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The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients
Clinical Neurophysiology 111 (2000) 1372±1379
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The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients G. érsnes a,*, C. Crone b, C. Krarup b, N. Petersen c, J. Nielsen c a
b
Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen é., Denmark Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen é., Denmark c Division of Neurophysiology, Department of Medical Physiology, The Panum Institute, Copenhagen University, Blegdamsvej 3, 2200 Copenhagen N., Denmark Accepted 8 May 2000
Abstract Objectives: To measure the effect of baclofen on the transmission in different spinal pathways to soleus motoneurones in spastic multiple sclerosis patients. Methods: Baclofen was administered orally in 14 and intrathecally in 8 patients. Hmax/Mmax, presynaptic inhibition by biceps femoris tendon tap of femoral nerve stimulation, depression of the soleus H-re¯ex following previous activation of the Ia afferents from the soleus muscle (i.e. postactivation depression), disynaptic reciprocal Ia inhibition of the soleus H-re¯ex and the number of backpropagating action potentials in primary afferents, which may be a sign of presynaptic inhibition, were examined. Results: Baclofen depressed the soleus Hmax/Mmax ratio signi®cantly following oral and intrathecal baclofen. None of the two tests of presynaptic inhibition, or the postactivation depression or the disynaptic reciprocal Ia inhibition of the soleus H-re¯ex were affected by baclofen administration. Also the action potentials of the primary afferents were unchanged during baclofen administration. Conclusions: The antispastic effect of baclofen is not caused by an effect on the transmitter release from Ia afferents or on disynaptic reciprocal Ia inhibition. One possible explanation of the depression of the H-re¯ex by baclofen is suggested to be a direct depression of motoneuronal excitability. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Baclofen; H-re¯ex; Compound sensory action potentials; Multiple sclerosis; Presynaptic inhibition; Spasticity
1. Introduction Although the pathophysiology of spasticity has been addressed in a number of studies during the past 20±30 years there is still no general agreement about the signi®cance of different spinal control mechanisms for the exaggerated stretch re¯ex activity and hypertonicity observed in spastic patients (Pierrot-Deseilligny, 1990; Nielsen and Hultborn, 1993). The treatment of spasticity therefore also rests almost solely on an empirical basis. Ideally an antispastic drug should depress the unwanted exaggerated stretch re¯ex activity and reduce the muscle tone without affecting the functional ability of the patients during voluntary movements, such as walking. For a long time it has been thought that baclofen ful®lled this criteria, since animal experiments have shown that baclofen rather selectively activates GABAB receptors, which are mainly found presynaptically (Tillakaratne et al., 1995). Baclofen * Corresponding author. E-mail address: [email protected] (G. érsnes).
has also been found to depress the transmitter release from Ia afferents in the cat without any postsynaptic effects on the motoneurones (Jimenez et al., 1991). Because of this baclofen has been thought to selectively depress the exaggerated stretch re¯ex activity mediated by stretch sensitive afferents without affecting the voluntary movements of the subjects. More recently some doubt about the selectivity of baclofen has been raised. Azouvi et al. (1993) demonstrated that the soleus H-re¯ex was depressed by intrathecal baclofen without any apparent change in the ef®cacy of synaptic inputs (based on lack of change in the monosynaptic facilitation of the soleus H-re¯ex evoked by femoral nerve stimulation) to the motoneurones, suggesting that baclofen mainly acted at a postsynaptic site. If this is correct baclofen is not an ideal antispastic drug and should be avoided in patients in whom preservation of their functional ability is of importance. There is consequently a great need of evaluating the mode of action of baclofen in spastic patients. In the present study we have evaluated the effect of orally and intrathecally administered baclofen on soleus H-re¯exes as
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0035 2-7
CLINPH 99743
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well as on 3 different mechanisms which regulate stretch re¯ex excitability. (1) We tested presynaptic inhibition of Ia afferents on soleus motoneurones by measuring either the depression of the soleus H-re¯ex evoked by a biceps femoris tendon tap (Nielsen and Petersen, 1994) or the monosynaptic heteronymous facilitation of the soleus H-re¯ex following femoral nerve stimulation (Hultborn et al., 1987). In addition compound sensory action potentials (CSAPs) were investigated (Shefner et al., 1992). Recurrent potentials in the CSAP have been suggested to be related to primary afferent depolarization and to presynaptic inhibition of the primary afferents (Shefner et al., 1992). (2) We tested the depression of the soleus H-re¯ex following previous activation of tibial nerve afferents (postactivation depression) by slow stretch of the ankle plantar ¯exors (Nielsen et al., 1993, 1995; Hultborn et al., 1996). (3) We tested disynaptic reciprocal Ia inhibition of the soleus Hre¯ex following stimulation of the antagonistic common peroneal nerve (Crone et al., 1994). 2. Materials and methods
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42.8 ^ 8.7) with clinically de®nite multiple sclerosis (MS) (Poser et al., 1983) participated in the study. In all patients the disease had been stable for at least 1 month and all gave informed consent to the examination which was approved by the local ethics committee. All patients were clinically evaluated and spasticity was graded according to the Ashworth Index (Table 1). Eight patients received baclofen intrathecally, whereas 14 patients received baclofen orally. The patients treated with oral baclofen had a median score of 5.25 (range 3.5±6) on Kurtzke's Extended Disability Status Scale (EDSS) and the median score on the Ashworth Index (hip abduction and ¯exion, knee and ankle ¯exion as a composite score for both legs) was 0.8 (range 0±2). The patients treated with intrathecal baclofen had a median score of 8 (range 2±8) on EDSS and 2.45 (range 1.5±3.3) on the Ashworth Index. None of the patients had any other neurological or psychiatric diseases. Three patients received antispastic medication (baclofen and/or tizanidine) before entering the study. All antispastic medication was stopped 72 h before the experiment. One patient withdrew his consent during the ®rst part of the study for non-medical reasons. 2.2. Drug administration and design of the study
2.1. Patients Twenty-two patients aged 24±57 years (mean ^ SD
The intrathecal study was an open-label design (Fig. 1A). A bolus of baclofen (25±50 mg) was injected into the lumbar
Table 1 Patient characteristics and baseline evaluation Type of MS a
EDSS b
Dose of baclofen
Ashworth Index c
Patients receiving intrathecal baclofen 1/F/33 8 2/M/42 8 3/M/49 25 4/F/37 18 5/M/36 8 6/F/35 21 7/M/34 13 8/F/56 17
RR PP SP SP PP PP SP SP
8.0 7.0 8.0 8.0 2.0 8.0 4.0 8.0
50 50 50 50 25 25 25 25
mg mg mg mg mg mg mg mg
1.5 2.3 3.1 3.3 1.4 3.3 1.6 2.6
Patients receiving oral baclofen 9/F/32 10/M/54 11/F/37 12/F/42 13/F/24 14/F/46 15/M/54 16/M/50 17/F/49 18/F/57 19/F/42 20/M/39 21/F/41 22/M/41
RR PP SP RR RR SP PP SP PP SP PP RR SP RR
4.5 5.5 5.0 3.5 6.0 6.0 6.0 4.5 6.0 6.0 6.0 5.0 4.0 3.5
15 mg £ 3
0.0 2.0 1.0 0.3 0.3 0.5 0.6 1.3 1.8 1.0 0.5 1.1 0.8 0.8
Subject no./sex/age (years)
a
Duration of MS (years)
10 28 11 15 5 19 22 33 6 27 8 4 21 19
d
15 15 15 10 15 15 15 10 10 15 15 15
mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3
RR, relapsing remitting; SP, secondary progressive; PP, primary progressive. EDSS, Kurtzke's Expanded Disability Status Scale. c Hip (abduction and ¯exion), knee and ankle as a composite score for both legs. All 8 joint movements were summed and divided by 8 for an overall scale rating. d Withdrew his consent. b
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Fig. 1. Design of the intrathecal and oral study. In both studies all antispastic medications were tapered over 1 week and stopped 72 h before the measurements. After the end of the studies the antispastic medications were escalated to the most optimal dosage. (A) The study was an open-label design. The patients were examined before intrathecal injections of baclofen at day 0, and 1 h after intrathecal injections of baclofen at day 1. (B) The study was a placebo-controlled, double-blind cross-over study. All patients were randomly assigned to baclofen or placebo treatment. Baclofen/placebo was administered orally and escalated to maximum tolerance dosage or a maximum of 15 mg 3 times daily. After 11 days on the dosage the measurements were performed and treatment was tapered over about 1 week. After a wash-out period of 2 weeks, the patients entered the second treatment period of placebo/baclofen. Examinations were performed before each of the two treatment periods and after 11 days of treatment at the maximum dosage.
subarachnoid space by percutaneous puncture. The patients were assessed by H-re¯ex examination before and 1 h after intrathecal injection of baclofen. The oral study design (Fig. 1B) was a placebocontrolled, double-blind cross-over study. All patients were randomly assigned to either baclofen or placebo treatment. Baclofen and placebo tablets were identical in size, shape, colour and container. In order to maintain blindness as much as possible, placebo/baclofen was administered orally with a starting dose of 5 mg 3 times daily and dose escalation by 5 mg every 3 days to 15 mg 3 times daily or the maximum tolerance dosage, de®ned as the maximum dose at which the patient had no severe side effects. After 11 days on this dosage, measurements were performed and the treatment was tapered over about 1 week. After a wash-out period of 2 weeks, the patients entered the second treatment period of baclofen/placebo with an identical dosage regime. Measurements were performed before each of the two treatment periods and after 11 days of treatment at the maximum dose. All tests were performed at the same time of day in order to minimize the in¯uence of diurnal variations.
