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“Presynaptic” inhibition in spasticity and the effect of β(4-chlorophenyl)Gaba
Journal of the neurological Sciences, 1973, 20:329--338 ' © Elsevier Scientific Publishing Company, A m s t e r d a m - Printed in The Netherlands
329
"Presynaptic" Inhibition in Spasticity and the Effect of
fl(4-Chlorophenyl)Gaba PETER ASHBY AND DAVID G. WHITE Neurophysiology unit, Toronto Western Hospital, Toronto (Canada) (Received 5 June, 1973)
INTRODUCTION
There is good evidence that the suppression of the monosynaptic reflex by muscle vibration in animals is due to "presynaptic" inhibition. It has been shown that the suppression is accompanied by depolarization of group la afferents and normal excitability of motoneurones, and that both the suppression and the associated dorsal root potential can be blocked by picrotoxin (Gillies, Lance, Neilson and Tassinari 1969; Barnes and Pompeiano 1970a). In man vibration of a limb is a much less specific stimulus but the suppression of the monosynaptic reflex by vibration is "central" (Gillies, Lance and Tassinari 1969) and"premotoneuronal" (Delwaide 1971) and is therefore also likely to be due to "presynaptic" inhibition. Delwaide (1969) and Burke and Ashby (1972) observed that the inhibition of the monosynaptic reflex by vibration was less marked in spastic patients and have suggested that a reduction of "presynaptic" inhibition might be one of the factors contributing to the hyperexcitability of motoneurones in spasticity. A derivative of gamma-amino-butyric-acid, fl(4-chlorophenyl)GABA, (baclofen, CIBA 34,647-Ba, Lioresal®), has been shown to be effective in spasticity (Zschocke and Brune 1965; Bergamini, Riccio and Bergamasco 1966; Birkmayer, Danielczyk and Weiler 1967; Castaneda 1967; Jerusalem 1968; Pedersen, Arlien-Soborg, Grynderup and Hendriksen 1970; Jones, Burke, Marosszeky and Gillies 1970; Hudgson and Weightman 1971), and Burke, Andrews and Knowles (1971) have suggested that the substance may increase "presynaptic" inhibition, an attractive theory since GABA may be the transmitter of "presynaptic" inhibition (Curtis and Felix 1971). In this study, inhibition of the H-reflex by vibration is used as an index of"presynaptic" inhibition. The inhibition is shown to be less in spastic patients. In a doubleblind cross-over trial fl(4-chlorophenyl)GABA is shown to reduce the exaggerated stretch reflexes in spasticity without significantly affecting "presynaptic" inhibition. MATERIALS AND METHODS
The trial involved 11 patients (mean age 42 years) with established spasticity and
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without contractures. The spasticity resulted from purely spinal lesions in 4 (arachnoiditis, transverse myelitis, cervical cord trauma and spinal extradural abcess), a purely cerebral lesion (trauma) in 1 and multiple sclerosis in 6. In the patient with arachnoiditis the spinal cord lesion was clinically complete. Five normal subjects (mean age 32 years) were used as controls for the H-reflex studies. The double-blind cross-over trial consisted of 2 periods each of 7-10 days duration. All medications that could influence gpasticity were discontinued at least 24 hr before starting the trial. The patients received at random, either placebo or the active preparation during the first period before switching to the alternative preparation. In each instance the initial dose was 10 mg t.i.d., increasing over the first 1 2 days to 20 mg t.i.d. In some patients the dose was increased up to 30 mg t.i.d. The patients were visited daily to enquire about side-effects but the principal clinical and electrophysiological assessments were made at the end of each period. Clinical a s s e s s m e n t
Clinical assessments were made upon the biceps and triceps of the upper limbs and on the quadriceps and hamstrings of the lower limbs. Since the response to muscle stretch may vary widely in spastic patients an attempt was made to subdivide the reflex responses to muscle stretch by scoring the responses under 3 headings (Table 1). The "velocity-dependent"reflex was scored by moving the limb at different rates and assessing that component of the stretch reflex related closely to the velocity of movement. The "tonic" component of the stretch reflex was graded by judging the duration of the reflex muscle contraction following a sudden brief stretching movement in midrange. The "static" component was assessed by judging the duration of the reflex muscle contraction following rapid full extension of the muscle. These scores for each muscle were combined to give a "total" score for the muscle. The combined total score for the 4 muscles (both quadriceps and both hamstrings) gave the score for the tone of the lower limbs of that patient (possible maximum score 32). TABLE 1 CLINICAL SCORING OF MUSCLE TONE
Clinical a.~se.~.~ment o/mu.~c'le trine Velocity-dependent reflex
0 absent at high velocity 1 detectableat high velocity 2 easilyobtained 3 present with even slowest movement Tonic reflex
0 absent 1 persists less than 1 sec 2 persists more than 1 sec 3 limb difficultto move Static reflex
0 absent I persists less than 1 sec 2 persists
"PRESYNAPTIC" INHIBITION IN SPASTICITY
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Tendon jerks were scored - 2 to + 2 (normal 0; maximum possible score for lower limbs 8). Muscle strength was scored on the MRC scale (possible maximum score for lower limbs 20). By pinching the second toe on each foot 3 times at 1 see intervals a flexion response could be scored (0, absent; 1, muscle contraction observed in hamstrings or tibialis anterior; 2, heel moves less than 6 inches; 3, heel moves more than 6 inches or is elevated from the bed. Normal score 0; possible maximum score 6).
Electromyographic measurement of spasticity The relationship between the velocity of stretch and the resulting reflex electromyogram (EMG) was used as an objective assessment of spasticity. The patients lay prone. The quadriceps and hamstrings muscles were stretched by moving the lower leg manually. Surface electrodes, in standardized positions 10-15 cm apart, were placed over the quadriceps and hamstrings to record the reflex EMG produced by muscle stretch. These potentials were monitored on an oscilloscope to detect artefact and field spread from antagonistic muscles. There is a linear relationship between knee-joint angle and the length of quadriceps and hamstrings muscles (Burke, Gillies and Lance 1970). Knee-joint angle was therefore measured by a goniometer and the output differentiated (time constant 0.3 sec) to supply a voltage proportional to the angular velocity. Direct EMG, integrated EMG (time constant 0.2 sec), knee-joint angle and angular velocity were recorded, for each muscle, on an Offner dynograph. Integrated EMG was plotted against angular velocity and regression analysis performed. The intercept of the regression line on the velocity axis was termed "threshold velocity". The mean integrated EMG in response to slow (100 degrees/sec) and fast (500 degrees/sec) movements was also recorded from the regression line.
