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Botulinum toxin treatment of muscle cramps A clinical and neurophysiological study.

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Botulrnum Toxin Treatment
of Muscle Cramps: A C h i d
and Neurophysiologid Study
Laura Bertolasi, MD,* Albert0 Priori, MD, PhD,? Giuliano Tomelleri, MD,* Luigi G. Bongiovanni, MD,*
Emiliana Fincati, MD,* Alessandro Simonati, MD,* Domenico De Grandis, MD,$ and Nicolo’ Rizzuto, MD*
Botulinum toxin is now widely used in the treatment of several hyperkinetic movement disorders. To evaluate its efficacy
in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum
toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign crampfasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency
was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection significantly lowered our
patients’ clinical cramp severity scores (mean f SD: before, 3.80 & 0.44; after, 1.40 k O.S4), left muscle strength
unchanged and significantly increased their cramp threshold frequencies (before, 4.22 & 2.26 Hz; after, 10.0 & 3.74
Hz). The clinical benefit induced by botulinum toxin lasted about 3 months. Botulinum toxin injections also significantly
reduced fasciculation potentials in relaxed muscles (before, 0.86 & 0.19 fasciculations/sec; after, 0.45 & 0.11
fasciculations/sec). These findings show that local intramuscular injections of botulinum toxin provide effective, safe,
and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and
by impairing the input/output function of intrafusal and extrafusal motor end plates.
Bertolasi L, Priori A, Tomelleri G, Bongiovanni LG, Fincati E, Sirnonati A, De Grandis D,
Rizzuto N. Botulinum toxin treatment of muscle cramps: a clinical and
neurophysiological study. Ann Neurol 1997;41:181-186
Muscle cramp is a painful, involuntary, paroxysmal
contraction of a part or all of a muscle [I]. O n electromyograms (EMGs), muscle cramps appear as high-frequency bursts of motor unit potentials that start in one
region and spread to the rest of the muscle [2]. Cramps
occur spontaneously or are triggered by muscle contraction. They can be a symptom of several neurological, metabolic, and endocrinological diseases [ 3 ] .
Cramps are also common in various physiological conditions including pregnancy, muscle fatigue, and aging.
Most healthy persons experience occasional cramps at
some time in their lives.
Muscle fasciculations are painless, repetitive fascicular twitches of muscle fibers belonging to one motor
unit [4].Although occasionally experienced by normal
persons, fasciculations are also seen in a number of
pathological conditions. Fasciculations accompanied by
cramps may indicate neurologic or systemic disease.
Cramps and fasciculations in otherwise normal subjects
are also a feature of a rare disorder, the benign crampfasciculation syndrome, sometimes inherited as an autosomal dominant trait [5]. Frequent muscle cramps,
often a very distressing and disabling disturbance, are
generally managed in clinical practice by systemic drug
treatment with quinine, carbamazepine, phenytoin, or
diazepam [G, 71. Especially when used in otherwise
healthy persons, these drugs unfortunately often cause
unacceptable systemic side effects, have potential toxicity, need daily administration, and frequently provide
inadequate relief [S].
Because muscular cramps cannot be evoked in curarized muscles [9], we hypothesized that a long-standing
block of the neuromuscular junction with botulinum
toxin [lo] might be useful in treating muscle cramps.
Hence, we used botulinum toxin to treat patients who
had an inherited benign cramp-fasciculation syndrome. Besides evaluating the improvement in muscle
cramps clinically, we assessed it neurophysiologically by
studying changes in the cramp threshold. For this purpose, we used repetitive peripheral nerve stimulation,
a technique that induces cramps in normal persons and
provides a quantitative measure of the cramp threshold
[ I l l . We also studied effects of botulinum toxin treatment on fasciculation activity.
From *Dipartimento di Scienze Neurologiche e della Visione, Sezione di Neurologia, Universita’ degli Studi di Verona, Verona; t D i visione di Neurologia, Ospedale Civile “Ettore Spalenza,” Rovato;
and ‘FDivisione di Neurologia, Arcispedak S Anna, Ferrara, Italy.
Received May 2, 1996, and in revised form JuI 18. Accepted for
publication JuI 19, 1996.