2.3. Methods Two fundamentally different experimental techniques were used in the study: (1) the transmission in different re¯ex pathways was investigated with the H-re¯ex technique; and (2) the conduction in sensory afferents and the presence of recurrent sensory action potentials were studied by measuring compound sensory action potentials. 2.3.1. H-re¯ex technique The experimental arrangement is illustrated in Fig. 2. The subjects were seated in an armchair with the examined leg semi¯exed in the hip (1208), the knee ¯exed to 1608 and the ankle in 1108 plantar ¯exion. The foot was mounted to a torque meter and the torque was displayed on an oscilloscope placed in front of the subject. The soleus H-re¯ex was evoked by stimulating the tibial nerve in the popliteal fossa through a monopolar stimulating electrode (1 ms rectangular pulse, anode placed above the patella). The re¯ex responses were measured as the peak-topeak amplitude of the non-recti®ed response. The re¯exes
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intrinsic decrease of the transmitter release probability in the synapses of the Ia afferents following previous activation of the synapses (Hultborn et al., 1996).
Fig. 2. Schematic illustration of the experimental procedure. The soleus Hre¯ex was evoked by a stimulation of the tibial nerve in the popliteal fossa (test stimulation). The Hmax/Mmax ratio was calculated at an interstimulus interval of 4 s. The soleus H-re¯ex was conditioned by 4 different procedures: (1) slow passive dorsi¯exion; (2) stimulation of the common peroneal nerve; (3) a tendon tap applied to the biceps femoris; (4) stimulation of the femoral nerve.
were recorded by bipolar electrodes (1 cm 2 recording area, 2 cm between poles) placed over the soleus muscle. The following measurements were made (see also Fig. 2). 2.3.1.1. Hmax/Mmax. An H-re¯ex recruitment curve was made by varying the intensity of the stimulation of the tibial nerve. Hmax was determined as the maximal H-re¯ex (average of 5 responses) that could be obtained and it was expressed as a percentage of the maximal M-response following supramaximal stimulation of the tibial nerve. 2.3.1.2. Slow stretch of the ankle plantar ¯exors. The size of the soleus H-re¯ex was measured before and 2 s after a passive dorsi¯exion of the ankle joint. One of the experimenters slowly changed the position of the ankle joint following a prescribed ramp drawn on an oscilloscope (1 s duration, amplitude 108). After 20 s the position of the joint was returned to its starting position and a new passive movement was made. The re¯exes were thus elicited every 20 s both in the control situation without the passive movement and when the re¯ex was elicited 2 s after the passive movement. The re¯ex was always elicited in both situations at an ankle joint position of 1108 to avoid the in¯uence on the re¯exes of changes in the muscle length (Gerilovsky et al., 1989). The re¯exes were adjusted to around 30% of Mmax in the control situation (cf. Nielsen et al., 1995). In healthy subjects the passive movement induces a pronounced, long-lasting depression of the H-re¯ex, which has been termed postactivation depression by Crone and Nielsen (1989). This depression is likely caused by an
2.3.1.3. Stimulation of the common peroneal nerve. The common peroneal nerve was stimulated (rectangular 1 ms pulse) by bipolar surface electrodes placed at or below the neck of the ®bula at a position where the threshold for the M-response in the tibialis anterior muscle was lower than the threshold for the M-response in the peroneal muscles. The conditioning stimulus strength was expressed in multiples of the M-threshold (£MT) in the tibialis anterior muscle and was kept at 1.0£ MT. In all subjects a time course of the effect of the CPN stimulation on the soleus H-re¯ex was made and the amount of disynaptic reciprocal inhibition was measured as the size of the conditioned re¯ex expressed as a percentage of the control re¯ex size at the conditioning-test interval (within the initial 5 ms) at which the maximal amount of inhibition was observed. If no inhibition was observed, which was the case in most of the patients (cf. also Crone et al., 1994), the measurement at a conditioning-test interval of 2 ms was used. 2.3.1.4. Stimulation of the femoral nerve. The femoral nerve was stimulated by a monopolar ball electrode placed in the femoral triangle just lateral to the femoral artery. The indifferent electrode was placed at the posterior aspect of the upper thigh, just below the gluteus maximus muscle. The intensity was adjusted to be just above the threshold for the direct and visible motor response in the quadriceps muscle (1.1 £ MT). A time course of the effect of the femoral nerve facilitation on the soleus H-re¯ex was obtained in each experiment. The onset of the facilitation was determined as the earliest conditioning-test interval at which the conditioned re¯ex was more than 5% larger than the control re¯ex and the conditioning-test interval used throughout the experiment was 0.5±1.0 ms longer. The size of the facilitation measured at this conditioning-test interval re¯ects the size of the monosynaptic excitatory postsynaptic potential in the soleus motor neurones evoked by activation of femoral nerve afferent ®bres (see Hultborn et al., 1987). 2.3.1.5. Biceps femoris tendon tap. A tendon tap applied to the biceps femoris tendon depresses the soleus H-re¯ex for a duration of around 300±400 ms. This depression is likely caused by presynaptic inhibition of soleus Ia afferents (Nielsen and Petersen, 1994). In the present study the tendon tap was applied by an electromagnetic hammer (BruÈel and Kjñr, Denmark, Vibration exciter model 4809) and the depression of the H-re¯ex was measured at a conditioning-test interval of 60 ms. It was expressed as the size of the conditioned re¯ex as a percentage of the control re¯ex size. The control re¯ex was adjusted to 20± 25% of Mmax.