Effect of vibration on the H-reflex A satisfactory H-reflex was obtained on 10 of the spastic patients. Five normal subjects served as the controls. The patients lay prone. Stimuli from a Grass $88 stimulator were delivered to the posterior tibial nerve in the popliteal fossa. The stimuli were triggered from a PDP 12 with a random interval always between 2-3 sec taken from random numbers stored in the memory. The EMG was recorded from 2 surface electrodes placed 10-15 cm apart over the soleus muscle. These potentials were amplified on a Tectronix amplifier and monitored on an oscilloscope. The stimulus level was adjusted to achieve maximum H and minimum M. Vibration was applied with a commercially available massage vibrator fitted with a 4 cm diameter sorbo rubber pad. Oscillations of 60 Hz with amplitude 2.5 mm (approximately) were used throughout. The vibration was applied on the lateral or medial aspect of the triceps surae at a level midway between the recording electrodes. In any individual the same side was used on all occasions. Care was taken that the stimulating and recording electrodes were not displaced either by the v~brator or by the developed tonic vibration reflex. Any recording in which there was a significant alteration in the M-response was therefore discarded. The responses to 50 consecutive stimuli were averaged by a PDP 12 computer and this constituted one "run". Control runs and runs with muscle vibration were alternated until 3 satisfactory pairs were completed. (In 2 patients where there was a risk of spontaneous flexor spasms
332
r,. ASHBY, D. G. WHITE
interrupting the procedure 8 runs of 30 stimuli were used instead). The average of 50 responses and the variance was plotted on an X-Y plotter and the peak to peak heights of H-control and H-vibration were measured. The H-vibration/H-control ratio was estimated for each pair and the mean ratio of the 3 (or more) estimates calculated.
Statistics The clinical scores, EMG values, threshold velocities, and the H-vibration/Hcontrol ratios were compared by Student's t-test. All calculations were completed and the conclusions established before the code was broken. RESULTS
Clinical assessment of spasticity Both the upper and lower limbs were assessed. However, identical conclusions resulted from combining the upper and lower limb scores or taking the lower limb scores alone (this probably indicates that most patients had either normal upper limbs or abnormalities that respond in the same way as the lower limbs). For simplicity, only the lower limb scores will be presented. In relaxed normal subjects no detectable velocity-dependent, tonic, or static reflex response occurred in response to muscle stretch, the tendon reflex score was 0, and no involuntary flexion reflex occurred. Muscle power score in the 2 quadriceps and 2 hamstrings totalled 20. In the spastic patients tone was increased. The mean scores on placebo (both quadriceps and both hamstrings combined) were: velocitydependent reflex 9.4, tonic reflex 6.1, static reflex 2.1, total 17.6; tendon reflexes were exaggerated (mean score 4.3), the flexion reflex was hyperactive (mean score 3,0) and significant weakness was present (mean score 11.8). The hamstrings tended to be slightly weaker than the quadriceps, the tendon jerks were brisker in quadriceps. STRETCH REFLEXES
Tendon
Flexio~
Total
jerks
reflex
V
T
S
Rawer
WORSE
BETTER
Fig. 1. Effect of 13(4-chlorophenyl)GABA on the clinical scores of spastic patients. Means and S.D. of individual differences between the scores (quadriceps and hamstrings of both legs combined) on placebo and active preparation (n = 11). There is a significant reduction in velo~ty dependent (V) and tonic (T) stretch reflexes accounting for a significant improvement in total stretch reflex score. The static stretch reflex (S) and other clinical parameters are unchanged.
"PRESYNAPTIC" INHIBITION IN SPASTICITY
333
There were no other significant differences between the flexor and extensor muscles. /~(4-chlorophenyl)GABA produced a significant decrease in tone (Fig. 1). Mean differences (both quadriceps and both hamstrings combined) were as follows. Difference in total score 7.2 (t=3.2, P>0.01), difference in velocity-dependent reflex score 3.2 (t = 4.0, P > 0.01 ), difference in tonic reflex score 2.9 (t = 2.7, P > 0.05). There were no statistically significant changes in the'other parameters. Quadriceps and hamstrings responded in an identical manner.
Electromyographic assessment of spasticity Muscle stretch, even at low velocity, resulted in a reflex EMG in the quadriceps and hamstrings of all spastic patients. The mean threshold velocity for quadriceps was 68.2 degrees/sec and for hamstrings 72.7 degrees/sec. The mean integrated EMG at 100 degrees/sec in quadriceps was 32.7 #V, and in hamstrings 57 #V; the mean integrated EMG at 500 degrees/sec in quadriceps was 318 #V, and in hamstrings 290 #V (differences between quadriceps and hamstrings were not significant). Threshold velocity was inversely related to the clinical scores of muscle tone. The best correlations were between the clinical scores of muscle tone and the EMG at 100 degrees/sec. /~(4-chlorophenyl)GABA caused substantial changes in the EMG velocity relationship in both muscles (Fig. 2). There was a significant increase in the threshold velocity for the production of EMG [mean difference in quadriceps 49 degrees/sec (t = 2.6, P > 0.05), and hamstrings 54 degrees/sec (t = 2.4, P > 0.05)] and a significant decrease in integrated EMG produced by movements at 100 degrees/sec [-mean difference in quadriceps 30 #V (t=2.3, P>0.05), and hamstrings 56 #V (t=2.8, P >0.05)], and at 500 degrees/sec [mean difference in quadriceps 109 #V (t= 2.6, P>0.05), and hamstrings 170 #V (t=4.3, P>0.01)]. There were no significant differences in the responses of the 2 muscles. C ~ IN TI'IRESHOLD VELOC I T Y
Q
Velocity
Y~
H
CHANGE IN INT. EMG AT AT
1OOTsec
Q
H
5OO~sec
Q
H
"'"l:J'"II ........ D 10 ltd.EMG~uv
I k Fig. 2. The effect of 13(4-chlorophenyl)GABA on the reflex EMG of spastic patients. Means and S.D. of individual differences between results on placebo and active preparation (n = 11). There is a significant increase in the threshold velocity required to produce reflex EMG and a significant decrease in the reflex EMG produced by slow (100 degrees/sec) and rapid (500 degrees/sec) muscle stretch. (Q, quadriceps; H, hamstrings).
