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Electrophysiological assessment of the effect of intrathecal baclofen in spastic children
Clinical Neurophysiology 113 (2002) 336–340 www.elsevier.com/locate/clinph
Electrophysiological assessment of the effect of intrathecal baclofen in spastic children B. Dachy a,*, B. Dan b a
Department of Neurology, CHU Brugmann (ULB), Place Van Gehuchten, 4, B-1020 Brussels, Belgium Department of Neurology, Hoˆpital Universitaire des Enfants Reine Fabiola (ULB), Brussels, Belgium
b
Accepted 17 December 2001
Abstract Objectives: To evaluate the effect of intrathecal baclofen in a group of spastic children using electrophysiological procedures described in adults. Methods: Six children (aged 1–14 years) with severe spasticity of various aetiologies underwent transcranial magnetic stimulation, H reflex and flexor reflex studies before and after intrathecal injection of baclofen. Ashworth scale was used for clinical evaluation of spasticity. Results: Motor evoked potentials, present in two patients before baclofen, were preserved after injection. Before baclofen, H reflex was present in 5 patients (Hmax/Mmax from 0.23 to 0.84) and absent in one who had infantile neuroaxonal dystrophy. After baclofen, it was absent in 4 patients and markedly reduced in one. Surface of flexor reflex significantly decreased after baclofen ðP ¼ 0:01Þ, while threshold significantly increased ðP ¼ 0:003Þ. Conclusions: In spastic children, the action of baclofen on spinal pathways may be quantified by the same electrophysiological procedures as in adults. This approach may contribute to select optimal dosage. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Spasticity; Intrathecal baclofen; H-reflex; Flexor reflex; Child
1. Introduction Spasticity is a major clinical problem in patients with lesions of central motor pathways. It results from disinhibition of spinal reflex activity. Various pharmacological agents have been used in the hope of modulating this activity, but the efficacy of antispastic drugs has been limited by side effects. However, the advent of reliable intrathecal infusion devices has generated much enthusiasm for continuous intrathecal administration of baclofen in patients with spasticity of spinal or supraspinal origin (Albright, 1996; Azouvi et al., 1996; Ochs et al., 1999). Despite the increasing use of this therapeutic approach, there has been little emphasis on neurophysiological evaluation of the effect of intrathecal baclofen (ITB) in treated patients. In adults, several tests have been proposed in order to quantify the effect of antispastic treatment, including the H reflex (Delwaide, 1985), recording of flexor spasms (Shahani and Young, 1973) and polysynaptic flexion reflexes (Parise et al., 1997; Ørsnes et al., 2000). In addition to exploring the action of baclofen on spinal mechanisms, it has been argued * Corresponding author. Tel.: 132-2-477-2598; fax: 132-2-477-2456. E-mail address: [email protected] (B. Dachy).
that these tests may also be used in order to define the optimal daily dosage to be delivered (Parise et al., 1997). The purpose of this study was to apply these electrophysiological procedures to a paediatric population with spasticity needing efficient treatment. We describe the effect of ITB on these parameters in 5 children aged between 1 and 14.
2. Methods 2.1. Patients Six children with spasticity participated in the study. Their clinical features are summarised in Table 1. Patients 1, 2, 5 and 6 have cerebral palsy; 1,2 and 5 of the spastic quadriplegia type and 6 of the mixed type. Patient 3 has infantile neuroaxonal dystrophy. Patient 4 has a congenital form of hereditary spastic paraparesis. Spasticity caused major discomfort in all the patients. Oral benzodiazepines were given to Patients 1, 2 and 5, and discontinued because they induced drowsiness. Oral baclofen was given to all the patients, and discontinued because it was ineffective (maximal dose 0.5 mg/kg tid) in Patients 1, 3 and 6, caused drowsiness in Patients 2, 3 and 4, and biological signs of liver
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Table 1 Clinical features of the patients a Patients Gender Age (years) Height (cm) Weight (kg) Aetiology Origin of spasticity Ashworth score without baclofen Ashworth score after 25 mg ITB Ashworth score after 50 mg ITB Ashworth score after 75 mg ITB Efficacious dose of baclofen (mg) 1
1 F 1.5 81 12 Septic shock Supraspinal 4.7 – 1.7 – 50
2 M 14 110 13 Birth asphyxia Supraspinal 4.3 – 1.3 – 50
3 F 7 120 20 INAD Supraspinal spinal? 4.3 – 1.3 – 25
4 F 4 95 14 Unknown Spinal 4.0 2.0 1.0 – 50
5 F 1 75 10 Drowning Supraspinal 4.3 – 4.0 1.3 75
6 M 5 118 11 Toxic Supraspinal 4.7 – 1.6 – 50
F, female; M, male; INAD, infantile neuroaxonal dystrophy; ITB, intrathecal baclofen.