Address correspondence to Dr Bertolasi, Diparrimento di Scienze
~
~universita’
~
~
Neurologiche della visione, sezionedi ~
degli Studi di Verona, 37134 Verona, Italy.
Copyright 0 1997 by the American Neurological Association
181
l
~
EMG study analyzing spontaneous activity and the morphology of single motor unit potentials recorded (50 Hz to 5 kHz
Subjects and Methods
Patients
We studied 5 patients, 4 men and 1 woman, mean age 48.00
2 13.54 (SD) years, with a benign cramp-fasciculation syndrome of autosomal dominant inheritance. All had a long
history (more than 8 years) of disabling, generalized muscular
cramps predominantly affecting the leg muscles. The diagnosis of benign cramp-fasciculation syndrome was made
according to the following criteria: generalized cramps and
fasciculations of many years’ duration, no clinical or electrophysiological evidence of peripheral or central nervous system
involvement, and autosomal dominant inheritance. Autosoma1 dominant inheritance was established by the maleto-male transmission in the pedigrees of Patients 1 to 4.
Although Patient 5 clearly had a syndrome of dominant inheritance, it could have been either autosomal or X linked.
An X-linked inheritance seems unlikely in this pedigree, however, because as far as we know 3n X-linked cramp-fasciculation syndrome has never been described (Table 1). In some
cases the authors also examined the affected relatives.
All patients received a full clinical assessment, laboratory
testing, and a neurophysiological study.
Neurologic examination in the 5 patients before botulinum toxin A injections (to)disclosed no abnormalities except
cramps and fasciculations especially in calf and small flexor
foot muscles. All patients had normal tendon jerks; none had
sensory disturbances or pyramidal, cerebellar, or extrapyramidal signs.
Routine blood tests including hematocrit, erythrocyte sedimentation rate, white-cell count, platelet count, protein and
creatinine, calcium, phosphorus, bilirubin, electrolytes, alkaline phosphatase, and lactate dehydrogenase also gave normal
findings. Creatine phosphokinase levels were mildly increased
(1.5 times the normal value) in 2 patients (Patients 1 and
3).
T o exclude concomitant peripheral nerve disease, at toall
patients underwent conventional electroneurographic testing
comprising measurement of motor conduction velocities of
the peroneal nerve; antidromic sensory conduction velocities
in the sural nerve; H reflex in the soleus muscle; and F waves
recorded from extensor digitorum brevis after peroneal nerve
stimulation and from flexor hallucis brevis muscles after tibial
nerve stimulation. They also underwent a conventional
Table 1. Affected Relatives and Previous Treatment
Prescribed f o r the Five Patients with Benign
Cramp-Fascirulation Syndrome
Patient
Affected Relatives
1
Grandfather, father, son
2
3
4
5
Grandmother, father
Father, sister
Mother, son, daughter
Father, daughter
182 Annals of Neurology Vol 41
Previous
Treatments
Carbamazepine,
quinine
Carbamazepine
Carbamazepine
Carbamazepine
Carbamazepine,
quinine
No 2
February 1997
band-pass filters) with standard concentric needle electrodes
during voluntary contraction in calf muscles and small flexor
muscles of the foot. Conventional baseline (to)electroneurographic testing before botulinum toxin treatment showed
normal peroneal nerve motor conduction velocity; sural
nerve sensory conduction velocity; and peroneal and tibial
nerve Fresponses. EMG recordings obtained during a voluntary effort showed that the morphology, amplitude, and duration of the motor unit potentials were normal. In contrast,
recordings in relaxed muscles showed abundant and spontaneous activity of fasciculation potentials especially in calf and
small flexor foot muscles. Motor and somatosensory evoked
potentials were normal in all patients. Values in patients were
compared with the normal reference values of our laboratory.
Patients gave their informed consent and the study was
approved by the local ethics committee.
Clinical Evaluation and Botulinum Toxin Injections
O n thc day of botulinum toxin injection (to),patients underwent baseline clinical and neurophysiological evaluations.
Later in the day, botulinum toxin type A was injected into
the calf (gastrocnemius) muscle and small flexor foot muscles
of both sides at the same dosage (Table 2). Calf and small
flexor muscles of the foot were injected, because although
our patients often had generalized cramps, they predominantly had leg and foot cramps, and these were the chief
causes of their disabilities. Botulinum toxin type A (Dysport,
Speywood Pharmaceuticals Ltd, UK) was used. None of the
patients had been treated with botulinum toxin before. All
patients refrained from caking other drugs for at least 4 weeks
before the study. All patients had previously received unsuccessful or not tolerated drug treatments (see Table 1).
