved compartment
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Vol. 41, No. 11, 2013
Compartment Syndrome and Botulinum Toxin
2561
TABLE 2
Doses of BoNT-A per Compartment and per Musclea
Anterior
Compartment
Tibialis
Anterior
Extensor
Digitorum Longus
Extensor
Hallucis Longus
Lateral
Compartment
Peroneus
Brevis
Peroneus
Longus
16
288 6 25
(230-330)
3.8 6 0.6
(3.0-5.2)
16
108 6 10
(90-120)
1.4 6 0.3
(0.3-1.9)
16
103 6 13
(70-120)
1.4 6 0.3
(0.3-1.9)
16
76 6 10
(50-100)
1.0 6 0.2
(0.7-1.5)
12
180 6 14
(150-200)
2.4 6 0.4
(1.9-3.0)
12
76 6 7
(70-90)
1.0 6 0.1
(0.7-1.3)
12
104 6 10
(80-120)
1.4 6 0.2
(0.7-1.3)
No.
BoNT-A, U
BoNT-A, U/kg
a
Data are given as mean 6 standard deviation (range). There was 1 injection site per muscle. BoNT-A, botulinum toxin A; No., number of
compartments or muscles.
TABLE 3
Intramuscular Injection of
Botulinum Toxin A in 42 Compartments
Anterior Compartment
Patient No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Lateral Compartment
Right
Left
Right
Left
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
and to avoid injecting a muscle more than once (Figure 2).
To identify the injection site, a needle electrode 0.46 mm in
diameter and 50 mm long (Bioject, Alpine Biomed Aps,
Skovlunde, Denmark) was connected to a muscle electrical
stimulation device (Cefar Rehab, Mouguerre, France) to
detect the point that produced a maximum contraction
with the minimum stimulation intensity for each muscle
in the compartment.
In patients with an anterior CECS, BoNT-A was
injected into each of the 3 muscles in the anterior compartment (tibialis anterior, extensor hallucis longus, extensor
digitorum longus). In patients with an anterolateral
CECS, BoNT-A was injected into the 3 muscles mentioned
above and into the 2 muscles of the lateral compartment
(peroneus brevis and peroneus longus).
The BoNT-A (Dysport, Ipsen, Boulogne-Billancourt,
France) was reconstituted with 2.5 mL of saline solution
for 500 U. Because of the lack of previous studies, the selection of the dose of BoNT-A was based on the literature and
on the authors’ experience and knowledge of spasticity7,40
and musculoskeletal disorders.41,49,54 The objective was
to use the minimum effective dose that would not lead to
muscle paralysis. This dose was one-third of the maximum
recommended dose used for the treatment of lower limb
spasticity,7,40 adjusted to the volume of the muscle and
the patient’s body weight. BoNT-A was injected into each
muscle in a single injection site.
The doses of BoNT-A administered in each muscle (measured in units) as well as the dose per muscle based on
the patient’s body weight (units per kilogram) were
recorded. The total dose of BoNT-A injected into each compartment was also recorded in units and units per kilogram (Table 2).
Statistical Analysis
To specifically test the effects of BoNT-A injection on the
anterior or anterolateral compartments, IMP values were
assessed per muscle compartment. For clinical data (ie,
pain and muscle strength), the statistical analysis was performed per patient.
The Student t test was used to compare the parameters
before and after BoNT-A.
The results were expressed in terms of mean, standard
deviation, and range. The significance level was P \ .05.
Correlation tests were based on the Pearson correlation
coefficient.
RESULTS
Effect of BoNT-A Injection on Intramuscular Pressure
The IMP was measured before and after the intramuscular
injection of BoNT-A in 42 compartments (25 anterior and
17 anterolateral compartments in 16 patients). Of note,
some patients presented mono/bilateral and/or anterior/
anterolateral CECS (Tables 1 and 3).
The mean interval between BoNT-A injection and postinjection IMP measurement was 4.4 6 1.6 months (range,
3-9 months).