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P. ASHBY, D. G. WHITE
Effect of vibration on the H-reflex Preliminary studies in this laboratory demonstrated that the H-vibration/Hcontrol ratio is virtually independent of the site of vibration in the lower leg and of the position on the H - M recruitment curve in normal subjects and spastic patients. It therefore appeared justifiable to employ this technique on successive occasions as the degree of suppression is not influenced by minor changes of electrode or vibrator placement. Attentuation of the H-reflex by vibration in 10 spastic patients on placebo was significantly reduced in comparison with normal controls (Figs. 3 and 4). The mean H-vibration/H-control ratio (expressed as a percentage) tbr 5 normal subjects was 2.1 ~ and for 10 spastic patients 26.9~o. This difference is highly significant. The H-vibration/H-control ratios in spastic patients on placebo show a considerable range but no significant correlations were achieved between the H-vibration/H-control ratio and the clinical estimates of tone, reflexes, flexion reflexes, strength or EMG results. fl(4-chlorophenyl)GABA had no significant effect on the mean H-vibration/Hcontrol ratio of spastic patients (Fig. 4). Improvement in spasticity could not be correlated with either the initial H-vibration/H-control ratio nor the improvement in this ratio with treatment. NORMAL
SPASTIC
CONTROL
1'' Fig. 3. Effect of muscle vibration on H-reflex. In a normal subject the H.reflex is almost completely inhibited. In a spastic patient this is less marked. Each trace represents the average of 50 responses. SPASTIC
40-
H vib ,~, H control 20"
NORMAL
t_ Fig. 4. Effect of vibration on the H-reflex. Mean and standard deviations. In normal subjects (n = 5) the H-reflex is almost completely inhibited. In spastic patients (n = 10) on placebo (B) the inhibition is less marked. This is not significantly affected by fl(4-chlorophenyl)GABA (A).
~PRESYNAPTIC" INHIBITION IN SPASTICITY
335
Side-effects Significant side-effects were encountered in 3 patients on the active preparation and minor symptoms were mentioned by a further 3. The most common side-effect (4 patients) was a feeling of intoxication characterized by indifference and lethargy ("--I could not care--" ; "--lack of drive--"). In one instance it was accompanied by difficulty in initiating movements " - - I t was right beside me but I did not care to move my hand--". Drowsiness was mentioned by 3 patients, 4 patients described dizziness and in 1 this was immediately aggravated by the inhalation of cigarette smoke. Two patients described distortions of sounds ("--Voices sound different~"), and 2 patients complained of altered respiration ("--As if I want to take a deep breath all the time--"). Significant side-effects on the active preparation were commoner in the female patients. The side-effects usually occurred at a dose of 20 mg t.i.d, but were encountered in 1 patient on 10 mg t.i.d, whereas another patient tolerated 30 mg t.i.d, with only minor symptoms. Side-effects occurred approximately 2 hr after ingesting the medication and all side-effects disappeared if the dose was reduced. Minor symptoms occurred in 4 patients while on placebo. These included muscle spasm, sleeplessness and peripheral paraesthesiae.
DISCUSSION
In this study muscle vibration resulted in almost total inhibition of the monosynaptic reflex in normal subjects but not in spastic patients. This confirms the observations of Delwaide (1969) and Burke and Ashby (1972) suggesting that "presynaptic" inhibition may be impaired in spasticity. The degree of this impairment varied considerably between patients but could not be correlated with the site of the lesion or with the severity of the spasticity. In animals primary afferent depolarization of 1 a afferents, accompanied by inhibition of the monosynaptic reflex, can be induced from the medial vestibular nucleus (Carpenter, Engberg and Lundberg 1966; Barnes and Pompeiano 1970b). The loss of some similar supraspinal enhancement could explain the impairment of"presynaptic" inhibition observed in spinal spasticity. //(4-chlorophenyl)GABA has been shown to produce a significant reduction in the stretch reflexes of spastic patients; some consideration may now be given to its site of action. The substance must have a direct effect on the spinal cord since it has been shown to be effective in patients with clinically complete spinal cord lesions both in this study and in that of Jones et al. (1970). The naturally occurring amino-acid GABA may be an inhibitory transmitter in the spinal cord. Iontophoretically-applied GABA inhibits ~- and 7- motoneurones, interneurones and Renshaw cells in the cat (Curtis and Watkins 1965). It is of interest that amino-oxyacetic acid, which causes an increase in central nervous system GABA, will reduce spasticity in congenitally spastic mice (Roberts and Kuriyama 1968). /~(4-chlorophenyl)GABA is chemically related to GABA. Iontophoreticallyapplied/~(4-chlorophenyl)GABA will also produce inhibition in certain cat spinal neurones (Curtis, D.R., personal communication) so it is tempting to suggest that
336
e. ASHBY, D. G. WHITE