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Table 2 Mean and SEM for the H-re¯ex measurements in the intrathecal study
Before treatment with baclofen During treatment with baclofen N7
Hmax/Mmax
FN facilitation
Reciprocal inhibition
63.7 (6.2) 14.8 (5.2) P , 0:001
126.5 (12.0) 120.5 (14.8) Non-signi®cant
90.8 (3.4) 96.3 (3.1) Non-signi®cant
2.3.2. Compound sensory action potentials (CSAP) The subject was lying on his/her stomach with support under the ankle to bend the knee to an angle of 1408. The sural nerve was stimulated at the lateral malleolus using rectangular supramaximal (2±5 mA) current pulses, 0.2 ms in duration, from a constant current stimulator. The electrodes for stimulation and recording were 0.7 mm in diameter and insulated except for a 3 mm bared tip. The CSAPs were recorded through needles placed close to the sural nerve at two sites along the calf at distances of 7 and 13 cm from the lateral malleolus. Both stimulating and recording electrodes were adjusted close to the nerve such that the threshold of the evoked nerve action potential was less than 0.5 mA. The reference electrode was an insulated needle, 0.7 mm in diameter, with a 5 mm bared tip placed subcutaneously at a medial transverse distance of 3±4 cm. The CSAPs from the two recording sites were ampli®ed (DANTEC 15C02, 200±4000 Hz, 3 dB down) simultaneously and responses of up to 500±1000 stimuli were electronically summed (Nicolet Pro20). The reproducibility of the responses was evaluated by recording the potentials in two traces of each 500 stimuli to ascertain that the recorded CSAPs remained constant. The CSAPs were recorded on an ink-jet writer (Siemens Mingograf) via a digital memory store. The temperature of the limb was kept above 35± 388C by an automatically controlled infrared heating lamp. To calculate the maximum sensory conduction velocity (CVmax), the latency to the initial positive peak of the main potential was measured. Minimum sensory conduction velocity (CVmin) was determined by measuring the latency to the latest component of the response with an amplitude of 0.1 mV. Amplitude was measured peak to peak. CVmax, amplitude and CVmin were classi®ed as normal or reduced according to previously established age-dependent norms (Horowitz and Krarup, 1992; Shefner et al., 1992). 2.3.3. Data analysis The data were stored on a computer for later statistical analysis. The mean and standard error of the mean were
calculated for all measurements on line. Differences in the size of conditioned and control re¯exes in individual subjects were tested using a Student's t test. After having tested that the data were normally distributed, analysis of variance (ANOVA) was used to compare changes before and under the placebo/baclofen treatments in the oral study. The results were adjusted by subtracting baseline values from the values of measurements during treatment with baclofen and placebo. Any effects of period were examined before testing for a possible treatment effect. Two sample t tests were used in the intrathecal baclofen study. The level of signi®cance was set at P , 0:05. 3. Results 3.1. H-re¯ex Administration of baclofen both orally and intrathecally produced a signi®cant decrease in the size of the soleus Hre¯ex measured as the Hmax/Mmax ratio. In all but 3 of the 13 patients who participated in the double-blind placebocontrolled study on the effect of oral baclofen, a signi®cantly (P , 0:05) smaller Hmax/Mmax ratio was observed during the period when the patients received oral baclofen daily (mean ^ SEM 44.0 ^ 6.2%) as compared to the period when they received either placebo (mean ^ SEM 60.3 ^ 5.5%) or no medication (mean ^ SEM 58.7 ^ 5.2%). No signi®cant difference in the size of Mmax was observed between the different recording sessions (Tables 2 and 3). It was not possible to elicit an H-re¯ex in one of the patients in whom baclofen was administered intrathecally and this patient was therefore not included in the re¯ex study. In 6 out of the 7 other patients, a strong and highly signi®cant depression of Hmax/Mmax was observed following baclofen administration. On average Hmax/Mmax was depressed from 63.7 ^ 8.2 to 14.8 ^ 5.2% in the 7 subjects (P , 0:001). Mmax was also smaller during the session where baclofen was administered (from 18.6 ^ 6 to
Table 3 Mean and SEM for the H-re¯ex measurements in the oral study
Before treatment with baclofen During treatment with baclofen During treatment with placebo N 13
Hmax/Mmax
FN facilitation
Reciprocal inhibition
Postactivation depression
Biceps femoris tendon tap
58.7 (5.2) 44.0 (6.2) 60.3 (5.5) P 0:0007
128.3 (3.9) 131.3 (3.7) 122.6 (2.8) P 0:05
98.8 (3.3) 97.9 (4.4) 105.7 (5.4) P 0:12
48.9 (6.3) 46.9 (7.2) 51.0 (5.4) P 0:62
85.4 (5.2) 88.0 (4.7) 86.3 (4.8) P 0:29
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Table 4 Mean and SD for the parameters of CSAP in the intrathecal study
Before treatment with baclofen During treatment with baclofen N8
Maximal conduction velocity (m/s)
Amplitude CSAP (gV)
Minimal conduction velocity (m/s)
Recurrent potentials (number)
48.3 (10.3) 48.6 (7.8) Non-signi®cant
25.4 (21.3) 23.8 (19.0) Non-signi®cant
10.0 (2.2) 12.8 (4.4) P 0:022
2 (0) 2 (0) Non-signi®cant
13.7 ^ 5.2 mV on average). This was likely not caused by the administration of baclofen, but more likely by a nonspeci®c decline in the responsiveness of the muscle to the nerve stimulus related to the duration of the experiment, as has recently been reported (Crone et al., 1999). However, this change could not explain the decrease in the Hmax/Mmax ratio. The effect of baclofen on Hmax/Mmax was positively correlated with the effect of baclofen on muscle tone and Achilles tendon re¯exes for the patients taken from both the oral and the intrathecal study. Stimulation of the CPN in general produced no or only very little disynaptic reciprocal inhibition of the soleus Hre¯ex in the patients, as has also been reported previously (Crone et al., 1994). Administration of baclofen orally or intrathecally had no effect on the amount of inhibition. Stimulation of the femoral nerve produced a short-latency facilitation of the soleus H-re¯ex in 4 of the 7 patients in whom baclofen was administered intrathecally and in 11 out of the 13 patients who received baclofen orally. On average the femoral nerve facilitation was smaller following baclofen administration in the ®rst group (120.5 ^ 3.2 as compared to 126.5 ^ 12.0%, non-signi®cant), whereas it was larger in the period when the patients in the second group received oral baclofen as compared to the periods when they received placebo or no medication (131.3 ^ 3.9 as compared to 128.3 ^ 3.9 and 122.6 ^ 2.8%, non-signi®cant). The effect of a previous slow stretch of the ankle plantar ¯exors or a biceps femoris tendon tap on the soleus H-re¯ex was also investigated in the patients who received baclofen orally. At an interval of 2 s after the stretch the soleus Hre¯ex was depressed to the same extent when the patients received baclofen, placebo or no medication (mean ^ SEM 46.9 ^ 6.3, 51.0 ^ 5.4 and 48.9 ^ 6.3%, respectively).
At an interval of 60 ms after the biceps femoris tendon tap the soleus H-re¯ex was inhibited to 88.0 ^ 4.7, 76.3 ^ 4.8 and 85.4 ^ 7.6% during the periods when the patients received baclofen, placebo and no medication, respectively. These differences were not statistically signi®cant. 3.2. Compound somatosensory action potentials (CSAP) The result of the CSAP recordings in individual patients at baseline and during baclofen treatment are listed in Tables 4 and 5. In the intrathecal study 5 patients had normal maximal conduction velocity (CVmax), and 3 patients had decreased CVmax. Five patients had normal amplitude and 3 patients had decreased amplitude. Only one patient had minimal conduction velocity (CVmin) within normal range and only two patients (25%) had recurrent potentials at baseline. During treatment with intrathecal baclofen the number of recurrent potentials changed from one to two in one patient and from 3 to two in the other patient. Of all parameters of CSAP only CVmin showed a signi®cant change (P 0:022); 7 patients showed increased CVmin. Of the patients who received baclofen orally, CVmax and amplitudes were within normal limits in 12 patients at baseline. In one patient CVmax was decreased. CVmin was reduced in 12 patients. Ten patients (76%) had recurrent potentials at baseline (range 1±3). When treated with oral baclofen there were no signi®cant differences in the parameters compared to placebo treatment, and in particular the number of recurrent potentials did not change. 4. Discussion This study has investigated the mode of action of baclofen in spastic MS patients. Baclofen was administered either intrathecally or orally. In the latter case the patients received
Table 5 Mean and SD for the parameters of CSAP in the oral study
Before treatment with baclofen During treatment with baclofen Before treatment with placebo During treatment with placebo N 13
Maximal conduction velocity (m/s)
Amplitude CSAP (gV)
Minimal conduction velocity (m/s)
Recurrent potentials (number)
53.3 (4.6) 53.4 (4.8) 53.3 (5.5) 53.7 (4.3) P 0:84
26.8 (12.9) 29.3 (19.4) 27.7 (13.2) 31.3 (22.1) P 0:79
6.6 (1.4) 6.8 (1.5) 7.7 (2.2) 7.4 (1.8) P 0:54
1.5 (1.6) 2.0 (1.5) 1.4 (1.1) 1.6 (2.0) P 0:71