toxicity in Patient 5. Therefore, a trial of ITB was considered as a preliminary testing for possible indication of ITB pump implantation. None of the patients were on medication known to influence spasticity at the time of the study. 2.2. Clinical evaluation Clinical evaluation of lower limb spasticity was performed using the Ashworth spasticity scale (Ashworth, 1964) during passive flexion and extension of the hips, knees and ankles with the patient lying supine. The intensity of spasticity was rated for flexion and extension of all the considered joints, then the mean Ashworth score was calculated. This evaluation was performed just before neurophysiological testing, prior to and following baclofen injection. 2.3. Baclofen injection Baclofen was administered intrathecally via lumbar puncture following recommended procedures (Albright, 1996), at dosages ranging from 25 to 75 mg. As recommended, a starting dose of 50 mg was tried first. A lower dose (25 mg) was injected the following day if side effects such as drowsiness or excessive hypotonia were observed. A higher dose (75 mg) was administered if the mean Ashworth score did not decrease by at least 2 points. 2.4. Neurophysiological study The electrophysiological procedures performed included transcranial magnetic stimulation (TMS), H reflex and flexion reflex (FR) recordings. The full evaluation was conducted before baclofen administration, and it was repeated 120 min later. However, if no response was obtained to one test, this test was not repeated after ITB. TMS was carried out with a circular coil (90 mm in diameter) connected to a Magstim 200 (2.0 T). The coil was oriented in such a way that the induced electric current flowed in a posterior-to-anterior direction over the appropriate cortical motor areas. Motor evoked potentials (MEP) were recorded at the surface of tibialis anterior muscles. A response was considered present if a reliable MEP was
recorded at rest in the absence of voluntary background contraction. The stimulus intensity was increased to 100% before a response was considered absent (Rossini et al., 1994). Reliability of TMS responses was assessed through its reproducibility across 4 consecutive stimuli. H reflex was elicited by percutaneous electrical stimulation of the tibial nerve at the popliteal fossa using square block pulses of 1 ms. Stimulation was given at a rate of 0.3 Hz. Surface recording silver/silver chloride electrodes were placed over the belly and the muscle–tendon junction of the soleus muscle. Mmax and Hmax were defined as the peak-to-peak maximal amplitudes of the M and H responses, respectively. FR were recorded by surface silver/silver chloride electrodes applied over the short head of biceps femoris or over the tibialis anterior muscle, after electrical stimulation of the ipsilateral sural or tibial nerve at the level of the ankle. Each stimulus, given every 5 s, consisted of a train of 5 electrical square pulses of 1 ms each, delivered at a rate of 300 Hz by a constant current stimulator. FR were recorded over a 1000 ms window, amplified with a band-pass of 30– 3000 Hz. The analysis of FR included the determination of the threshold and the area of the response. The former was defined as the minimal intensity in milliamperes (mA) necessary to obtain reproducible FR. The latter was measured by integrating the electromyographic (EMG) activity of the response over the analysis window of 1000 ms, expressed in mV ms. Stimulus intensity was increased until maximal response was obtained. This saturation level was maintained for comparison between consecutive recordings. 2.5. Statistical analysis SPSS for Windows package was used for statistical analysis. One-factor repeated measures ANOVA (withinsubjects factors) was performed. Statistical significance was considered for P-values below or equal to 0.01. 2.6. Ethical aspects The local Ethics Committee has approved this project.