After the BoNT-A injection, in the anterior compartment, P1 and P5 decreased by 63% 6 17% (P \ .00001)
and 59% 6 24% (P \ .0001), respectively (Figure 3). Specifically, P1 dropped to 30 mm Hg and P5 to 20 mm Hg in
14 patients, whereas these values remained greater than
normal in 2 patients. The first of these patients became
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2562 Isner-Horobeti et al
The American Journal of Sports Medicine
100
**
100
$
80
80
*
70
mmHg
70
mmHg
$$
90
90
60
50
60
50
40
40
30
30
20
20
10
10
0
0
P1 before
P1 after
P5 before
P5 after
Figure 3. Intramuscular pressure in the anterior compartment
before and after botulinum toxin injection. P1, intramuscular
pressure 1 minute after the exercise. P5, intramuscular pressure 5 minutes after the exercise. Statistically significant results
compared with preinjection values: *P \ .0001. **P \ .00001.
asymptomatic, but IMP values remained high (P1 =
35 mm Hg, P5 = 24 mm Hg). Of note, preinjection values
were high (P1 = 75 mm Hg, P5 = 62 mm Hg). For the second patient, postinjection IMP values remained high (P1 =
46 mm Hg, P5 = 21 mm Hg) and pain persisted. This
patient was directed to successful fasciotomy.
After the BoNT-A injection, in the lateral compartment, P1
and P5 decreased by 68% 6 21% (P \ .001) and 63% 6 21%
(P \ .01), respectively (Figure 4). Specifically, P1 dropped to
30 mm Hg and P5 to 20 mm Hg in 15 patients, whereas
they remained greater than normal in 1 patient, in whom P1
was 34 mm Hg (vs 57 mm Hg before BoNT-A injection) and
P5 was normalized (10 mm Hg vs 36 mm Hg before BoNTA injection). This patient became asymptomatic.
The extent of the reductions in P1 and P5 in the anterior
and lateral compartments was similar. No correlation was
found between the reduction in IMP in the anterior and/or
lateral compartment and the total dose of BoNT-A injected
into the compartment (Table 4).
Effect of BoNT-A Injection on Clinical Data
Clinical data were evaluated after 1 month and between 3
to 9 months (mean 6 SD, 4.4 6 1.6 months).
Exertional Pain. The exertional pain disappeared completely during the follow-up period in 15 patients (94%).
The pain disappeared in less than 1 month in 10 patients
(67%), in 1 to 3 months in 2 patients (13%), and in 3 to 5
months in 3 patients (20%). The 15 patients without pain
after BoNT-A injection could exercise more at follow-up as
they did not report any pain. Only 1 patient reported no
pain reduction. This patient had persistently high IMP values after injection (cf IMP results) despite receiving a similar dose of BoNT-A (total dose of 300 U: 110 U in tibialis
anterior, 110 U in extensor digitorum longus, and 80 U in
extensor hallucis longus). At 5 months, a fasciotomy was
recommended, and the patient completely recovered.
Muscle Strength. Muscle strength was rated as normal
(5 on a scale from 0 to 5) for all muscles before BoNT-A
injection.
P1 before
P1 after
P5 before
P5 after
Figure 4. Intramuscular pressure in the lateral compartment
before and after botulinum toxin injection. P1, intramuscular
pressure 1 minute after the exercise. P5, intramuscular pres$
$$
sure 5 minutes after the exercise. P \ .01. P\ .001.
The strength values per muscle 1 month after BoNT-A
injection produced the following results: The mean (6SD)
strength of the tibialis anterior was 4.6 6 0.4 (4-5, P =
.001) (values were normal [5/5] in 5 patients [31%], 4.5 in
8 patients [50%], and 4 in 3 patients [19%]). The mean
strength of the extensor digitorum longus was 4.7 6 0.4
(4-5, P = .001) (normal in 9 patients [56%], 4.5 in 5 patients
[31%], and 4 in 2 patients [13%]). The mean strength of the
extensor hallucis longus was 4.5 6 0.6 (3.5-5, P = .001)
(normal in 8 patients [50%], 4.5 in 3 patients [19%], 4 in
3 patients [19%], and 3.5 in 2 patients [12%]). The mean
strength of the peroneus longus was 4.9 6 0.3 (4-5, P =
.19) (normal in 10 patients [84%], 4.5 in 1 patient [8%],
and 4 in 1 patient [8%]); and the mean strength of the peroneus brevis was 4.9 6 0.3 (4-5, P = .19) (normal in 10
patients [84%], 4.5 in 1 patient [8%], and 4 in 1 patient
[8%]). Muscle strength rated normal for all muscles at
4.4 6 1.6 months after BoNT-A injection.