fl(4-chlorophenyl)GABA simply mimics the action of GABA. Animal studies performed by CIBA laboratories with fi(4-chlorophenyl)GABA have demonstrated effects on fusimotor activity. However there was no significant alteration in the tendon jerks in this study or in that of Jones et al. (1970). Thus there is no positive evidence to support any alterations in fusimotor drive in man. Birkmayer et al. (1967), using intravenous/3(4-chlorophenyl)GABA, found a reduction in the H-reflex and suggested that the drug had a direct action on the e-motoneurone; but such an effect on the monosynaptic reflex is not prominent after oral administration even though the spasticity may be profoundly reduced. Recently Curtis and Felix (1971) provided evidence that GABA may be the transmitter of"presynaptic" inhibition, and Burke et al. (1971 ), have postulated that /~(4-chlorophenyl)GABA may restore "'presynaptic" inhibition in spastic patients. This hypothesis was examined in the present study using the H-vibration/H-control ratio as a measure of "presynaptic" inhibition. Although/~(4-chlorophenyl)GABA produced a clear reduction in the stretch reflex there was no significant alteration in the mean H-vibration/H-control ratio. There is no evidence, therefore, from this study that fl(4-chlorophenyl)GABA reduces spasticity by increasing "presynaptic'" inhibition. Although iontophoretically-applied GABA inhibits c~- and ?,-motoneurones and interneurones (Curtis and Watkins 1965) these neurones may have graded susceptibilities since intravenous GABA can produce differential effects upon reflex pathways (Kuno 1961; Basil, Blair and Holmes 1964). Kuno (1961) has postulated that certain interneurones are the most sensitive to GABA inhibition. In this study stretch reflexes that employ tonic mechanisms were more affected than phasic responses such as the tendon jerk. The reduction in spasticity produced by /~(4chlorophenyl)GABA could therefore result from an inhibitory action primarily upon interneurones, an effect on the e-motoneurone only becoming apparent with large doses or intravenous administration (Birkmayer et al. 1967). Kuno (1961) found that GABA had no effect upon the interneurones of a decerebrate preparation and suggested that they were already under tonic inhibition from the brain-stern. A similar explanation might underly the failure of/~(4-chlorophenyl)GABA to improve patients with cerebral spasticity which was noted in this trial and that of Bergamini et al. (1966). In conclusion it is suggested that while/~(4-chlorophenyl)GABA may inhibit all types of neurone in the spinal cord its principal action when administered orally to spastic patients is probably upon interneurones. Side-effects were prominent in this study occurring in approximately 50 ~o of the patients. This has been reported in some previous studies (Pedersen et al. 1970) while others have reported only minimal side-effects (Jerusalem 1968; Jones et al, 1970; Hudgson and Weightman 1971) possibly because the doses were increased more slowly. This present study was principally concerned with the mode of action of the drug and no attempt was made to evaluate the patient's functional improvement. Nevertheless the drug is evidently beneficial in reducing intense spasticity and 2 patients chose to continue the preparation in preference to their previous antispastic medication.
"PRESYNAPTIC" INHIBITION IN SPASTICITY
337
ACKNOWLEDGEMENTS
The authors are grateful to Dr. Jousse for permission to study the patients under his care and to Dr. D. Burke (University of New South Wales) for advice and criticism. The illustrations were photographed by the department of medical photography of the Toronto Western Hospital and the manuscript was prepared by Mrs. E. Nielsen. CIBA-Geigy Canada Limited kindly supplied Lioresal* and identical placebo for use in this study. SUMMARY
Muscle vibration produces less inhibition of the H-reflex in spastic patients than in normal subjects suggesting that "presynaptic" inhibition may be impaired in spasticity. In a double-blind cross-over trial on 11 spastic patients fl(4-chlorophenyl)GABA reduced the stretch reflexes without any significant effect on the inhibition of the H-reflex by vibration. There is, therefore, no evidence from this study that fl(4-chlorophenyl)GABA improves spasticity by restoring "presynaptic" inhibition.
REFERENCES
BARNES,C. D. AND O. POMPEIANO(1970 a) Inhibition of monosynaptic extensor reflex attributable to presynaptic depolarization of the group la afferent fibers produced by vibration of a flexor muscle, Arch. ital. Biol., 108: 233-258. BARNES,C. n . AND O. POMPEIANO(1970 b) Dissociation of presynaptic and postsynaptic effects produced in the lumbar cord by vestibular volleys, Arch. ital. Biol., 108: 295-324. BASIL, B., A. M. J. N. BLAIRAND S. W. HOLMES(1964) The action of sodium-4-hydroxybutyrate on spinal reflexes, Brit. J. Pharmacol., 22: 318-328. BERGAMINI, L., A. RICCIO AND B. BERGAMASCO(1966) Un farmaco ad azione antispastica della muscolatura striata. Sperimentazione clinica di un derivato del Gaba, Minerva reed., 57 : 2723-2729. B1RKMAYER,VONW., W. DANIELCZYKUND G. WEILER(1967) Zur Objekt!vierbarkeit des myotonolytisches Effekts eines Aminobuttersiiurederivates (Ciba 34, 647-Ba), Wien. reed. Wschr., 1!7: 7-9. BURKE, n . AND P. ASHBY(1972) Are spinal "presynaptic" inhibitory mechanisms suppressed in spasticity? J. neurol. Sci., 15: 321-326. BURKE, D., C. J. ANDREWSAND L. KNOWLES(1971) The action of a GABA derivate in human spasticity, J. neurol. Sci., 14: 199-208. BURKE, n., J. D. GILLIES AND J. W. LANCE (1970) The quadriceps stretch reflex in human spasticity, J. Neurol. Neurosurg. Psychiat., 33:216-223. CARPENTER, D., I. ENGBERGAND A. LUNDBERG(1966) Primary afferent depolarization evoked from the brainstem and the cerebellum, Arch. ital. Biol., 104: 50-72. CASTANEDA,C. (1967) Investigaci6n de CIBA 34, 647-Ba en los sindromes esp~isticos neurol6gicos, Sere. m~d. M~x., 54: 13-16. CURTIS, D. R. AND D. FELIX (1971) GABA and prolonged spinal inhibition, Nature New Biology, 231: 187-188. CURTIS, D. R. ANDJ. C. WATKINS(1965)The pharmacology of aminoacids related to gamma-aminobutyric acid, Pharmacol. Rev., 17: 347-391. DELWAIDE,P. J. (1969)Approche de la physiopathologie de la spasticit6. R6flexe de Hoffmann et vibrations appliqu6es sur le tendon d'Achille, Rev. neurol., 121 : 72-74. DELWAIDE, P. J. (1971) Etude Exp~rimentale de l'Hyperr~flexie Tendineuse en Clinique Neurologique, Arscia, Brussels. GILLmS, J. D., J. W. LANCEAND C. A. TASSlNARI(1969) The mechanism of the suppression of the monosynaptic reflexes by vibration, Proc. Aust. Ass. neurol., 7: 97-102. GILLIES, J. D., J. W. LANCE, P. D. NEILSON AND C. A. TASSINARI(1969) Presynaptic inhibition of the monosynaptic reflex by vibration, J. Physiol. (Lond.), 205: 329-339.