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Informed consent was obtained from the parents after the nature of the procedure had been fully explained. 3. Results 3.1. Before intrathecal injection of baclofen Mean Ashworth scores ranged between 4.0 and 4.7 (Table 1). TMS elicited MEP in two children (Patients 2 and 6). At 100% of maximal stimulation output, the response latencies were within normal limits, respectively, 15.7 and 16.6 ms at the right and left tibialis anterior muscles for Patient 2, 16.6 and 16.1 ms at the same muscles for Patient 6. H reflexes were elicited in 5 patients (all but Patient 3). In these patients, the values of the Hmax/Mmax ratio were 0.84, 0.82, 0.23, 0.56 and 0.59. H reflex was absent in the patient with associated axonal neuropathy. For FR recording, detection electrodes were initially applied at the surface of the biceps femoris muscle in all patients, according to Parise et al. (1997). Consistent responses were obtained in 4 patients. In these, mean left/right FR threshold values were 11.8, 19.0, 15.2 and 20 mA. The mean areas of left and right FR responses were 54.6, 18.7, 45.8 and 174.1 mV ms. In the other two patients, as the responses were not consistent at the level of the biceps femoris muscle, electrodes were also applied over the tibialis anterior muscle in order to record responses to tibial nerve stimulation. In these patients, mean left/right FR threshold values were 11.5 and 9.0 mA. The mean areas of these responses were 17.6 and 47.7 mV ms. 3.2. After intrathecal injection of baclofen After the injection of 50 mg of baclofen, the mean Ashworth score decreased in all the patients (Table 1). One patient required a lower dose (25 mg) because the first injection was followed by drowsiness and marked hypotonia. Following the 25 mg injection, this patient’s Ashworth score was 2.0 points lower than before ITB. One patient required a higher dose (75 mg), as the first injection led to a decrease in Ashworth score by only 0.3 point. Following the 75 mg injection, Ashworth score went down to 1.3. After optimal ITB dose, TMS results were similar to those obtained before ITB, except for a reduction in MEP amplitude (0.6– 0.2 mV and 0.5–0.1 mV). No consistent H reflex was recorded in all but one patient (Patient 6). In the latter, Hmax/Mmax was reduced by 56%. The patient who showed an optimal clinical response to 25 mg ITB, had no consistent H reflex with either 25 or 50 mg ITB, although it was present before ITB. In the patient with an optimal clinical response to 75 mg ITB, the H reflex was already absent at 50 mg ITB. Fig. 1 shows the changes in FR threshold values after the optimal ITB dose. The values were significantly higher after ITB ðP ¼ 0:003Þ. Fig. 2 shows the changes of FR surface after the optimal ITB dose. In all patients, FR surfaces decreased after ITB ðP ¼ 0:01Þ. As illustrated in Fig. 3A, FR includes two main EMG bursts when stimulation intensity is
Fig. 1. Effect of ITB on threshold values of the flexor reflex. Each patient is identified by a symbol (V, X, etc.). Open symbols indicate right side responses. Filled symbols indicate left side responses.
increased, namely the short-latency response (SLR) and the long-latency response (LLR). At threshold intensities, only the LLR component was identified. At higher intensities, SLR gradually appeared. Both the SLR and the LLR were attenuated after ITB (Fig. 3B), in contrast with the situation prior to ITB (Fig. 3A). 4. Discussion 4.1. Neurophysiological assessment of spastic children The techniques we used for the neurophysiological assessment of reflex parameters in children with spasticity in this study derive from those previously described in adults (Shahani and Young, 1973; Delwaide, 1985; Parise et al., 1997). In some of the children we evaluated, adaptation of the FR recording technique was required, regarding the choice of the recorded muscle in order to obtain reliable responses. In agreement with Milanov (1992), responses could be more stable over the tibialis anterior than the biceps femoris muscle. According to Shahani and Young (1973), responses from either muscle are equally representative of flexor spasm activity. With reference to a paediatric population, a study of FR responses in neonates revealed that EMG activities seen in the tibialis anterior had a shorter
Fig. 2. Effect of ITB on flexor reflex area. Each patient is identified by a symbol (V, X, etc.). Open symbols indicate right side responses. Filled symbols indicate left side responses.
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Fig. 3. Flexor reflex recording in one patient before (A) and after ITB (B). The uppermost traces were obtained at threshold level. Lower traces correspond to gradually increasing stimulus intensities, up to saturation level. The two components of the flexor reflex are identified as SLR and LLR.