The severity of leg cramps was graded clinically (0 to 4 )
according to functional criteria (Cramp Severity Score, CSS):
0, no cramps; 1, occasional day and night cramps not interfering with daily activities or with nocturnal sleep; 2, frequent muscle cramps triggered by muscle exercise not significantly interfering with daily activities or with nocturnal
sleep; 3, continuous or subcontinuous muscle cramps triggered by muscle contraction and limiting daily activities and
nocturnal sleep; and 4,continuous muscle cramping severely
interfering with daily activities and nocturnal sleep.
Patients were reevaluated clinically and neurophysiologically 8 days after receiving botulinum toxin injection ( t , ) ,
and clinically 4 weeks later (t2)with cramp severity score.
The patients kept a diary for describing changes in their
cramps, and the data were used at follow-up 5 months later
to determine the onset of botulinum toxin’s effect, the time
of peak effect, and the duration of the effect.
Neu rophysiological Studies
The Cramp Threshold Frequency (CTF) was assessed according to a method described in detail elsewhere [11]. In
brief, responses to electrical stimuli delivered to the left tibial
nerve at the ankle were recorded through standard surface
Ag/AgC1 electrodes from the left flexor hailucis brevis muscle (belly tendon placement, 100 Hz to 5 kHz band-pass
filters). Stimulus trains of 40 supramaximal stimuli each
Table 2. Clinical and Neurophysiological Features of Patients with Autosomal Dominant Cramp-Fasciculation Syndrome
Cramp
Severity
Score
Dose of
Botulinum
36
1
M
2
65
M
3
50
M
4
44
M
5
72
F
M
=
Fasciculations
(nlsec)
Muscle
400
100
400
100
350
80
350
80
400
100
male; F = female; MU = mouse units; 1. GM
Cramp
Threshold (Hz)
=
1. GM
1. SFF
1. GM
1. SFF
1. GM
1. SFF
I. GM
1. SFF
4
1
5.5
10.0
1.18
0.66
4
2
2.5
4.0
0.84
0.42
3
1
7.6
14.0
0.68
0.38
4
2
3.0
12.0
0.75
0.38
1. GM
1. SFF
4
1
2.5
10.0
0.87
0.4 1
lefr gastrocnemius muscle; 1. SFF = left small foot flexor muscles.
(square waves of 0.10-msec duration) were delivered every
15 minutes. The frequency of stimulation started from 1 Hz
and was gradually increased until it reached a value that triggered a true cramp at the end of stimulus train (Fig 1). The
C T F was reassessed a few minutes later. Cramp was defined
electromyographically as the presence of EMG activity outlasting the nerve stimulation. Like spontaneous cramps, electrically induced cramps appeared clinically as painful involuntary shortening of the muscle. The C T F was assessed again
8 days later (t,).With the same experimental protocol, CTF
was studied in a group of 10 normal subjects (age, 43.5 2
11.1 years; 7 men and 3 women) with no family history
of cramps and no clinical or neurophysiological evidence of
peripheral nervous system disease [ 1 11. For CTF assessment,
we used a computerized program allowing recording of 100
consecutive rectified traces.
The number of fasciculations was estimated by recording
spontaneous EMG activity with a standard concentric needle
electrode (band-pass filters, 50 Hz to 5 kHz) in the relaxed
left flexor hallucis brevis muscle for 5 minutes at to and at
t,. EMG fasciculation activity was recorded at rest for 5 minutes and was expressed in fasciculation potentials per second
(FPslsec) .
M-wave changes in response to a single nerve stimulus
were also studied at to and ti.
Neurophysiologic data were recorded with a Biomedica
BASIS myograph (BASIS, Florence, Italy).
Data were stored on floppy disks and analyzed off-line.
Statistical Analysis
Results are expressed as mean ? 1 SD values. Data were
evaluated by paired and unpaired Student's t test. A p value
of <0.05 was defined as statistically significant.