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a daily dose of baclofen for 3 weeks prior to the investigation and the study was designed as a double-blind placebocontrolled study. The study on the effect of intrathecal baclofen was designed as an open-label study. In both cases a clear depression of the soleus H-re¯ex was observed. Although a similar depression of H-re¯exes by baclofen administration has been reported in several previous studies (Macdonell et al., 1989; Milanov, 1992; Azouvi et al., 1993), it is to the best of our knowledge the ®rst time that this has been documented in a double-blind, placebocontrolled experiment. It is not straightforward to draw conclusions regarding stretch re¯ex activity based on H-re¯ex ®ndings (Burke et al., 1984; Morita et al., 1998) and it might therefore be questioned whether the depression of transmission in the re¯ex pathway underlying the H-re¯ex by baclofen is of importance for the antispastic effect ± i.e. decrease of muscle tone and phasic stretch re¯exes ± of the drug. However, there was a clear correspondence in the present study between on one hand the decrease of the H-re¯ex and on the other hand the decrease in muscle tone and tendon re¯exes following baclofen administration. Despite the ®ndings by Burke et al. (1984) and Morita et al. (1998), we therefore believe that the depression of the H-re¯ex is a useful marker of the antispastic effect of baclofen and that the mechanism involved in the depression of the H-re¯ex is also ± to a large extent ± responsible for the antispastic effect of the drug. Baclofen is a selective GABAB receptor agonist (Bowery and Pratt, 1992). These receptors are found abundantly on the terminals of primary afferents, but also on the terminals of descending ®bres as well as on the soma of different spinal neurones including the motoneurones (Misgeld et al., 1995; Tillakaratne et al., 1995). The role of these receptors in mediating presynaptic inhibition of Ia afferents has been somewhat debated, but the majority of animal studies now seem to agree that baclofen has no role in the classical GABA-mediated presynaptic inhibition of Ia afferents which is associated with depolarization of the dorsal roots (Stuart and Redman, 1992). The present ®nding that baclofen had no effect on any of the parameters that we believe to re¯ect GABA-mediated presynaptic inhibition (biceps femoris induced depression of the soleus H-re¯ex, femoral nerve facilitation of the soleus H-re¯ex, recurrent somatosensory action potentials) is well in line with this. Azouvi et al. (1993) similarly found that the femoral nerve facilitation was unchanged following intrathecal baclofen and concluded that increased presynaptic inhibition seemed not to be responsible for the depressant effect of baclofen on the soleus H-re¯ex. GABAB receptors may, however, interfere with transmitter release from Ia afferents in other ways. In the neonatal rat it has been demonstrated that baclofen decreases the longlasting depression of monosynaptic re¯exes following previous activation of the same afferents that mediate the re¯exes (Lev-Tov and Pinco, 1992). This effect is explained
by the reduction of the baseline availability of transmitter substance in the synapses following baclofen administration (Lev-Tov and Pinco, 1992). The human soleus H-re¯ex is also depressed following previous activation of soleus Ia afferents. This depression has been termed postactivation depression by Crone and Nielsen (1989). In con®rmation of previous studies we found that the depression was less pronounced in the spastic patients than in a population of healthy subjects (see Nielsen et al., 1993, 1995). Based on the data from the neonatal rat it could be expected that postactivation depression was increased following baclofen, but this was not the case. In the patients who received baclofen orally it may be that too little baclofen was transported into the CNS, but this cannot explain the lack of effect in the patients in whom baclofen was given intrathecally and in whom the Hmax/Mmax ratio was very strongly depressed. More likely explanations are therefore that the distribution of GABAB receptors or the mechanisms regulated by these receptors are different for the adult human Ia afferents as compared to the neonatal rat. There is a remote possibility that the depression of the re¯ex could be caused by a peripheral effect on the muscle. GABAergic receptors have indeed been found around the motor end plate in the cray ®sh (Barry, 1984; Fischer and Parnas, 1996). However, we observed no depression of Mmax in the oral study where the highest doses of baclofen in the periphery are likely to have occurred. We did see a depression of Mmax in the intrathecal study, but in this case only a limited amount of baclofen is likely to have reached the peripheral circulation. Furthermore, the depression of Mmax was more likely explained by the tendency for Mmax to decrease in the course of an experiment (Crone et al., 1999). In separate control experiments in which this factor was taken into account intrathecal baclofen was indeed found not to have any selective effect on Mmax (érsnes and Crone, unpublished observations). One ®nal possibility is that the depression of Hmax by baclofen was exerted on the spinal motoneurones. There is a theoretical possibility that baclofen increased the transmission from inhibitory neurones or alternatively decreased the transmission from excitatory neurones projecting to the motoneurones. We did not ®nd any evidence that transmission in the disynaptic reciprocal Ia inhibitory pathway was increased following either intrathecal or oral baclofen, but we did not investigate any other postsynaptic inhibitory pathways and there is a possibility that baclofen increased the transmission in pathways mediating autogenic Ib inhibition or recurrent inhibition. The decrease of the H-re¯exes following baclofen treatment could also be explained by a decreased corticospinal excitatory drive to the spinal motoneurones, possibly secondary to a decrease in intracortical excitability as demonstrated by Ziemann et al. (1996). In addition to this, we agree with Azouvi et al. (1993) that binding of baclofen directly to GABAB receptors on the spinal motoneurones is probably a major explanation of the decreased motoneuro-
G. érsnes et al. / Clinical Neurophysiology 111 (2000) 1372±1379
nal excitability. Such postsynaptic receptors may be more common than what has previously been assumed (Misgeld et al., 1995). 4.1. Signi®cance for antispastic treatment If ± as it appears ± the main antispastic effect of baclofen is related to its depression of motoneuronal excitability, it has to be concluded that baclofen is far from being an ideal antispastic drug. The depression of motoneuronal excitability will reduce not only the unwanted involuntary movements and muscle stiffness elicited by activation of sensory afferents, but also the voluntary movement repertoire that may be essential for the daily function of the patient. This point of view is also well in line with the growing clinical experience that baclofen is a valuable drug in the management of severe spasticity in patients with little or no remaining voluntary motor function. In patients for whom the ability to walk and move around is in the foreground and the spastic symptoms are of minor importance our data as well as the clinical experience suggests that baclofen should only be given with caution (Hoogstraten et al., 1988; Dones et al., 1995). It is obvious to us that in any individual patient an evaluation of the functional disability should be weighted against the severity of spasticity before baclofen is prescribed. This can only be done by a combination of careful clinical and electrophysiological examination. Acknowledgements This study was supported by grants from the Danish Society of Multiple Sclerosis, Warwara Larsens Foundation, Lily Benthine Lunds Foundation, Dagmar Marshalls Foundation, Hestehandler Ole Jakobsens Foundation and Foundation for Research in Neurology. Novartis supplied identical baclofen and placebo tablets. References Azouvi P, et al. Effect of intrathecal baclofen on the monosynaptic re¯ex in humans: evidence for a postsynaptic action. J Neurol Neurosurg Psychiatry 1993;56(5):515±519. Barry SR. Baclofen has a presynaptic action at the cray®sh neuromuscular junction. Brain Res 1984;311(1):152±156. Bowery NG, Pratt GD. GABAB receptors as targets for drug action. Arzneimittelforschung 1992;42(2A):215±223. Burke D, et al. Monosynaptic and oligosynaptic contributions to human ankle jerk and H-re¯ex. J Neurophysiol 1984;52(3):435±448. Crone C, Nielsen J. Methodological implications of the post-activation depression. Exp Brain Res 1989;78:28±32. Crone C, et al. Disynaptic reciprocal inhibition of ankle extensors in spastic patients. Brain 1994;117:1161±1168. Crone C, et al. Amplitude of the maximum motor response (Mmax) in
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human muscles typically decreases during the course of an experiment. Exp Brain Res 1999;124(2):265±270. Dones I, et al. A neurophysiological method for the evaluation of motor performance in spastic walking patients. Acta Neurochir Suppl (Wien) 1995;64:26±29. Fischer Y, Parnas I. Activation of GABAB receptors at individual release boutons of the cray®sh opener neuromuscular junction produces presynaptic inhibition. J Neurophysiol 1996;75(4):1377±1385. Gerilovsky L, et al. Peripheral effects on the amplitude of monopolar and bipolar H-re¯ex potentials from the soleus muscle. Exp Brain Res 1989;76(1):173±181. Hoogstraten MC, et al. Tizanidine versus baclofen in the treatment of spasticity in multiple sclerosis patients. Acta Neurol Scand 1988;77(3):224±230. Horowitz SH, Krarup C. Conduction studies of the normal sural nerve. Muscle Nerve 1992;15:374±383. Hultborn H, et al. Assessing changes in presynaptic inhibition of I a ®bres: a study in man and the cat. J Physiol (London) 1987;389:729±756. Hultborn H, et al. On the mechanism of the post-activation depression of the H-re¯ex in human subjects. Exp Brain Res 1996;108:450±462. Jimenez I, et al. Differential effects of (2)-baclofen on Ia and descending monosynaptic EPSPs. Exp Brain Res 1991;85(1):103±113. Lev-Tov A, Pinco M. In vitro studies of prolonged synaptic depression in the neonatal rat spinal cord. J Physiol (London) 1992;447:149±169. Macdonell RA, et al. Intrathecal baclofen and the H-re¯ex. J Neurol Neurosurg Psychiatry 1989;52(9):1110±1112. Milanov IG. Mechanisms of baclofen action on spasticity. Acta Neurol Scand 1992;85(5):305±310. Misgeld U, et al. A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system. Prog Neurobiol 1995;46(4):423±462. Morita H, et al. Sensitivity of H-re¯exes and stretch re¯exes to presynaptic inhibition in humans. J Neurophysiol 1998;80(2):610±620. Nielsen J, Hultborn H. Regulated properties of motoneurons and primary afferents: new aspects on possible spinal mechanisms underlying spasticity. In: Thilmann AF, editor. Spasticity: mechanism and management, Berlin: Springer, 1993. pp. 177±191. Nielsen J, Petersen N. Is presynaptic inhibition distributed to corticospinal ®bres in man? J Physiol (London) 1994;477(1):47±58. Nielsen J, et al. H-re¯exes are less depressed following muscle stretch in spastic spinal cord injured patients than in healthy subjects. Exp Brain Res 1993;97:173±176. Nielsen J, et al. Changes in transmission across synapses of peripheral afferents in spastic multiple sclerosis patients. Brain 1995;118:995± 1004. Pierrot-Deseilligny E. Electrophysiological assessment of the spinal mechanisms underlying spasticity. Electroenceph clin Neurophysiol Suppl 1990;41:264±273. Poser CM, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13(3):227±231. Shefner JM, et al. Peripheral sensory abnormalities in patients with multiple sclerosis. Muscle Nerve 1992;15:73±76. Stuart GJ, Redman SJ. The role of GABAA and GABAB receptors in presynaptic inhibition of Ia EPSPs in cat spinal motoneurones. J Physiol (London) 1992;447:675±692. Tillakaratne NJ, et al. Gamma-aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol 1995;112(2):247±263. Ziemann U, et al. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40(3):367±378.