latency and were larger than in the biceps femoris muscle. This was associated with the positive ‘Babinski sign’ and therefore was thought to reflect immaturity in spinal processing (Andrews and Fitzgerald, 2000). Moreover, as children may have difficulty in adequately reporting the quality of the sensation elicited by the stimulation, the use of a mixed, sensory and motor nerve may allow to confirm that an adequate stimulus was applied, through the motor twitch. 4.2. Effect of baclofen on electrophysiological parameters While we did not find an elevation of TMS threshold sufficient to preclude MEP recording after ITB, we noted a systematic reduction in MEP amplitudes. TMS threshold reflects the excitability of corticospinal neurons and interneurons projecting onto these cells in the motor cortex, and also the excitability of the postsynaptic motor neurons in the spinal cord (Moll et al., 1999). In accordance with our findings, Ziemann et al. (1996) showed that baclofen did not affect TMS threshold. At the spinal level, it has been suggested that MEP amplitude depends on the number of discharging anterior horn cells (Mall et al., 2001). In this respect, Ørsnes et al. (2000) emphasised the postsynaptic site of action of baclofen. Our results suggest a lack of cortical pharmacological action, consistent with the low cisternal-to-lumbar ratio of baclofen following lumbar injection (Mu¨ ller et al., 1988). In this context, the main interest of TMS might therefore be to evaluate the pathways on which remaining voluntary motor function relies. Although some authors found no influence of progabide, another g-aminobutyric acid (GABA) agonist, on Hmax/Mmax
ratio (Mondrup and Pedersen, 1984), we observed a clear depression of the soleus H reflex following ITB in agreement with many previous studies (Milanov, 1992; Capaday, 1995; Azouvi et al., 1996). Ørsnes et al. (2000) proposed that this depression reflects decreased motoneuronal excitability. However, decreased Hmax/Mmax ratio does not imply reduction of spasticity (Pisano et al., 2000). Furthermore, decreased motoneuronal excitability is expected to impair the remaining voluntary motor function (Landau, 1974), although in selected situations, ITB might improve motor control (Latash et al., 1990; Dan and Cheron, 2000a). However, in patients with severe impairment of corticospinal tracts, reflected by TMS abnormalities, deleterious effect of ITB should not be a clinical problem. In this population, the main therapeutic goal is to alleviate discomfort associated with exaggerated reflexes. Among these, flexor spasms are clinically indistinguishable from flexor reflexes produced by electrocutaneous stimulation, i.e. FR (Shahani and Young, 1973). In particular, FR of high magnitude, long duration and low threshold are correlated with patients’ complaints of painful spasms that follow even light stimulation (Parise et al., 1997). Our results show that ITB increases FR threshold values and decreases FR surfaces in spastic children, as previously demonstrated in spastic adults (Parise et al., 1997). This increase in FR threshold is likely related to a specific agonist action of baclofen on GABA-receptor type B, reducing the release by primary afferent terminals in laminae II and III of excitatory neurotransmitters onto ventral horn motoneurons in the spinal cord (Bowery et al., 1980, 1987). The SLR component of FR corresponds to the so-called RA III reflex evoked in normal
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subjects by nociceptive stimulation (Hugon, 1973). In contrast, LLR only occurs in pathological conditions, and has been related to clinical flexor spasms (Shahani and Young, 1973). The undissociated effect of ITB on the SLR and LLR components of the FR and on the H reflex may indicate non-specific action on mono and polysynaptic reflexes at the spinal level (Ørsnes et al., 2000). The clinical interest of FR studies has been previously demonstrated in adults with spasticity of spinal origin (Casale et al., 1995). Our work suggests that this technique can be of value in a paediatric population. 