Results
Clinical Evaluation
Eight days after botulinum toxin treatment ( t J ,all patients reported considerable relief of muscle cramps.
Their cramp scores were significantly lower than those
Fig 1. Cramp tbresboldj-equenry asessment in a normal subject. At I-Hz stimulus frequency (upper traces), M and F
waves are normally followed by the silent period. At 6.5-Hz
stimulus ji-equenry [mia'dlt traces) spontaneous activity appean
after M and F waves. A t tbe end of stimulation it disappears.
A t 10.0-Hz threshold fiequenry (lower traces), the spontaneous activity u more a b u n h n t and is self-maintaining at the
end of stimulation A true cramp is triggered. Recording
traces are &ll wave rectijed and superimposed, proceeding
ji-om bottom to top.
Bertolasi et al: Botulinum Toxin and Cramps
183
at to (to,3.80 5 0.44; ti, 1.40 f 0.54; p < 0.05,
paired data) (see Table 2). No patient reported increased fatigability or weakness of lower limb muscles
after botulinum toxin treatment. All patients were able
to walk on tiptoe with no difficulties after the injection. All patients had already resumed their normal
daily activities and could sleep better at night. At t,,
no patient complained of changes in the frequency or
severity of cramps in the uriinjected muscles of the upper limbs.
The onset of the beneficial effect ranged from 4 to
6 days (mean, 5 f 1.05 days) after botulinum toxin
injection. The effect peaked at 10 2 4 days and lasted
94.2 2 7.4 days. The effect of botulinum toxin in
relieving muscle cramps disappeared after 104 t 10.4
days. Follow-up assessment 5 months after treatment
showed that cramps had returned in all patients.
Neurophysiological Studies
CTF in patients before botulinum toxin injection was
significantly lower than in normal subjects (patients,
4.22 i 2.26 Hz; normal subjects, 10.71 IT 4.19 Hz;
p < 0.05, t test, unpaired data).
Repetitive nerve stimulation tests 8 days after botuliiium toxin injection (t,)showed that the CTF values
had significantly increased (to,4.22 2 2.26 Hz; t,, 10.0
2 3.74 Hz; p < 0.05, paired data) almost reaching
normal values (Fig 2 and Table 2). Fasciculation activ-
ity was significantly reduced after the toxin (to,0.86
t_ 0.19 FPslsec; tl, 0.45 t 0.11 FPs/sec; p < 0.05,
paired data) (Fig 3 and Table 2).
Nerve stimulation at t, elicited M waves slightly
smaller (18 f- 6%, p < 0.05, paired data) than those
at to.
Discussion
This study shows that patients with inherited crampfasciculation syndrome have a lower cramp threshold
frequency than normal subjects, and it provides clinical
and neurophysiological evidence that botulinum toxin
type A injections effectively relieve leg cramps and fasciculations in these patients. Patients tolerate local botulinum toxin treatment better than the other available
medical options for two reasons. First, it is free of the
poorly tolerated side effects, dizziness, asthenia, and
somnolence, and potential toxicity typically caused by
systemic drugs. Second, botulinum toxin does not need
daily administration because the effects of a single injection last for several weeks. The onset and duration
of the effect are comparable with those observed when
botulinum toxin is used to treat dysconias [ 121. Even
though for ethics reasons we studied only a specific
group of patients who had benign cramps, our findings
suggest that botulinum toxin should be effective in
treating nonbenign cramps in other disorders.
Botulinum toxin's mechanism of action in relieving
-
-
1.3 Hz
2.0 H,
"
THRESHOLD FRF,(>I E S C Y "
"THRESHOLD FRCQLLZCY"
3.0 HZ
A 2 0 0yY
20 "3%
Fig 2. Thresholdfrequency c h a n p befire (lej) and afier (right) botulinum toxin injection in a representative patient. Be$m botuh u m toxin injection, 3-Hz (lower traces on the lej) stimulation fiequency triggers a cramp, A j e r botulinum toxin injection, the
same stimulus fiequency (upper traces on the right) induces no involuntary activity following the M and F waves and the F wave
comes out clear&. Stimulus fiequeney must reach 12.0 Hz to induce a cramp (lower traces on the right).
184 Annals of Neurology
Vol 41
No 2
February 1997
100 p v
.--:
i
:
i
2-.