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The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients G. érsnes a,*, C. Crone b, C. Krarup b, N. Petersen c, J. Nielsen c a
b
Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen é., Denmark Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen é., Denmark c Division of Neurophysiology, Department of Medical Physiology, The Panum Institute, Copenhagen University, Blegdamsvej 3, 2200 Copenhagen N., Denmark Accepted 8 May 2000
Abstract Objectives: To measure the effect of baclofen on the transmission in different spinal pathways to soleus motoneurones in spastic multiple sclerosis patients. Methods: Baclofen was administered orally in 14 and intrathecally in 8 patients. Hmax/Mmax, presynaptic inhibition by biceps femoris tendon tap of femoral nerve stimulation, depression of the soleus H-re¯ex following previous activation of the Ia afferents from the soleus muscle (i.e. postactivation depression), disynaptic reciprocal Ia inhibition of the soleus H-re¯ex and the number of backpropagating action potentials in primary afferents, which may be a sign of presynaptic inhibition, were examined. Results: Baclofen depressed the soleus Hmax/Mmax ratio signi®cantly following oral and intrathecal baclofen. None of the two tests of presynaptic inhibition, or the postactivation depression or the disynaptic reciprocal Ia inhibition of the soleus H-re¯ex were affected by baclofen administration. Also the action potentials of the primary afferents were unchanged during baclofen administration. Conclusions: The antispastic effect of baclofen is not caused by an effect on the transmitter release from Ia afferents or on disynaptic reciprocal Ia inhibition. One possible explanation of the depression of the H-re¯ex by baclofen is suggested to be a direct depression of motoneuronal excitability. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Baclofen; H-re¯ex; Compound sensory action potentials; Multiple sclerosis; Presynaptic inhibition; Spasticity
1. Introduction Although the pathophysiology of spasticity has been addressed in a number of studies during the past 20±30 years there is still no general agreement about the signi®cance of different spinal control mechanisms for the exaggerated stretch re¯ex activity and hypertonicity observed in spastic patients (Pierrot-Deseilligny, 1990; Nielsen and Hultborn, 1993). The treatment of spasticity therefore also rests almost solely on an empirical basis. Ideally an antispastic drug should depress the unwanted exaggerated stretch re¯ex activity and reduce the muscle tone without affecting the functional ability of the patients during voluntary movements, such as walking. For a long time it has been thought that baclofen ful®lled this criteria, since animal experiments have shown that baclofen rather selectively activates GABAB receptors, which are mainly found presynaptically (Tillakaratne et al., 1995). Baclofen * Corresponding author. E-mail address: [email protected] (G. érsnes).
has also been found to depress the transmitter release from Ia afferents in the cat without any postsynaptic effects on the motoneurones (Jimenez et al., 1991). Because of this baclofen has been thought to selectively depress the exaggerated stretch re¯ex activity mediated by stretch sensitive afferents without affecting the voluntary movements of the subjects. More recently some doubt about the selectivity of baclofen has been raised. Azouvi et al. (1993) demonstrated that the soleus H-re¯ex was depressed by intrathecal baclofen without any apparent change in the ef®cacy of synaptic inputs (based on lack of change in the monosynaptic facilitation of the soleus H-re¯ex evoked by femoral nerve stimulation) to the motoneurones, suggesting that baclofen mainly acted at a postsynaptic site. If this is correct baclofen is not an ideal antispastic drug and should be avoided in patients in whom preservation of their functional ability is of importance. There is consequently a great need of evaluating the mode of action of baclofen in spastic patients. In the present study we have evaluated the effect of orally and intrathecally administered baclofen on soleus H-re¯exes as
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0035 2-7
CLINPH 99743
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well as on 3 different mechanisms which regulate stretch re¯ex excitability. (1) We tested presynaptic inhibition of Ia afferents on soleus motoneurones by measuring either the depression of the soleus H-re¯ex evoked by a biceps femoris tendon tap (Nielsen and Petersen, 1994) or the monosynaptic heteronymous facilitation of the soleus H-re¯ex following femoral nerve stimulation (Hultborn et al., 1987). In addition compound sensory action potentials (CSAPs) were investigated (Shefner et al., 1992). Recurrent potentials in the CSAP have been suggested to be related to primary afferent depolarization and to presynaptic inhibition of the primary afferents (Shefner et al., 1992). (2) We tested the depression of the soleus H-re¯ex following previous activation of tibial nerve afferents (postactivation depression) by slow stretch of the ankle plantar ¯exors (Nielsen et al., 1993, 1995; Hultborn et al., 1996). (3) We tested disynaptic reciprocal Ia inhibition of the soleus Hre¯ex following stimulation of the antagonistic common peroneal nerve (Crone et al., 1994). 2. Materials and methods
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42.8 ^ 8.7) with clinically de®nite multiple sclerosis (MS) (Poser et al., 1983) participated in the study. In all patients the disease had been stable for at least 1 month and all gave informed consent to the examination which was approved by the local ethics committee. All patients were clinically evaluated and spasticity was graded according to the Ashworth Index (Table 1). Eight patients received baclofen intrathecally, whereas 14 patients received baclofen orally. The patients treated with oral baclofen had a median score of 5.25 (range 3.5±6) on Kurtzke's Extended Disability Status Scale (EDSS) and the median score on the Ashworth Index (hip abduction and ¯exion, knee and ankle ¯exion as a composite score for both legs) was 0.8 (range 0±2). The patients treated with intrathecal baclofen had a median score of 8 (range 2±8) on EDSS and 2.45 (range 1.5±3.3) on the Ashworth Index. None of the patients had any other neurological or psychiatric diseases. Three patients received antispastic medication (baclofen and/or tizanidine) before entering the study. All antispastic medication was stopped 72 h before the experiment. One patient withdrew his consent during the ®rst part of the study for non-medical reasons. 2.2. Drug administration and design of the study
2.1. Patients Twenty-two patients aged 24±57 years (mean ^ SD
The intrathecal study was an open-label design (Fig. 1A). A bolus of baclofen (25±50 mg) was injected into the lumbar
Table 1 Patient characteristics and baseline evaluation Type of MS a
EDSS b
Dose of baclofen
Ashworth Index c
Patients receiving intrathecal baclofen 1/F/33 8 2/M/42 8 3/M/49 25 4/F/37 18 5/M/36 8 6/F/35 21 7/M/34 13 8/F/56 17
RR PP SP SP PP PP SP SP
8.0 7.0 8.0 8.0 2.0 8.0 4.0 8.0
50 50 50 50 25 25 25 25
mg mg mg mg mg mg mg mg
1.5 2.3 3.1 3.3 1.4 3.3 1.6 2.6
Patients receiving oral baclofen 9/F/32 10/M/54 11/F/37 12/F/42 13/F/24 14/F/46 15/M/54 16/M/50 17/F/49 18/F/57 19/F/42 20/M/39 21/F/41 22/M/41
RR PP SP RR RR SP PP SP PP SP PP RR SP RR
4.5 5.5 5.0 3.5 6.0 6.0 6.0 4.5 6.0 6.0 6.0 5.0 4.0 3.5
15 mg £ 3
0.0 2.0 1.0 0.3 0.3 0.5 0.6 1.3 1.8 1.0 0.5 1.1 0.8 0.8
Subject no./sex/age (years)
a
Duration of MS (years)
10 28 11 15 5 19 22 33 6 27 8 4 21 19
d
15 15 15 10 15 15 15 10 10 15 15 15
mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3 mg £ 3
RR, relapsing remitting; SP, secondary progressive; PP, primary progressive. EDSS, Kurtzke's Expanded Disability Status Scale. c Hip (abduction and ¯exion), knee and ankle as a composite score for both legs. All 8 joint movements were summed and divided by 8 for an overall scale rating. d Withdrew his consent. b
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Fig. 1. Design of the intrathecal and oral study. In both studies all antispastic medications were tapered over 1 week and stopped 72 h before the measurements. After the end of the studies the antispastic medications were escalated to the most optimal dosage. (A) The study was an open-label design. The patients were examined before intrathecal injections of baclofen at day 0, and 1 h after intrathecal injections of baclofen at day 1. (B) The study was a placebo-controlled, double-blind cross-over study. All patients were randomly assigned to baclofen or placebo treatment. Baclofen/placebo was administered orally and escalated to maximum tolerance dosage or a maximum of 15 mg 3 times daily. After 11 days on the dosage the measurements were performed and treatment was tapered over about 1 week. After a wash-out period of 2 weeks, the patients entered the second treatment period of placebo/baclofen. Examinations were performed before each of the two treatment periods and after 11 days of treatment at the maximum dosage.