4.3. Conclusions In the present study, we showed that some electrophysiological procedures relevant for the assessment of spasticity and its management may be used in children. This is of particular interest in the current context where the relevance of clinical testing of spasticity and motor dysfunction is limited (Katz et al., 1992; Dan and Cheron, 2000b). The pharmacological action of baclofen concerns multiple levels. Therefore, ITB may have several indications (Ochs et al., 1999). Neurophysiological testing may contribute to objectively assess specific therapeutic objectives of ITB. If the clinical problem is related to flexor spasms, the effect of ITB on FR parameters seems to be useful. However, in spastic patients where functional goals are set, neurophysiological appraisal of the benefit of ITB should also include EMG-biomechanical techniques (Pisano et al., 2000; Dan et al., 2000). References Albright AL. Baclofen in cerebral palsy. J Child Neurol 1996;11:77–83. Andrews K, Fitzgerald M. Flexion reflex responses in biceps femoris and tibialis anterior in human neonates. Early Hum Dev 2000;57:105–110. Ashworth B. Preliminary trial of Carisprodol in multiple sclerosis. Practitioner 1964;192:540–542. Azouvi P, Mane M, Thiebaut JB, Denys P, Remy-Neris O, Bussel B. Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up. Arch Phys Med Rehabil 1996;77:35–39. Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M. Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 1980;283:92–94. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987;20: 365–383. Capaday C. The effects of baclofen on the stretch reflex parameters of the cat. Exp Brain Res 1995;104:287–296. Casale R, Glynn CJ, Buonocore M. Reduction of spastic hypertonia in patients with spinal cord injury: a double-blind comparison of intravenous orphenadrine citrate and placebo. Arch Phys Med Rehabil 1995; 76:660–665. Dan B, Cheron G. Intrathecal baclofen normalizes motor strategy for squat-
ting in familial spastic paraplegia: a case study. Neurophysiol Clin 2000a;30:43–48. Dan B, Cheron G. Linking motor impairment to function. Dev Med Child Neurol 2000b;41:69. Dan B, Bouillot E, Bengoetxea A, Cheron G. Effect of intrathecal baclofen on gait control in human hereditary spastic paraparesis. Neurosci Lett 2000;280:175–178. Delwaide PJ. Electrophysiological analysis of the mode of action of muscle relaxants in spasticity. Ann Neurol 1985;17:90–95. Hugon M. Exteroceptive reflexes to the stimulation of the sural nerve in normal man. In: Desmedt JE, editor. New developments in electromyography and clinical neurophysiology, vol. 3. Basel: Karger, 1973. pp. 713–729. Katz R, Rovai GP, Brait C, Rymer WZ. Objective quantification of spastic hypertonia: correlation with clinical findings. Arch Phys Med Rehabil 1992;73:339–347. Landau WM. Spasticity: the fable of a neurological demon and the emperor’s new therapy. Arch Neurol 1974;31:217–219. Latash ML, Penn RD, Corcos DM, Gottlieb GL. Effects of intrathecal baclofen on voluntary motor control in spastic paresis. J Neurosurg 1990;72:388–392. Mall V, Glocker FX, Fietzek U, Heinen F, Berweck S, Korinthenberg R, Ro¨ sler KM. Inhibitory conditioning stimulus in transcranial magnetic stimulation reduces the number of excited spinal motor neurons. Clin Neurophysiol 2001;112:1810–1813. Milanov IG. Flexor reflex for assessment of common interneurone activity in spasticity. Electromyogr Clin Neurophysiol 1992;32:621–629. Moll GH, Heinrich H, Wischer S, Tergau F, Paulus W, Rothenberger A. Motor system excitability in healthy children: developmental aspects from transcranial magnetic stimulation. Electroenceph clin Neurophysiol Suppl 1999;51:243–249. Mondrup K, Pedersen E. The effect of the GABA-agonist, progabide, on stretch and flexor reflexes and on voluntary power in spastic patients. Acta Neurol Scand 1984;69:191–199. Mu¨ ller H, Ziersky J, Dralle D. Pharmacokinetics of intrathecal baclofen. In: Mu¨ ller H, Ziersky J, Penn RD, editors. Local-spinal therapy of spasticity, New York, NY: Springer, 1988. pp. 223–226. Ochs G, Nauman C, Dimitrijevic M, Saindou M. Intrathecal baclofen therapy for spinal origin spasticity: spinal cord injury, spinal cord disease, and multiple sclerosis. Neuromodulation 1999;2:108–119. Ørsnes G, Crone C, Krarup C, Petersen N, Nielsen J. The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients. Clin Neurophysiol 2000;111:1372–1379. Parise M, Garcia-Larrea L, Mertens P, Sindou M, Maugiere F. Clinical use of polysynaptic flexion reflexes in the management of spasticity with intrathecal baclofen. Electroenceph clin Neurophysiol 1997;105:141– 148. Pisano F, Miscio G, Del Conte C, Pianca D, Candeloro E, Colombo R. Quantitative measures of spasticity in post-stroke patients. Clin Neurophysiol 2000;111:1015–1022. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lu¨ cking CH, Maertens de Noordhout AL, Marsden CD, Murray NMF, Rothwell JC, Swash M, Tomberg C. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroenceph clin Neurophysiol 1994;91:79–92. Shahani BT, Young RR. Human flexor spasms. In: Desmedt JE, editor. New developments in electromyography and clinical neurophysiology, vol. 3. Basel: Karger, 1973. pp. 734–743. Ziemann U, Lo¨ nnecker S, Steinhoff BJ, Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40:367–378.