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HUDGSON, P. AND D. WEIGHTMAN (1971) Baclofen in the treatment of spasticity, Brit, med. J,, 4:15 17. JERUSALEM,F. (1968) Doppeltblindstudie fiber den antispastischen Effekt von/~(4-Chlorophenyl)-gammaAminobutters/iure (CIBA) bei Multipler Sklerose, Nervenarzt, 39 : 515-517. JONES, R. F., D. BURKE,J. E. MAROSSZEKYAND J. D. GILLIES (1970) A new agent for the control of spasticity. J. Neurol. Neurosurg. Psychiat., 33 : 464-468. KuNo, M. (1961) Site of action of systemic gamma-aminobutyric acid in the spinal cord, Jap. J. Phsio/.. 11 : 304-318. PEDERSEN,E., P. ARLIEN-SoBORG,V. GRYNDERUPAND O. HENDRIKSEN(1970) GABA derivative in spasticity. Acta neurol, scand., 46 : 257-266. ROBEgTS, E. AND K. KURIVAMA(1968) Biochemical-physiological correlations in studies of the gammaaminobutyric acid system, Brain Res., 8 : 1-35. ZSCHOCKE, S. AND G. BRUNE (1965) Klinische und elektromyographische Studien fiber die pharmakologische Beeinflussung der Spastik, Verh. dtsch. Ges. inn. Med., 71 : 662-665.
329
"Presynaptic" Inhibition in Spasticity and the Effect of
fl(4-Chlorophenyl)Gaba PETER ASHBY AND DAVID G. WHITE Neurophysiology unit, Toronto Western Hospital, Toronto (Canada) (Received 5 June, 1973)
INTRODUCTION
There is good evidence that the suppression of the monosynaptic reflex by muscle vibration in animals is due to "presynaptic" inhibition. It has been shown that the suppression is accompanied by depolarization of group la afferents and normal excitability of motoneurones, and that both the suppression and the associated dorsal root potential can be blocked by picrotoxin (Gillies, Lance, Neilson and Tassinari 1969; Barnes and Pompeiano 1970a). In man vibration of a limb is a much less specific stimulus but the suppression of the monosynaptic reflex by vibration is "central" (Gillies, Lance and Tassinari 1969) and"premotoneuronal" (Delwaide 1971) and is therefore also likely to be due to "presynaptic" inhibition. Delwaide (1969) and Burke and Ashby (1972) observed that the inhibition of the monosynaptic reflex by vibration was less marked in spastic patients and have suggested that a reduction of "presynaptic" inhibition might be one of the factors contributing to the hyperexcitability of motoneurones in spasticity. A derivative of gamma-amino-butyric-acid, fl(4-chlorophenyl)GABA, (baclofen, CIBA 34,647-Ba, Lioresal®), has been shown to be effective in spasticity (Zschocke and Brune 1965; Bergamini, Riccio and Bergamasco 1966; Birkmayer, Danielczyk and Weiler 1967; Castaneda 1967; Jerusalem 1968; Pedersen, Arlien-Soborg, Grynderup and Hendriksen 1970; Jones, Burke, Marosszeky and Gillies 1970; Hudgson and Weightman 1971), and Burke, Andrews and Knowles (1971) have suggested that the substance may increase "presynaptic" inhibition, an attractive theory since GABA may be the transmitter of "presynaptic" inhibition (Curtis and Felix 1971). In this study, inhibition of the H-reflex by vibration is used as an index of"presynaptic" inhibition. The inhibition is shown to be less in spastic patients. In a doubleblind cross-over trial fl(4-chlorophenyl)GABA is shown to reduce the exaggerated stretch reflexes in spasticity without significantly affecting "presynaptic" inhibition. MATERIALS AND METHODS
The trial involved 11 patients (mean age 42 years) with established spasticity and
330
P. ASHBY, D. G. WHITE
without contractures. The spasticity resulted from purely spinal lesions in 4 (arachnoiditis, transverse myelitis, cervical cord trauma and spinal extradural abcess), a purely cerebral lesion (trauma) in 1 and multiple sclerosis in 6. In the patient with arachnoiditis the spinal cord lesion was clinically complete. Five normal subjects (mean age 32 years) were used as controls for the H-reflex studies. The double-blind cross-over trial consisted of 2 periods each of 7-10 days duration. All medications that could influence gpasticity were discontinued at least 24 hr before starting the trial. The patients received at random, either placebo or the active preparation during the first period before switching to the alternative preparation. In each instance the initial dose was 10 mg t.i.d., increasing over the first 1 2 days to 20 mg t.i.d. In some patients the dose was increased up to 30 mg t.i.d. The patients were visited daily to enquire about side-effects but the principal clinical and electrophysiological assessments were made at the end of each period. Clinical a s s e s s m e n t
Clinical assessments were made upon the biceps and triceps of the upper limbs and on the quadriceps and hamstrings of the lower limbs. Since the response to muscle stretch may vary widely in spastic patients an attempt was made to subdivide the reflex responses to muscle stretch by scoring the responses under 3 headings (Table 1). The "velocity-dependent"reflex was scored by moving the limb at different rates and assessing that component of the stretch reflex related closely to the velocity of movement. The "tonic" component of the stretch reflex was graded by judging the duration of the reflex muscle contraction following a sudden brief stretching movement in midrange. The "static" component was assessed by judging the duration of the reflex muscle contraction following rapid full extension of the muscle. These scores for each muscle were combined to give a "total" score for the muscle. The combined total score for the 4 muscles (both quadriceps and both hamstrings) gave the score for the tone of the lower limbs of that patient (possible maximum score 32). TABLE 1 CLINICAL SCORING OF MUSCLE TONE
Clinical a.~se.~.~ment o/mu.~c'le trine Velocity-dependent reflex
0 absent at high velocity 1 detectableat high velocity 2 easilyobtained 3 present with even slowest movement Tonic reflex
0 absent 1 persists less than 1 sec 2 persists more than 1 sec 3 limb difficultto move Static reflex
0 absent I persists less than 1 sec 2 persists
"PRESYNAPTIC" INHIBITION IN SPASTICITY
331
Tendon jerks were scored - 2 to + 2 (normal 0; maximum possible score for lower limbs 8). Muscle strength was scored on the MRC scale (possible maximum score for lower limbs 20). By pinching the second toe on each foot 3 times at 1 see intervals a flexion response could be scored (0, absent; 1, muscle contraction observed in hamstrings or tibialis anterior; 2, heel moves less than 6 inches; 3, heel moves more than 6 inches or is elevated from the bed. Normal score 0; possible maximum score 6).