The evaluation per study subject provided the following
results: The strength of all muscles was normal (5/5) in 5
patients (31%), whereas it was reduced in 11 patients
(69%). In these 11 individuals, the average muscle
strength 1 month after BoNT-A injection was 4.5 in 6
patients and 4 in 5 patients without functional consequences. No correlation was found between the evaluation of
strength of each of the 5 muscles and the dose of BoNT-A
injected per muscle expressed in units or in units per kilogram of body weight (Table 5).
Safety. In 15 patients, no adverse effects were observed.
Only 1 patient reported pain in the posterior compartment
of her legs that was different from the anterolateral pain
described previously. For this individual, BoNT-A was
injected into the 3 muscles of the anterior compartment
(total dose of 250 U: 90 U in tibialis anterior, 90 U in extensor digitorum longus, and 70 U in extensor hallucis longus). The BoNT-A dose was similar to the one used for
the other 15 patients; the mean value was 288 6 25 U.
The IMP measured in the right deep posterior compartment and the muscle strength were both normal. There
was no evidence suggesting that the pain reported might
have been caused by the BoNT-A injection.
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Vol. 41, No. 11, 2013
Compartment Syndrome and Botulinum Toxin
2563
TABLE 4
Correlation Between the Reduction in IMP and Doses of BoNT-Aa
BoNT-A, U
BoNT-A, U/kg
P1, Anterior Compartment
P5, Anterior Compartment
P1, Lateral Compartment
P5, Lateral Compartment
r = 0.12
(P = .61)
r = –0.37
(P = .11)
r = 0.17
(P = .46)
r = –0.23
(P = .33)
r = 0.24
(P = .24)
r = –0.35
(P = .39)
r = 0.43
(P = .43)
r = –0.01
(P = .99)
a
BoNT-A, botulinum toxin A; IMP, intramuscular pressure; P1, IMP at 1 minute after cessation of exercise. P5, IMP at 5 minutes after
cessation of exercise.
TABLE 5
Correlation Between the Tested Muscle Strength and Dose of BoNT-Aa
BoNT-A, U
BoNT-A, U/kg
Tibialis Anterior
Extensor Digitorum Longus
Extensor Hallucis Longus
Peroneus Brevis
Peroneus Longus
r = 0.21
(P = .43)
r = –0.01
(P = .97)
r = 0.12
(P = .636)
r = 0.25
(P = .33)
r = –0.25
(P = .33)
r = 0.22
(P = .39)
r = –0.18
(P = .55)
r = –0.22
(P = .47)
r = –0.23
(P = .45)
r = –0.16
(P = .60)
a
BoNT-A, botulinum toxin A.
Moreover, after BoNT-A injection the patients did not
complain about ankle instability during walking or running, and all were able to walk on their heels without pain.
DISCUSSION
The results of this case series show that an intramuscular
injection of BoNT-A reduces intramuscular pressure in the
compartments involved and eliminates exertional pain.
These findings support our initial results in 2008 in a series
of 7 patients who reported pain reduction after a BoNT-A
injection in the muscles of the compartments affected by
a CECS.27 This new case series is the first to examine
the effects of BoNT-A on IMP, muscle pain, and muscle
strength score in CECS patients.
Effect of Intramuscular BoNT-A Injection
on Intramuscular Pressure
Our sample is representative of the population with CECS,
as its characteristics are similar to those of other studies
on anterior or anterolateral CECS of the leg.11,44,46,48,52
The patients’ average age was 23 years, and there was
a marked male predominance (13 of 16 patients). The
CECS was bilateral in almost two-thirds of the cases.
The time to diagnosis, an average of 40 months, was close
to that reported by Turnipseed et al52: 60 months. The IMP
in the painful compartments was abnormal in all patients
based on the criteria of Pedowitz et al.38 The choice of a cutoff value of 30 mm Hg at 1 minute after exercise was confirmed a posteriori by a 2012 systematic review,2 which
showed that at 1 minute after exercise there was no overlap between IMP values in CECS patients and healthy controls and that in healthy controls, the IMP was never
greater than 27.5 mm Hg at 1 minute after exercise.
To date, surgical decompression52,24 is the only treatment for CECS recognized as curative. All other treatment
alternatives are preventive or treat only the symptom. The
medical approaches include reducing sports activities
below the level that triggers pain or changing sports.46
Various physiotherapy techniques have been suggested to
treat the pain, but none have had any lasting or proven
efficacy.20,46 All these treatments were evaluated in studies using only posttreatment pain as the end point, not
the IMP. However, because IMP is the only objective diagnostic parameter of CECS, it seemed logical to use it as the
primary efficacy end point. Moreover, unlike the present
study, most previous studies looked at pain reduction
only, not complete elimination of pain.