Electrophysiological assessment of the effect of intrathecal baclofen in spastic children B. Dachy a,*, B. Dan b a
Department of Neurology, CHU Brugmann (ULB), Place Van Gehuchten, 4, B-1020 Brussels, Belgium Department of Neurology, Hoˆpital Universitaire des Enfants Reine Fabiola (ULB), Brussels, Belgium
b
Accepted 17 December 2001
Abstract Objectives: To evaluate the effect of intrathecal baclofen in a group of spastic children using electrophysiological procedures described in adults. Methods: Six children (aged 1–14 years) with severe spasticity of various aetiologies underwent transcranial magnetic stimulation, H reflex and flexor reflex studies before and after intrathecal injection of baclofen. Ashworth scale was used for clinical evaluation of spasticity. Results: Motor evoked potentials, present in two patients before baclofen, were preserved after injection. Before baclofen, H reflex was present in 5 patients (Hmax/Mmax from 0.23 to 0.84) and absent in one who had infantile neuroaxonal dystrophy. After baclofen, it was absent in 4 patients and markedly reduced in one. Surface of flexor reflex significantly decreased after baclofen ðP ¼ 0:01Þ, while threshold significantly increased ðP ¼ 0:003Þ. Conclusions: In spastic children, the action of baclofen on spinal pathways may be quantified by the same electrophysiological procedures as in adults. This approach may contribute to select optimal dosage. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Spasticity; Intrathecal baclofen; H-reflex; Flexor reflex; Child
1. Introduction Spasticity is a major clinical problem in patients with lesions of central motor pathways. It results from disinhibition of spinal reflex activity. Various pharmacological agents have been used in the hope of modulating this activity, but the efficacy of antispastic drugs has been limited by side effects. However, the advent of reliable intrathecal infusion devices has generated much enthusiasm for continuous intrathecal administration of baclofen in patients with spasticity of spinal or supraspinal origin (Albright, 1996; Azouvi et al., 1996; Ochs et al., 1999). Despite the increasing use of this therapeutic approach, there has been little emphasis on neurophysiological evaluation of the effect of intrathecal baclofen (ITB) in treated patients. In adults, several tests have been proposed in order to quantify the effect of antispastic treatment, including the H reflex (Delwaide, 1985), recording of flexor spasms (Shahani and Young, 1973) and polysynaptic flexion reflexes (Parise et al., 1997; Ørsnes et al., 2000). In addition to exploring the action of baclofen on spinal mechanisms, it has been argued * Corresponding author. Tel.: 132-2-477-2598; fax: 132-2-477-2456. E-mail address: [email protected] (B. Dachy).
that these tests may also be used in order to define the optimal daily dosage to be delivered (Parise et al., 1997). The purpose of this study was to apply these electrophysiological procedures to a paediatric population with spasticity needing efficient treatment. We describe the effect of ITB on these parameters in 5 children aged between 1 and 14.
2. Methods 2.1. Patients Six children with spasticity participated in the study. Their clinical features are summarised in Table 1. Patients 1, 2, 5 and 6 have cerebral palsy; 1,2 and 5 of the spastic quadriplegia type and 6 of the mixed type. Patient 3 has infantile neuroaxonal dystrophy. Patient 4 has a congenital form of hereditary spastic paraparesis. Spasticity caused major discomfort in all the patients. Oral benzodiazepines were given to Patients 1, 2 and 5, and discontinued because they induced drowsiness. Oral baclofen was given to all the patients, and discontinued because it was ineffective (maximal dose 0.5 mg/kg tid) in Patients 1, 3 and 6, caused drowsiness in Patients 2, 3 and 4, and biological signs of liver
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88- 2457(02)0001 0-X
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Table 1 Clinical features of the patients a Patients Gender Age (years) Height (cm) Weight (kg) Aetiology Origin of spasticity Ashworth score without baclofen Ashworth score after 25 mg ITB Ashworth score after 50 mg ITB Ashworth score after 75 mg ITB Efficacious dose of baclofen (mg) 1
1 F 1.5 81 12 Septic shock Supraspinal 4.7 – 1.7 – 50
2 M 14 110 13 Birth asphyxia Supraspinal 4.3 – 1.3 – 50
3 F 7 120 20 INAD Supraspinal spinal? 4.3 – 1.3 – 25
4 F 4 95 14 Unknown Spinal 4.0 2.0 1.0 – 50
5 F 1 75 10 Drowning Supraspinal 4.3 – 4.0 1.3 75
6 M 5 118 11 Toxic Supraspinal 4.7 – 1.6 – 50
F, female; M, male; INAD, infantile neuroaxonal dystrophy; ITB, intrathecal baclofen.