Electromyographic measurement of spasticity The relationship between the velocity of stretch and the resulting reflex electromyogram (EMG) was used as an objective assessment of spasticity. The patients lay prone. The quadriceps and hamstrings muscles were stretched by moving the lower leg manually. Surface electrodes, in standardized positions 10-15 cm apart, were placed over the quadriceps and hamstrings to record the reflex EMG produced by muscle stretch. These potentials were monitored on an oscilloscope to detect artefact and field spread from antagonistic muscles. There is a linear relationship between knee-joint angle and the length of quadriceps and hamstrings muscles (Burke, Gillies and Lance 1970). Knee-joint angle was therefore measured by a goniometer and the output differentiated (time constant 0.3 sec) to supply a voltage proportional to the angular velocity. Direct EMG, integrated EMG (time constant 0.2 sec), knee-joint angle and angular velocity were recorded, for each muscle, on an Offner dynograph. Integrated EMG was plotted against angular velocity and regression analysis performed. The intercept of the regression line on the velocity axis was termed "threshold velocity". The mean integrated EMG in response to slow (100 degrees/sec) and fast (500 degrees/sec) movements was also recorded from the regression line.
Effect of vibration on the H-reflex A satisfactory H-reflex was obtained on 10 of the spastic patients. Five normal subjects served as the controls. The patients lay prone. Stimuli from a Grass $88 stimulator were delivered to the posterior tibial nerve in the popliteal fossa. The stimuli were triggered from a PDP 12 with a random interval always between 2-3 sec taken from random numbers stored in the memory. The EMG was recorded from 2 surface electrodes placed 10-15 cm apart over the soleus muscle. These potentials were amplified on a Tectronix amplifier and monitored on an oscilloscope. The stimulus level was adjusted to achieve maximum H and minimum M. Vibration was applied with a commercially available massage vibrator fitted with a 4 cm diameter sorbo rubber pad. Oscillations of 60 Hz with amplitude 2.5 mm (approximately) were used throughout. The vibration was applied on the lateral or medial aspect of the triceps surae at a level midway between the recording electrodes. In any individual the same side was used on all occasions. Care was taken that the stimulating and recording electrodes were not displaced either by the v~brator or by the developed tonic vibration reflex. Any recording in which there was a significant alteration in the M-response was therefore discarded. The responses to 50 consecutive stimuli were averaged by a PDP 12 computer and this constituted one "run". Control runs and runs with muscle vibration were alternated until 3 satisfactory pairs were completed. (In 2 patients where there was a risk of spontaneous flexor spasms
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r,. ASHBY, D. G. WHITE
interrupting the procedure 8 runs of 30 stimuli were used instead). The average of 50 responses and the variance was plotted on an X-Y plotter and the peak to peak heights of H-control and H-vibration were measured. The H-vibration/H-control ratio was estimated for each pair and the mean ratio of the 3 (or more) estimates calculated.
Statistics The clinical scores, EMG values, threshold velocities, and the H-vibration/Hcontrol ratios were compared by Student's t-test. All calculations were completed and the conclusions established before the code was broken. RESULTS
Clinical assessment of spasticity Both the upper and lower limbs were assessed. However, identical conclusions resulted from combining the upper and lower limb scores or taking the lower limb scores alone (this probably indicates that most patients had either normal upper limbs or abnormalities that respond in the same way as the lower limbs). For simplicity, only the lower limb scores will be presented. In relaxed normal subjects no detectable velocity-dependent, tonic, or static reflex response occurred in response to muscle stretch, the tendon reflex score was 0, and no involuntary flexion reflex occurred. Muscle power score in the 2 quadriceps and 2 hamstrings totalled 20. In the spastic patients tone was increased. The mean scores on placebo (both quadriceps and both hamstrings combined) were: velocitydependent reflex 9.4, tonic reflex 6.1, static reflex 2.1, total 17.6; tendon reflexes were exaggerated (mean score 4.3), the flexion reflex was hyperactive (mean score 3,0) and significant weakness was present (mean score 11.8). The hamstrings tended to be slightly weaker than the quadriceps, the tendon jerks were brisker in quadriceps. STRETCH REFLEXES
Tendon
Flexio~
Total
jerks
reflex
V
T
S
Rawer
WORSE
BETTER
Fig. 1. Effect of 13(4-chlorophenyl)GABA on the clinical scores of spastic patients. Means and S.D. of individual differences between the scores (quadriceps and hamstrings of both legs combined) on placebo and active preparation (n = 11). There is a significant reduction in velo~ty dependent (V) and tonic (T) stretch reflexes accounting for a significant improvement in total stretch reflex score. The static stretch reflex (S) and other clinical parameters are unchanged.
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333
There were no other significant differences between the flexor and extensor muscles. /~(4-chlorophenyl)GABA produced a significant decrease in tone (Fig. 1). Mean differences (both quadriceps and both hamstrings combined) were as follows. Difference in total score 7.2 (t=3.2, P>0.01), difference in velocity-dependent reflex score 3.2 (t = 4.0, P > 0.01 ), difference in tonic reflex score 2.9 (t = 2.7, P > 0.05). There were no statistically significant changes in the'other parameters. Quadriceps and hamstrings responded in an identical manner.