In the present study, IMP measured ~4.4 months after
BoNT-A injection in the 42 compartments was 59% to
69% lower than the preinjection values, with a significance
level of .01 to .00001 depending on the compartment. The
IMP values returned to normal in the majority of patients
(87.5%, n = 14). To date, only 2 studies comparing IMP
before and after treatment have been reported in the literature. Blackman et al5 studied 7 athletes with anterior
CECS of the leg; no changes in IMP (63 vs 68 mm Hg;
P = .15) were found, but athletes reported some pain reduction after 5 weeks of treatment with massage and stretching. Biedert and Marti,4 in a study of 15 patients 8 to 72
months after a fasciotomy of the deep posterior compartment of the leg, reported a 91% reduction in the average
IMP (18.5 mm Hg vs 1.6 mm Hg; P = .0001) as well as
a reduction in pain.
These results do not allow us to determine the time
when IMP reduction starts or the duration of the effect
of BoNT-A in lowering IMP. Further studies on the
kinetics of BoNT-A are necessary to define the onset of
action and total duration of efficacy of BoNT-A in lowering IMP.
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2564 Isner-Horobeti et al
The American Journal of Sports Medicine
Effect of Intramuscular BoNT-A Injection
on Clinical Parameters
Exertional pain in CECS was considered an accessory criterion as it is a subjective functional parameter. The pain was
followed up 1 month after the injection of BoNT-A, and a second evaluation was performed between 3 and 9 months
(mean 6 SD, 4.4 6 1.6 months). The duration of action of
BoNT-A on exertional pain beyond this period has yet to be
examined. The efficacy of BoNT-A on exertional pain, measured as binary data (present or absent), may be considered
positive since 15 of the 16 patients reported no exertional
pain at 9 months after BoNT-A injection. The only participant
who reported no pain relief had the highest IMP after the
injection (P1 = 46 mm Hg and P5 = 21 mm Hg). Of note,
the dose of BoNT-A used for this patient in the anterior compartment (300 U) was similar to the one used for the other 15
patients and was close to the mean value (288 6 25 U).
The lack of previous studies using BoNT-A in this indication led us to choose the dose of BoNT-A according to our
clinical experience and based on the literature. Our goal
was to use the smallest dose possible in order to avoid muscle paralysis and functional impairment. This dose was onethird of the maximum recommended dose used for the treatment of lower limb spasticity,7,40 which is adjusted to the
volume of the muscle to be injected and the patient’s body
weight. Therefore, these initial results raise a question
about the optimum dose of BoNT-A per muscle.
Motor impairment was observed in 11 of the participants,
but this effect had no functional consequences and was fully
reversed after 3 months in 7 patients and after 4 months in
the remaining 4 patients. Therefore, BoNT-A doses should
be adjusted to maintain an optimum effect on IMP and
pain while causing minimal motor deficit or side effects.
The safety profile was excellent; only 1 patient reported
a side effect, not serious and unexplained, involving pain
in the treated leg but not in the territory injected. The
BoNT-A dose injected into the anterior compartment of this
patient was similar to the one used for the other study participants. The causality with respect to BoNT-A is unlikely.
Regarding muscle strength, no correlation was found
between the BoNT-A dose per muscle and muscle strength,
but the doses injected were almost identical in all patients.
The BoNT-A doses were chosen arbitrarily, based on doses
used for other conditions, but this case series will help
determine the doses for a future randomized, controlled
study. Additionally, this study found no relation between
the dose of BoNT-A injected and the reduction in IMP,
probably because the doses were almost identical in all
patients. We did not look for a correlation between exertional pain and the BoNT-A dose, as the total dose per
patient was based on the number of affected compartments
(anterior or anterolateral, unilateral or bilateral).
Plausible Pathophysiological Mechanisms
of BoNT-A in CECS
The mechanism by which BoNT-A affects IMP and pain
associated with CECS has yet to be determined, and several hypotheses have been suggested. Muscle fiber atrophy
might be an indirect effect of BoNT-A given the reduced
release of acetylcholine. The number of fibers remains
unchanged, but their diameter is reduced.18,42
The first hypothesis is based on the known action of
BoNT-A resulting in muscle hypotonia, which may cause
moderate amyotrophy16,51,53 in muscles injected over a long
period. This mode of action has been used for the treatment
of unsightly hypertrophy of the masseter1,25 or triceps surae
muscles.8,21,29 Therefore, a reduction of the hypertrophy of
the lower leg muscles, even if only minimal, should help
reduce CECS. This action of BoNT-A was targeted in our
study, and further studies using medical imaging are necessary to support this pathophysiological hypothesis.