subarachnoid space by percutaneous puncture. The patients were assessed by H-re¯ex examination before and 1 h after intrathecal injection of baclofen. The oral study design (Fig. 1B) was a placebocontrolled, double-blind cross-over study. All patients were randomly assigned to either baclofen or placebo treatment. Baclofen and placebo tablets were identical in size, shape, colour and container. In order to maintain blindness as much as possible, placebo/baclofen was administered orally with a starting dose of 5 mg 3 times daily and dose escalation by 5 mg every 3 days to 15 mg 3 times daily or the maximum tolerance dosage, de®ned as the maximum dose at which the patient had no severe side effects. After 11 days on this dosage, measurements were performed and the treatment was tapered over about 1 week. After a wash-out period of 2 weeks, the patients entered the second treatment period of baclofen/placebo with an identical dosage regime. Measurements were performed before each of the two treatment periods and after 11 days of treatment at the maximum dose. All tests were performed at the same time of day in order to minimize the in¯uence of diurnal variations.
2.3. Methods Two fundamentally different experimental techniques were used in the study: (1) the transmission in different re¯ex pathways was investigated with the H-re¯ex technique; and (2) the conduction in sensory afferents and the presence of recurrent sensory action potentials were studied by measuring compound sensory action potentials. 2.3.1. H-re¯ex technique The experimental arrangement is illustrated in Fig. 2. The subjects were seated in an armchair with the examined leg semi¯exed in the hip (1208), the knee ¯exed to 1608 and the ankle in 1108 plantar ¯exion. The foot was mounted to a torque meter and the torque was displayed on an oscilloscope placed in front of the subject. The soleus H-re¯ex was evoked by stimulating the tibial nerve in the popliteal fossa through a monopolar stimulating electrode (1 ms rectangular pulse, anode placed above the patella). The re¯ex responses were measured as the peak-topeak amplitude of the non-recti®ed response. The re¯exes
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intrinsic decrease of the transmitter release probability in the synapses of the Ia afferents following previous activation of the synapses (Hultborn et al., 1996).
Fig. 2. Schematic illustration of the experimental procedure. The soleus Hre¯ex was evoked by a stimulation of the tibial nerve in the popliteal fossa (test stimulation). The Hmax/Mmax ratio was calculated at an interstimulus interval of 4 s. The soleus H-re¯ex was conditioned by 4 different procedures: (1) slow passive dorsi¯exion; (2) stimulation of the common peroneal nerve; (3) a tendon tap applied to the biceps femoris; (4) stimulation of the femoral nerve.
were recorded by bipolar electrodes (1 cm 2 recording area, 2 cm between poles) placed over the soleus muscle. The following measurements were made (see also Fig. 2). 2.3.1.1. Hmax/Mmax. An H-re¯ex recruitment curve was made by varying the intensity of the stimulation of the tibial nerve. Hmax was determined as the maximal H-re¯ex (average of 5 responses) that could be obtained and it was expressed as a percentage of the maximal M-response following supramaximal stimulation of the tibial nerve. 2.3.1.2. Slow stretch of the ankle plantar ¯exors. The size of the soleus H-re¯ex was measured before and 2 s after a passive dorsi¯exion of the ankle joint. One of the experimenters slowly changed the position of the ankle joint following a prescribed ramp drawn on an oscilloscope (1 s duration, amplitude 108). After 20 s the position of the joint was returned to its starting position and a new passive movement was made. The re¯exes were thus elicited every 20 s both in the control situation without the passive movement and when the re¯ex was elicited 2 s after the passive movement. The re¯ex was always elicited in both situations at an ankle joint position of 1108 to avoid the in¯uence on the re¯exes of changes in the muscle length (Gerilovsky et al., 1989). The re¯exes were adjusted to around 30% of Mmax in the control situation (cf. Nielsen et al., 1995). In healthy subjects the passive movement induces a pronounced, long-lasting depression of the H-re¯ex, which has been termed postactivation depression by Crone and Nielsen (1989). This depression is likely caused by an
2.3.1.3. Stimulation of the common peroneal nerve. The common peroneal nerve was stimulated (rectangular 1 ms pulse) by bipolar surface electrodes placed at or below the neck of the ®bula at a position where the threshold for the M-response in the tibialis anterior muscle was lower than the threshold for the M-response in the peroneal muscles. The conditioning stimulus strength was expressed in multiples of the M-threshold (£MT) in the tibialis anterior muscle and was kept at 1.0£ MT. In all subjects a time course of the effect of the CPN stimulation on the soleus H-re¯ex was made and the amount of disynaptic reciprocal inhibition was measured as the size of the conditioned re¯ex expressed as a percentage of the control re¯ex size at the conditioning-test interval (within the initial 5 ms) at which the maximal amount of inhibition was observed. If no inhibition was observed, which was the case in most of the patients (cf. also Crone et al., 1994), the measurement at a conditioning-test interval of 2 ms was used. 2.3.1.4. Stimulation of the femoral nerve. The femoral nerve was stimulated by a monopolar ball electrode placed in the femoral triangle just lateral to the femoral artery. The indifferent electrode was placed at the posterior aspect of the upper thigh, just below the gluteus maximus muscle. The intensity was adjusted to be just above the threshold for the direct and visible motor response in the quadriceps muscle (1.1 £ MT). A time course of the effect of the femoral nerve facilitation on the soleus H-re¯ex was obtained in each experiment. The onset of the facilitation was determined as the earliest conditioning-test interval at which the conditioned re¯ex was more than 5% larger than the control re¯ex and the conditioning-test interval used throughout the experiment was 0.5±1.0 ms longer. The size of the facilitation measured at this conditioning-test interval re¯ects the size of the monosynaptic excitatory postsynaptic potential in the soleus motor neurones evoked by activation of femoral nerve afferent ®bres (see Hultborn et al., 1987). 2.3.1.5. Biceps femoris tendon tap. A tendon tap applied to the biceps femoris tendon depresses the soleus H-re¯ex for a duration of around 300±400 ms. This depression is likely caused by presynaptic inhibition of soleus Ia afferents (Nielsen and Petersen, 1994). In the present study the tendon tap was applied by an electromagnetic hammer (BruÈel and Kjñr, Denmark, Vibration exciter model 4809) and the depression of the H-re¯ex was measured at a conditioning-test interval of 60 ms. It was expressed as the size of the conditioned re¯ex as a percentage of the control re¯ex size. The control re¯ex was adjusted to 20± 25% of Mmax.