Electromyographic assessment of spasticity Muscle stretch, even at low velocity, resulted in a reflex EMG in the quadriceps and hamstrings of all spastic patients. The mean threshold velocity for quadriceps was 68.2 degrees/sec and for hamstrings 72.7 degrees/sec. The mean integrated EMG at 100 degrees/sec in quadriceps was 32.7 #V, and in hamstrings 57 #V; the mean integrated EMG at 500 degrees/sec in quadriceps was 318 #V, and in hamstrings 290 #V (differences between quadriceps and hamstrings were not significant). Threshold velocity was inversely related to the clinical scores of muscle tone. The best correlations were between the clinical scores of muscle tone and the EMG at 100 degrees/sec. /~(4-chlorophenyl)GABA caused substantial changes in the EMG velocity relationship in both muscles (Fig. 2). There was a significant increase in the threshold velocity for the production of EMG [mean difference in quadriceps 49 degrees/sec (t = 2.6, P > 0.05), and hamstrings 54 degrees/sec (t = 2.4, P > 0.05)] and a significant decrease in integrated EMG produced by movements at 100 degrees/sec [-mean difference in quadriceps 30 #V (t=2.3, P>0.05), and hamstrings 56 #V (t=2.8, P >0.05)], and at 500 degrees/sec [mean difference in quadriceps 109 #V (t= 2.6, P>0.05), and hamstrings 170 #V (t=4.3, P>0.01)]. There were no significant differences in the responses of the 2 muscles. C ~ IN TI'IRESHOLD VELOC I T Y
Q
Velocity
Y~
H
CHANGE IN INT. EMG AT AT
1OOTsec
Q
H
5OO~sec
Q
H
"'"l:J'"II ........ D 10 ltd.EMG~uv
I k Fig. 2. The effect of 13(4-chlorophenyl)GABA on the reflex EMG of spastic patients. Means and S.D. of individual differences between results on placebo and active preparation (n = 11). There is a significant increase in the threshold velocity required to produce reflex EMG and a significant decrease in the reflex EMG produced by slow (100 degrees/sec) and rapid (500 degrees/sec) muscle stretch. (Q, quadriceps; H, hamstrings).
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P. ASHBY, D. G. WHITE
Effect of vibration on the H-reflex Preliminary studies in this laboratory demonstrated that the H-vibration/Hcontrol ratio is virtually independent of the site of vibration in the lower leg and of the position on the H - M recruitment curve in normal subjects and spastic patients. It therefore appeared justifiable to employ this technique on successive occasions as the degree of suppression is not influenced by minor changes of electrode or vibrator placement. Attentuation of the H-reflex by vibration in 10 spastic patients on placebo was significantly reduced in comparison with normal controls (Figs. 3 and 4). The mean H-vibration/H-control ratio (expressed as a percentage) tbr 5 normal subjects was 2.1 ~ and for 10 spastic patients 26.9~o. This difference is highly significant. The H-vibration/H-control ratios in spastic patients on placebo show a considerable range but no significant correlations were achieved between the H-vibration/H-control ratio and the clinical estimates of tone, reflexes, flexion reflexes, strength or EMG results. fl(4-chlorophenyl)GABA had no significant effect on the mean H-vibration/Hcontrol ratio of spastic patients (Fig. 4). Improvement in spasticity could not be correlated with either the initial H-vibration/H-control ratio nor the improvement in this ratio with treatment. NORMAL
SPASTIC
CONTROL
1'' Fig. 3. Effect of muscle vibration on H-reflex. In a normal subject the H.reflex is almost completely inhibited. In a spastic patient this is less marked. Each trace represents the average of 50 responses. SPASTIC
40-
H vib ,~, H control 20"
NORMAL
t_ Fig. 4. Effect of vibration on the H-reflex. Mean and standard deviations. In normal subjects (n = 5) the H-reflex is almost completely inhibited. In spastic patients (n = 10) on placebo (B) the inhibition is less marked. This is not significantly affected by fl(4-chlorophenyl)GABA (A).
~PRESYNAPTIC" INHIBITION IN SPASTICITY
335
Side-effects Significant side-effects were encountered in 3 patients on the active preparation and minor symptoms were mentioned by a further 3. The most common side-effect (4 patients) was a feeling of intoxication characterized by indifference and lethargy ("--I could not care--" ; "--lack of drive--"). In one instance it was accompanied by difficulty in initiating movements " - - I t was right beside me but I did not care to move my hand--". Drowsiness was mentioned by 3 patients, 4 patients described dizziness and in 1 this was immediately aggravated by the inhalation of cigarette smoke. Two patients described distortions of sounds ("--Voices sound different~"), and 2 patients complained of altered respiration ("--As if I want to take a deep breath all the time--"). Significant side-effects on the active preparation were commoner in the female patients. The side-effects usually occurred at a dose of 20 mg t.i.d, but were encountered in 1 patient on 10 mg t.i.d, whereas another patient tolerated 30 mg t.i.d, with only minor symptoms. Side-effects occurred approximately 2 hr after ingesting the medication and all side-effects disappeared if the dose was reduced. Minor symptoms occurred in 4 patients while on placebo. These included muscle spasm, sleeplessness and peripheral paraesthesiae.