toxicity in Patient 5. Therefore, a trial of ITB was considered as a preliminary testing for possible indication of ITB pump implantation. None of the patients were on medication known to influence spasticity at the time of the study. 2.2. Clinical evaluation Clinical evaluation of lower limb spasticity was performed using the Ashworth spasticity scale (Ashworth, 1964) during passive flexion and extension of the hips, knees and ankles with the patient lying supine. The intensity of spasticity was rated for flexion and extension of all the considered joints, then the mean Ashworth score was calculated. This evaluation was performed just before neurophysiological testing, prior to and following baclofen injection. 2.3. Baclofen injection Baclofen was administered intrathecally via lumbar puncture following recommended procedures (Albright, 1996), at dosages ranging from 25 to 75 mg. As recommended, a starting dose of 50 mg was tried first. A lower dose (25 mg) was injected the following day if side effects such as drowsiness or excessive hypotonia were observed. A higher dose (75 mg) was administered if the mean Ashworth score did not decrease by at least 2 points. 2.4. Neurophysiological study The electrophysiological procedures performed included transcranial magnetic stimulation (TMS), H reflex and flexion reflex (FR) recordings. The full evaluation was conducted before baclofen administration, and it was repeated 120 min later. However, if no response was obtained to one test, this test was not repeated after ITB. TMS was carried out with a circular coil (90 mm in diameter) connected to a Magstim 200 (2.0 T). The coil was oriented in such a way that the induced electric current flowed in a posterior-to-anterior direction over the appropriate cortical motor areas. Motor evoked potentials (MEP) were recorded at the surface of tibialis anterior muscles. A response was considered present if a reliable MEP was
recorded at rest in the absence of voluntary background contraction. The stimulus intensity was increased to 100% before a response was considered absent (Rossini et al., 1994). Reliability of TMS responses was assessed through its reproducibility across 4 consecutive stimuli. H reflex was elicited by percutaneous electrical stimulation of the tibial nerve at the popliteal fossa using square block pulses of 1 ms. Stimulation was given at a rate of 0.3 Hz. Surface recording silver/silver chloride electrodes were placed over the belly and the muscle–tendon junction of the soleus muscle. Mmax and Hmax were defined as the peak-to-peak maximal amplitudes of the M and H responses, respectively. FR were recorded by surface silver/silver chloride electrodes applied over the short head of biceps femoris or over the tibialis anterior muscle, after electrical stimulation of the ipsilateral sural or tibial nerve at the level of the ankle. Each stimulus, given every 5 s, consisted of a train of 5 electrical square pulses of 1 ms each, delivered at a rate of 300 Hz by a constant current stimulator. FR were recorded over a 1000 ms window, amplified with a band-pass of 30– 3000 Hz. The analysis of FR included the determination of the threshold and the area of the response. The former was defined as the minimal intensity in milliamperes (mA) necessary to obtain reproducible FR. The latter was measured by integrating the electromyographic (EMG) activity of the response over the analysis window of 1000 ms, expressed in mV ms. Stimulus intensity was increased until maximal response was obtained. This saturation level was maintained for comparison between consecutive recordings. 2.5. Statistical analysis SPSS for Windows package was used for statistical analysis. One-factor repeated measures ANOVA (withinsubjects factors) was performed. Statistical significance was considered for P-values below or equal to 0.01. 2.6. Ethical aspects The local Ethics Committee has approved this project.