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Table 2 Mean and SEM for the H-re¯ex measurements in the intrathecal study
Before treatment with baclofen During treatment with baclofen N7
Hmax/Mmax
FN facilitation
Reciprocal inhibition
63.7 (6.2) 14.8 (5.2) P , 0:001
126.5 (12.0) 120.5 (14.8) Non-signi®cant
90.8 (3.4) 96.3 (3.1) Non-signi®cant
2.3.2. Compound sensory action potentials (CSAP) The subject was lying on his/her stomach with support under the ankle to bend the knee to an angle of 1408. The sural nerve was stimulated at the lateral malleolus using rectangular supramaximal (2±5 mA) current pulses, 0.2 ms in duration, from a constant current stimulator. The electrodes for stimulation and recording were 0.7 mm in diameter and insulated except for a 3 mm bared tip. The CSAPs were recorded through needles placed close to the sural nerve at two sites along the calf at distances of 7 and 13 cm from the lateral malleolus. Both stimulating and recording electrodes were adjusted close to the nerve such that the threshold of the evoked nerve action potential was less than 0.5 mA. The reference electrode was an insulated needle, 0.7 mm in diameter, with a 5 mm bared tip placed subcutaneously at a medial transverse distance of 3±4 cm. The CSAPs from the two recording sites were ampli®ed (DANTEC 15C02, 200±4000 Hz, 3 dB down) simultaneously and responses of up to 500±1000 stimuli were electronically summed (Nicolet Pro20). The reproducibility of the responses was evaluated by recording the potentials in two traces of each 500 stimuli to ascertain that the recorded CSAPs remained constant. The CSAPs were recorded on an ink-jet writer (Siemens Mingograf) via a digital memory store. The temperature of the limb was kept above 35± 388C by an automatically controlled infrared heating lamp. To calculate the maximum sensory conduction velocity (CVmax), the latency to the initial positive peak of the main potential was measured. Minimum sensory conduction velocity (CVmin) was determined by measuring the latency to the latest component of the response with an amplitude of 0.1 mV. Amplitude was measured peak to peak. CVmax, amplitude and CVmin were classi®ed as normal or reduced according to previously established age-dependent norms (Horowitz and Krarup, 1992; Shefner et al., 1992). 2.3.3. Data analysis The data were stored on a computer for later statistical analysis. The mean and standard error of the mean were
calculated for all measurements on line. Differences in the size of conditioned and control re¯exes in individual subjects were tested using a Student's t test. After having tested that the data were normally distributed, analysis of variance (ANOVA) was used to compare changes before and under the placebo/baclofen treatments in the oral study. The results were adjusted by subtracting baseline values from the values of measurements during treatment with baclofen and placebo. Any effects of period were examined before testing for a possible treatment effect. Two sample t tests were used in the intrathecal baclofen study. The level of signi®cance was set at P , 0:05. 3. Results 3.1. H-re¯ex Administration of baclofen both orally and intrathecally produced a signi®cant decrease in the size of the soleus Hre¯ex measured as the Hmax/Mmax ratio. In all but 3 of the 13 patients who participated in the double-blind placebocontrolled study on the effect of oral baclofen, a signi®cantly (P , 0:05) smaller Hmax/Mmax ratio was observed during the period when the patients received oral baclofen daily (mean ^ SEM 44.0 ^ 6.2%) as compared to the period when they received either placebo (mean ^ SEM 60.3 ^ 5.5%) or no medication (mean ^ SEM 58.7 ^ 5.2%). No signi®cant difference in the size of Mmax was observed between the different recording sessions (Tables 2 and 3). It was not possible to elicit an H-re¯ex in one of the patients in whom baclofen was administered intrathecally and this patient was therefore not included in the re¯ex study. In 6 out of the 7 other patients, a strong and highly signi®cant depression of Hmax/Mmax was observed following baclofen administration. On average Hmax/Mmax was depressed from 63.7 ^ 8.2 to 14.8 ^ 5.2% in the 7 subjects (P , 0:001). Mmax was also smaller during the session where baclofen was administered (from 18.6 ^ 6 to
Table 3 Mean and SEM for the H-re¯ex measurements in the oral study
Before treatment with baclofen During treatment with baclofen During treatment with placebo N 13
Hmax/Mmax
FN facilitation
Reciprocal inhibition
Postactivation depression
Biceps femoris tendon tap
58.7 (5.2) 44.0 (6.2) 60.3 (5.5) P 0:0007
128.3 (3.9) 131.3 (3.7) 122.6 (2.8) P 0:05
98.8 (3.3) 97.9 (4.4) 105.7 (5.4) P 0:12
48.9 (6.3) 46.9 (7.2) 51.0 (5.4) P 0:62
85.4 (5.2) 88.0 (4.7) 86.3 (4.8) P 0:29
G. érsnes et al. / Clinical Neurophysiology 111 (2000) 1372±1379
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Table 4 Mean and SD for the parameters of CSAP in the intrathecal study
Before treatment with baclofen During treatment with baclofen N8
Maximal conduction velocity (m/s)
Amplitude CSAP (gV)
Minimal conduction velocity (m/s)
Recurrent potentials (number)
48.3 (10.3) 48.6 (7.8) Non-signi®cant
25.4 (21.3) 23.8 (19.0) Non-signi®cant
10.0 (2.2) 12.8 (4.4) P 0:022
2 (0) 2 (0) Non-signi®cant
13.7 ^ 5.2 mV on average). This was likely not caused by the administration of baclofen, but more likely by a nonspeci®c decline in the responsiveness of the muscle to the nerve stimulus related to the duration of the experiment, as has recently been reported (Crone et al., 1999). However, this change could not explain the decrease in the Hmax/Mmax ratio. The effect of baclofen on Hmax/Mmax was positively correlated with the effect of baclofen on muscle tone and Achilles tendon re¯exes for the patients taken from both the oral and the intrathecal study. Stimulation of the CPN in general produced no or only very little disynaptic reciprocal inhibition of the soleus Hre¯ex in the patients, as has also been reported previously (Crone et al., 1994). Administration of baclofen orally or intrathecally had no effect on the amount of inhibition. Stimulation of the femoral nerve produced a short-latency facilitation of the soleus H-re¯ex in 4 of the 7 patients in whom baclofen was administered intrathecally and in 11 out of the 13 patients who received baclofen orally. On average the femoral nerve facilitation was smaller following baclofen administration in the ®rst group (120.5 ^ 3.2 as compared to 126.5 ^ 12.0%, non-signi®cant), whereas it was larger in the period when the patients in the second group received oral baclofen as compared to the periods when they received placebo or no medication (131.3 ^ 3.9 as compared to 128.3 ^ 3.9 and 122.6 ^ 2.8%, non-signi®cant). The effect of a previous slow stretch of the ankle plantar ¯exors or a biceps femoris tendon tap on the soleus H-re¯ex was also investigated in the patients who received baclofen orally. At an interval of 2 s after the stretch the soleus Hre¯ex was depressed to the same extent when the patients received baclofen, placebo or no medication (mean ^ SEM 46.9 ^ 6.3, 51.0 ^ 5.4 and 48.9 ^ 6.3%, respectively).