DISCUSSION
In this study muscle vibration resulted in almost total inhibition of the monosynaptic reflex in normal subjects but not in spastic patients. This confirms the observations of Delwaide (1969) and Burke and Ashby (1972) suggesting that "presynaptic" inhibition may be impaired in spasticity. The degree of this impairment varied considerably between patients but could not be correlated with the site of the lesion or with the severity of the spasticity. In animals primary afferent depolarization of 1 a afferents, accompanied by inhibition of the monosynaptic reflex, can be induced from the medial vestibular nucleus (Carpenter, Engberg and Lundberg 1966; Barnes and Pompeiano 1970b). The loss of some similar supraspinal enhancement could explain the impairment of"presynaptic" inhibition observed in spinal spasticity. //(4-chlorophenyl)GABA has been shown to produce a significant reduction in the stretch reflexes of spastic patients; some consideration may now be given to its site of action. The substance must have a direct effect on the spinal cord since it has been shown to be effective in patients with clinically complete spinal cord lesions both in this study and in that of Jones et al. (1970). The naturally occurring amino-acid GABA may be an inhibitory transmitter in the spinal cord. Iontophoretically-applied GABA inhibits ~- and 7- motoneurones, interneurones and Renshaw cells in the cat (Curtis and Watkins 1965). It is of interest that amino-oxyacetic acid, which causes an increase in central nervous system GABA, will reduce spasticity in congenitally spastic mice (Roberts and Kuriyama 1968). /~(4-chlorophenyl)GABA is chemically related to GABA. Iontophoreticallyapplied/~(4-chlorophenyl)GABA will also produce inhibition in certain cat spinal neurones (Curtis, D.R., personal communication) so it is tempting to suggest that
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fl(4-chlorophenyl)GABA simply mimics the action of GABA. Animal studies performed by CIBA laboratories with fi(4-chlorophenyl)GABA have demonstrated effects on fusimotor activity. However there was no significant alteration in the tendon jerks in this study or in that of Jones et al. (1970). Thus there is no positive evidence to support any alterations in fusimotor drive in man. Birkmayer et al. (1967), using intravenous/3(4-chlorophenyl)GABA, found a reduction in the H-reflex and suggested that the drug had a direct action on the e-motoneurone; but such an effect on the monosynaptic reflex is not prominent after oral administration even though the spasticity may be profoundly reduced. Recently Curtis and Felix (1971) provided evidence that GABA may be the transmitter of"presynaptic" inhibition, and Burke et al. (1971 ), have postulated that /~(4-chlorophenyl)GABA may restore "'presynaptic" inhibition in spastic patients. This hypothesis was examined in the present study using the H-vibration/H-control ratio as a measure of "presynaptic" inhibition. Although/~(4-chlorophenyl)GABA produced a clear reduction in the stretch reflex there was no significant alteration in the mean H-vibration/H-control ratio. There is no evidence, therefore, from this study that fl(4-chlorophenyl)GABA reduces spasticity by increasing "presynaptic'" inhibition. Although iontophoretically-applied GABA inhibits c~- and ?,-motoneurones and interneurones (Curtis and Watkins 1965) these neurones may have graded susceptibilities since intravenous GABA can produce differential effects upon reflex pathways (Kuno 1961; Basil, Blair and Holmes 1964). Kuno (1961) has postulated that certain interneurones are the most sensitive to GABA inhibition. In this study stretch reflexes that employ tonic mechanisms were more affected than phasic responses such as the tendon jerk. The reduction in spasticity produced by /~(4chlorophenyl)GABA could therefore result from an inhibitory action primarily upon interneurones, an effect on the e-motoneurone only becoming apparent with large doses or intravenous administration (Birkmayer et al. 1967). Kuno (1961) found that GABA had no effect upon the interneurones of a decerebrate preparation and suggested that they were already under tonic inhibition from the brain-stern. A similar explanation might underly the failure of/~(4-chlorophenyl)GABA to improve patients with cerebral spasticity which was noted in this trial and that of Bergamini et al. (1966). In conclusion it is suggested that while/~(4-chlorophenyl)GABA may inhibit all types of neurone in the spinal cord its principal action when administered orally to spastic patients is probably upon interneurones. Side-effects were prominent in this study occurring in approximately 50 ~o of the patients. This has been reported in some previous studies (Pedersen et al. 1970) while others have reported only minimal side-effects (Jerusalem 1968; Jones et al, 1970; Hudgson and Weightman 1971) possibly because the doses were increased more slowly. This present study was principally concerned with the mode of action of the drug and no attempt was made to evaluate the patient's functional improvement. Nevertheless the drug is evidently beneficial in reducing intense spasticity and 2 patients chose to continue the preparation in preference to their previous antispastic medication.
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ACKNOWLEDGEMENTS
The authors are grateful to Dr. Jousse for permission to study the patients under his care and to Dr. D. Burke (University of New South Wales) for advice and criticism. The illustrations were photographed by the department of medical photography of the Toronto Western Hospital and the manuscript was prepared by Mrs. E. Nielsen. CIBA-Geigy Canada Limited kindly supplied Lioresal* and identical placebo for use in this study. SUMMARY
Muscle vibration produces less inhibition of the H-reflex in spastic patients than in normal subjects suggesting that "presynaptic" inhibition may be impaired in spasticity. In a double-blind cross-over trial on 11 spastic patients fl(4-chlorophenyl)GABA reduced the stretch reflexes without any significant effect on the inhibition of the H-reflex by vibration. There is, therefore, no evidence from this study that fl(4-chlorophenyl)GABA improves spasticity by restoring "presynaptic" inhibition.
REFERENCES
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HUDGSON, P. AND D. WEIGHTMAN (1971) Baclofen in the treatment of spasticity, Brit, med. J,, 4:15 17. JERUSALEM,F. (1968) Doppeltblindstudie fiber den antispastischen Effekt von/~(4-Chlorophenyl)-gammaAminobutters/iure (CIBA) bei Multipler Sklerose, Nervenarzt, 39 : 515-517. JONES, R. F., D. BURKE,J. E. MAROSSZEKYAND J. D. GILLIES (1970) A new agent for the control of spasticity. J. Neurol. Neurosurg. Psychiat., 33 : 464-468. KuNo, M. (1961) Site of action of systemic gamma-aminobutyric acid in the spinal cord, Jap. J. Phsio/.. 11 : 304-318. PEDERSEN,E., P. ARLIEN-SoBORG,V. GRYNDERUPAND O. HENDRIKSEN(1970) GABA derivative in spasticity. Acta neurol, scand., 46 : 257-266. ROBEgTS, E. AND K. KURIVAMA(1968) Biochemical-physiological correlations in studies of the gammaaminobutyric acid system, Brain Res., 8 : 1-35. ZSCHOCKE, S. AND G. BRUNE (1965) Klinische und elektromyographische Studien fiber die pharmakologische Beeinflussung der Spastik, Verh. dtsch. Ges. inn. Med., 71 : 662-665.