L
:
-
i__
.
.
500 i n s
Fig 3. Electromyographic recordings of spontaneous activity from left halhcis brevis muscle before (upper trace) and 8 days after
botulinum toxin injection (lower trace) in Subject I . Before treatment, abundant fasciculations sometime tviggered a brief inuolunt a y burst of high-frequency motor unit potentials (at the beginning of the upper trace). This phenomenon disappeared after treatment (lower trace)
muscle cramps remains conjectural, mainly because research has never identified a unifying theoretical model
for muscle cramps. Two models have been proposed
to explain their origin. The first postulates that cramps
originate from paroxysmal spontaneous activity in the
intramuscular motor nerve endings [ l , 10, 111. The
other favors a central origin of muscle cramps due to
changes in motoneuronal excitability [ 131. The two
models do not reciprocally exclude each other and are
suitable to explain cramps occurring in physiologic or
in pathologic conditions. A review of current knowledge is far beyond the scope of this report; nevertheless,
we agree with the “peripheral model” [3, 111 and that
the primary site of origin of muscle cramps is the intramuscular branches of motor axons. This model does
not exclude that in physiological conditions, high-frequency volleys due to changes of motoneuron excitability in the spinal cord could also induce paroxysmal
activity of intramuscular motor axons, thereby precipitating a cramp [ 131. Muscle cramps in pathologic conditions probably depend on a hypersensitivity to mechanical and chemical stimuli occurring in the distal
branches of motor axons [3]. Most fasciculation potentials originate in the motor nerve terminal and propagate to the remaining arborization [3]. Fasciculations
are produced by direct presynaptic effect of acetylcholine on intramuscular nerve terminals [3, 141.
Cramps and fasciculations are not observed in curarized muscles [9]. Hence, botulinum toxin’s action in
relieving muscle cramping and fasciculations probably
depends on the induced cholinergic presynaptic block
of the motor end-plate. This would have numerous
consequences. For example, it would reduce the total
amount of acetylcholine in the muscle [ 101, thus relieving fasciculations. Our results agree with those of Forster and Alpers [15] who showed that nonparalyzing
doses of curare abolished spontaneous fasciculations in
patients with amyotrophic lateral sclerosis. It is interesting that also in our patients the effect of botulinum
toxin exerted its effect without causing noticeable muscle paralysis. Its cramp-relieving action therefore seems
to depend less on mechanical factors than on reduction
of acetylcholine in the extracellular muscle space secondary to the presynaptic block produced by the toxin.
In other words, the effect of botulinum toxin suggests
that like fasciculations [3, 131 cramps arise from a presynaptic action of acetylcholine on motor nerve terminals in the muscle. Second, an impaired nerve-muscle
coupling would produce fewer chemical catabolites
able to excite the distal motor axons. Third, a reduced
muscle shortening would result in a decreased mechanical stimulation of intramuscular nerve fibers possibly
caused also by the decrease in muscle fiber size owing
to botulinum toxin-induced myopathy [ 161.
Bertolasi et al: Botulinum Toxin and Cramps
185
Besides these “peripheral” effects, botulinum toxin
might also act through a second, concurrent mechanism. Recent experimental evidence suggests that muscle cramps in healthy subjects arise from changes in
spinal motoneuron excitability due to a positive feedback loop between muscle afferents and a-motoneurons [17]. Botulinum toxin reduces proprioceptive input from muscle spindles in animals probably by
blocking fusimotor synapses [ 181. The therapeutic effect of botulinum toxin in dystonia could also result
from the reduction of muscle afferent input [ 191 possibly due to the block of the fusimotor synapse. Reduced
input would reduce the excitatory drive of spinal motoneurons, decreasing the probability of high-frequency
discharges able to give rise to cramps. The two mechanisms described might be concurrent, the second
boosting the first.
In conclusion, this pilot open study shows that intramuscular injection of botulinum toxin is an effective,
safe, and long-lasting treatment of muscle cramps and
fasciculations. Botulinum toxin probably exerts its effect by blocking intrafusal and extrafusal motor end
plates, thereby reducing acetylcholine in the extracellular space of the muscle. Our data also suggest the importance in relieving cramps of a toxin-induced reduction of presynaptic cholinergic stimulation of motor
nerve terminals.
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