At an interval of 60 ms after the biceps femoris tendon tap the soleus H-re¯ex was inhibited to 88.0 ^ 4.7, 76.3 ^ 4.8 and 85.4 ^ 7.6% during the periods when the patients received baclofen, placebo and no medication, respectively. These differences were not statistically signi®cant. 3.2. Compound somatosensory action potentials (CSAP) The result of the CSAP recordings in individual patients at baseline and during baclofen treatment are listed in Tables 4 and 5. In the intrathecal study 5 patients had normal maximal conduction velocity (CVmax), and 3 patients had decreased CVmax. Five patients had normal amplitude and 3 patients had decreased amplitude. Only one patient had minimal conduction velocity (CVmin) within normal range and only two patients (25%) had recurrent potentials at baseline. During treatment with intrathecal baclofen the number of recurrent potentials changed from one to two in one patient and from 3 to two in the other patient. Of all parameters of CSAP only CVmin showed a signi®cant change (P 0:022); 7 patients showed increased CVmin. Of the patients who received baclofen orally, CVmax and amplitudes were within normal limits in 12 patients at baseline. In one patient CVmax was decreased. CVmin was reduced in 12 patients. Ten patients (76%) had recurrent potentials at baseline (range 1±3). When treated with oral baclofen there were no signi®cant differences in the parameters compared to placebo treatment, and in particular the number of recurrent potentials did not change. 4. Discussion This study has investigated the mode of action of baclofen in spastic MS patients. Baclofen was administered either intrathecally or orally. In the latter case the patients received
Table 5 Mean and SD for the parameters of CSAP in the oral study
Before treatment with baclofen During treatment with baclofen Before treatment with placebo During treatment with placebo N 13
Maximal conduction velocity (m/s)
Amplitude CSAP (gV)
Minimal conduction velocity (m/s)
Recurrent potentials (number)
53.3 (4.6) 53.4 (4.8) 53.3 (5.5) 53.7 (4.3) P 0:84
26.8 (12.9) 29.3 (19.4) 27.7 (13.2) 31.3 (22.1) P 0:79
6.6 (1.4) 6.8 (1.5) 7.7 (2.2) 7.4 (1.8) P 0:54
1.5 (1.6) 2.0 (1.5) 1.4 (1.1) 1.6 (2.0) P 0:71
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G. érsnes et al. / Clinical Neurophysiology 111 (2000) 1372±1379
a daily dose of baclofen for 3 weeks prior to the investigation and the study was designed as a double-blind placebocontrolled study. The study on the effect of intrathecal baclofen was designed as an open-label study. In both cases a clear depression of the soleus H-re¯ex was observed. Although a similar depression of H-re¯exes by baclofen administration has been reported in several previous studies (Macdonell et al., 1989; Milanov, 1992; Azouvi et al., 1993), it is to the best of our knowledge the ®rst time that this has been documented in a double-blind, placebocontrolled experiment. It is not straightforward to draw conclusions regarding stretch re¯ex activity based on H-re¯ex ®ndings (Burke et al., 1984; Morita et al., 1998) and it might therefore be questioned whether the depression of transmission in the re¯ex pathway underlying the H-re¯ex by baclofen is of importance for the antispastic effect ± i.e. decrease of muscle tone and phasic stretch re¯exes ± of the drug. However, there was a clear correspondence in the present study between on one hand the decrease of the H-re¯ex and on the other hand the decrease in muscle tone and tendon re¯exes following baclofen administration. Despite the ®ndings by Burke et al. (1984) and Morita et al. (1998), we therefore believe that the depression of the H-re¯ex is a useful marker of the antispastic effect of baclofen and that the mechanism involved in the depression of the H-re¯ex is also ± to a large extent ± responsible for the antispastic effect of the drug. Baclofen is a selective GABAB receptor agonist (Bowery and Pratt, 1992). These receptors are found abundantly on the terminals of primary afferents, but also on the terminals of descending ®bres as well as on the soma of different spinal neurones including the motoneurones (Misgeld et al., 1995; Tillakaratne et al., 1995). The role of these receptors in mediating presynaptic inhibition of Ia afferents has been somewhat debated, but the majority of animal studies now seem to agree that baclofen has no role in the classical GABA-mediated presynaptic inhibition of Ia afferents which is associated with depolarization of the dorsal roots (Stuart and Redman, 1992). The present ®nding that baclofen had no effect on any of the parameters that we believe to re¯ect GABA-mediated presynaptic inhibition (biceps femoris induced depression of the soleus H-re¯ex, femoral nerve facilitation of the soleus H-re¯ex, recurrent somatosensory action potentials) is well in line with this. Azouvi et al. (1993) similarly found that the femoral nerve facilitation was unchanged following intrathecal baclofen and concluded that increased presynaptic inhibition seemed not to be responsible for the depressant effect of baclofen on the soleus H-re¯ex. GABAB receptors may, however, interfere with transmitter release from Ia afferents in other ways. In the neonatal rat it has been demonstrated that baclofen decreases the longlasting depression of monosynaptic re¯exes following previous activation of the same afferents that mediate the re¯exes (Lev-Tov and Pinco, 1992). This effect is explained
by the reduction of the baseline availability of transmitter substance in the synapses following baclofen administration (Lev-Tov and Pinco, 1992). The human soleus H-re¯ex is also depressed following previous activation of soleus Ia afferents. This depression has been termed postactivation depression by Crone and Nielsen (1989). In con®rmation of previous studies we found that the depression was less pronounced in the spastic patients than in a population of healthy subjects (see Nielsen et al., 1993, 1995). Based on the data from the neonatal rat it could be expected that postactivation depression was increased following baclofen, but this was not the case. In the patients who received baclofen orally it may be that too little baclofen was transported into the CNS, but this cannot explain the lack of effect in the patients in whom baclofen was given intrathecally and in whom the Hmax/Mmax ratio was very strongly depressed. More likely explanations are therefore that the distribution of GABAB receptors or the mechanisms regulated by these receptors are different for the adult human Ia afferents as compared to the neonatal rat. There is a remote possibility that the depression of the re¯ex could be caused by a peripheral effect on the muscle. GABAergic receptors have indeed been found around the motor end plate in the cray ®sh (Barry, 1984; Fischer and Parnas, 1996). However, we observed no depression of Mmax in the oral study where the highest doses of baclofen in the periphery are likely to have occurred. We did see a depression of Mmax in the intrathecal study, but in this case only a limited amount of baclofen is likely to have reached the peripheral circulation. Furthermore, the depression of Mmax was more likely explained by the tendency for Mmax to decrease in the course of an experiment (Crone et al., 1999). In separate control experiments in which this factor was taken into account intrathecal baclofen was indeed found not to have any selective effect on Mmax (érsnes and Crone, unpublished observations). One ®nal possibility is that the depression of Hmax by baclofen was exerted on the spinal motoneurones. There is a theoretical possibility that baclofen increased the transmission from inhibitory neurones or alternatively decreased the transmission from excitatory neurones projecting to the motoneurones. We did not ®nd any evidence that transmission in the disynaptic reciprocal Ia inhibitory pathway was increased following either intrathecal or oral baclofen, but we did not investigate any other postsynaptic inhibitory pathways and there is a possibility that baclofen increased the transmission in pathways mediating autogenic Ib inhibition or recurrent inhibition. The decrease of the H-re¯exes following baclofen treatment could also be explained by a decreased corticospinal excitatory drive to the spinal motoneurones, possibly secondary to a decrease in intracortical excitability as demonstrated by Ziemann et al. (1996). In addition to this, we agree with Azouvi et al. (1993) that binding of baclofen directly to GABAB receptors on the spinal motoneurones is probably a major explanation of the decreased motoneuro-
G. érsnes et al. / Clinical Neurophysiology 111 (2000) 1372±1379
nal excitability. Such postsynaptic receptors may be more common than what has previously been assumed (Misgeld et al., 1995). 4.1. Signi®cance for antispastic treatment If ± as it appears ± the main antispastic effect of baclofen is related to its depression of motoneuronal excitability, it has to be concluded that baclofen is far from being an ideal antispastic drug. The depression of motoneuronal excitability will reduce not only the unwanted involuntary movements and muscle stiffness elicited by activation of sensory afferents, but also the voluntary movement repertoire that may be essential for the daily function of the patient. This point of view is also well in line with the growing clinical experience that baclofen is a valuable drug in the management of severe spasticity in patients with little or no remaining voluntary motor function. In patients for whom the ability to walk and move around is in the foreground and the spastic symptoms are of minor importance our data as well as the clinical experience suggests that baclofen should only be given with caution (Hoogstraten et al., 1988; Dones et al., 1995). It is obvious to us that in any individual patient an evaluation of the functional disability should be weighted against the severity of spasticity before baclofen is prescribed. This can only be done by a combination of careful clinical and electrophysiological examination. Acknowledgements This study was supported by grants from the Danish Society of Multiple Sclerosis, Warwara Larsens Foundation, Lily Benthine Lunds Foundation, Dagmar Marshalls Foundation, Hestehandler Ole Jakobsens Foundation and Foundation for Research in Neurology. Novartis supplied identical baclofen and placebo tablets. References Azouvi P, et al. Effect of intrathecal baclofen on the monosynaptic re¯ex in humans: evidence for a postsynaptic action. J Neurol Neurosurg Psychiatry 1993;56(5):515±519. Barry SR. Baclofen has a presynaptic action at the cray®sh neuromuscular junction. Brain Res 1984;311(1):152±156. Bowery NG, Pratt GD. GABAB receptors as targets for drug action. Arzneimittelforschung 1992;42(2A):215±223. Burke D, et al. Monosynaptic and oligosynaptic contributions to human ankle jerk and H-re¯ex. J Neurophysiol 1984;52(3):435±448. Crone C, Nielsen J. Methodological implications of the post-activation depression. Exp Brain Res 1989;78:28±32. Crone C, et al. Disynaptic reciprocal inhibition of ankle extensors in spastic patients. Brain 1994;117:1161±1168. Crone C, et al. Amplitude of the maximum motor response (Mmax) in
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