The second hypothesis is based on the muscle relaxation
induced by BoNT-A. The muscle hypotonia obtained may
prolong the duration of the relaxation phase and reduce
IMP,6 thereby improving blood flow to the muscles. One of
the pathophysiological hypotheses formulated to explain
CECS is the presence of muscle ischemia resulting in edema
inside the compartment, which in turn explains the
increases in IMP and in pain. Oskarsson et al,36 in a study
of patients suffering from epicondylitis, showed that intramuscular BoNT-A injection in the extensor of the wrist
improved blood flow in this muscle and was accompanied
by pain belief. By analogy, muscle BoNT-A injection might
improve blood flow in other pathological situations, such
as CECS, leading to reduced IMP and pain relief. More
recently, Edmundsson et al13 analyzed muscle biopsy specimens from patients during fasciotomy for CECS. The investigators showed a lower capillary supply of the tibialis
anterior muscle in CECS, suggesting that local ischemia
may be involved in the pathogenesis of CECS.
The third hypothesis is related to the possible analgesic
action of BoNT-A, as suggested in recent studies.15,39,43
The exertional pain associated with CECS may be related
to the stimulation of nociceptors in the muscles and the fascia. This action could explain the elimination of exertional
pain in 94% of the patients but cannot explain the posttreatment reduction of IMP. These 3 modes of action of BoNT-A
are not necessarily exclusive and could work together.
Limitations of the Study
The present study is a retrospective analysis of clinical
patient files that was performed to deepen our understanding of the possible beneficial effect of BoNT-A injection in
painful muscle compartments resulting from CECS. Therefore, the timing of data measurements was not set a priori
and it differed between patients, leading to a large variability in the follow-up period, ranging from 3 to 9 months
after BoNT-A injection. Such a study design does not allow
comparison of all participants at specific time points in the
recovery period but provides a view of the recovery process
at different time points. Another potential weakness of the
study design is that IMP and clinical parameters (ie, muscle strength and pain) were not always assessed simultaneously, which prevents direct comparison of the time
course of these variables. Nevertheless, we believe that
these potential limitations do not affect the main findings
of the study: muscular injection of BoNT-A into painful
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Vol. 41, No. 11, 2013
Compartment Syndrome and Botulinum Toxin
compartments of study subjects with CECS characterized
by abnormally elevated IMP restored normal IMP in 88%
of participants and alleviated the associated muscle pain
in 94% of participants. The remaining symptomatic patient
was directed to fasciotomy and fully recovered. Therefore,
a major outcome of this study is that a therapeutic strategy
combining BoNT-A injection and (if injection is not successful) fasciotomy allowed all our patients with CECS to
resume their normal level of physical activity.
Of note, the present result that BoNT-A injection lowered
IMP and muscle pain was observed without dramatic impairment of muscle function, as indicated by significant but moderate reductions of Medical Research Council scores.
Although muscle function might be more accurately evaluated in future studies to further ascertain the functional
effect of BoNT-A injection, we believe that muscle function
was mostly preserved because of the low volume of BoNT-A
injected into the painful muscle compartments of our CECS
patients. Although the BoNT-A dose was established from
previous reports as well as the experience of our clinicians,
it might well be further optimized to favor the reduction of
IMP while maintaining the most muscle function.
In conclusion, the initial results of this case series
showed that the intramuscular injection of BoNT-A has
a short-term effect in reducing IMP and lowering exertional pain in patients with CECS in the anterior or anterolateral compartment of the leg. These encouraging
results need to be confirmed by a randomized controlled
study carried out over a longer period. Such a study would
help define the onset and duration of action as well as the
optimum dose of BoNT-A in this indication. Further studies are also necessary to define the mechanisms of action
of BoNT-A on IMP and exertional pain in CECS.
ACKNOWLEDGMENT
Special thanks goes to Professor Bernard Poulain, deputy
scientific director, Neurosciences et Cognition, Institut
des Sciences Biologiques du Centre National de la
Recherche Scientifique (France), for reading the manuscript and for his advice.
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