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Informed consent was obtained from the parents after the nature of the procedure had been fully explained. 3. Results 3.1. Before intrathecal injection of baclofen Mean Ashworth scores ranged between 4.0 and 4.7 (Table 1). TMS elicited MEP in two children (Patients 2 and 6). At 100% of maximal stimulation output, the response latencies were within normal limits, respectively, 15.7 and 16.6 ms at the right and left tibialis anterior muscles for Patient 2, 16.6 and 16.1 ms at the same muscles for Patient 6. H reflexes were elicited in 5 patients (all but Patient 3). In these patients, the values of the Hmax/Mmax ratio were 0.84, 0.82, 0.23, 0.56 and 0.59. H reflex was absent in the patient with associated axonal neuropathy. For FR recording, detection electrodes were initially applied at the surface of the biceps femoris muscle in all patients, according to Parise et al. (1997). Consistent responses were obtained in 4 patients. In these, mean left/right FR threshold values were 11.8, 19.0, 15.2 and 20 mA. The mean areas of left and right FR responses were 54.6, 18.7, 45.8 and 174.1 mV ms. In the other two patients, as the responses were not consistent at the level of the biceps femoris muscle, electrodes were also applied over the tibialis anterior muscle in order to record responses to tibial nerve stimulation. In these patients, mean left/right FR threshold values were 11.5 and 9.0 mA. The mean areas of these responses were 17.6 and 47.7 mV ms. 3.2. After intrathecal injection of baclofen After the injection of 50 mg of baclofen, the mean Ashworth score decreased in all the patients (Table 1). One patient required a lower dose (25 mg) because the first injection was followed by drowsiness and marked hypotonia. Following the 25 mg injection, this patient’s Ashworth score was 2.0 points lower than before ITB. One patient required a higher dose (75 mg), as the first injection led to a decrease in Ashworth score by only 0.3 point. Following the 75 mg injection, Ashworth score went down to 1.3. After optimal ITB dose, TMS results were similar to those obtained before ITB, except for a reduction in MEP amplitude (0.6– 0.2 mV and 0.5–0.1 mV). No consistent H reflex was recorded in all but one patient (Patient 6). In the latter, Hmax/Mmax was reduced by 56%. The patient who showed an optimal clinical response to 25 mg ITB, had no consistent H reflex with either 25 or 50 mg ITB, although it was present before ITB. In the patient with an optimal clinical response to 75 mg ITB, the H reflex was already absent at 50 mg ITB. Fig. 1 shows the changes in FR threshold values after the optimal ITB dose. The values were significantly higher after ITB ðP ¼ 0:003Þ. Fig. 2 shows the changes of FR surface after the optimal ITB dose. In all patients, FR surfaces decreased after ITB ðP ¼ 0:01Þ. As illustrated in Fig. 3A, FR includes two main EMG bursts when stimulation intensity is
Fig. 1. Effect of ITB on threshold values of the flexor reflex. Each patient is identified by a symbol (V, X, etc.). Open symbols indicate right side responses. Filled symbols indicate left side responses.
increased, namely the short-latency response (SLR) and the long-latency response (LLR). At threshold intensities, only the LLR component was identified. At higher intensities, SLR gradually appeared. Both the SLR and the LLR were attenuated after ITB (Fig. 3B), in contrast with the situation prior to ITB (Fig. 3A). 4. Discussion 4.1. Neurophysiological assessment of spastic children The techniques we used for the neurophysiological assessment of reflex parameters in children with spasticity in this study derive from those previously described in adults (Shahani and Young, 1973; Delwaide, 1985; Parise et al., 1997). In some of the children we evaluated, adaptation of the FR recording technique was required, regarding the choice of the recorded muscle in order to obtain reliable responses. In agreement with Milanov (1992), responses could be more stable over the tibialis anterior than the biceps femoris muscle. According to Shahani and Young (1973), responses from either muscle are equally representative of flexor spasm activity. With reference to a paediatric population, a study of FR responses in neonates revealed that EMG activities seen in the tibialis anterior had a shorter
Fig. 2. Effect of ITB on flexor reflex area. Each patient is identified by a symbol (V, X, etc.). Open symbols indicate right side responses. Filled symbols indicate left side responses.
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Fig. 3. Flexor reflex recording in one patient before (A) and after ITB (B). The uppermost traces were obtained at threshold level. Lower traces correspond to gradually increasing stimulus intensities, up to saturation level. The two components of the flexor reflex are identified as SLR and LLR.
latency and were larger than in the biceps femoris muscle. This was associated with the positive ‘Babinski sign’ and therefore was thought to reflect immaturity in spinal processing (Andrews and Fitzgerald, 2000). Moreover, as children may have difficulty in adequately reporting the quality of the sensation elicited by the stimulation, the use of a mixed, sensory and motor nerve may allow to confirm that an adequate stimulus was applied, through the motor twitch. 4.2. Effect of baclofen on electrophysiological parameters While we did not find an elevation of TMS threshold sufficient to preclude MEP recording after ITB, we noted a systematic reduction in MEP amplitudes. TMS threshold reflects the excitability of corticospinal neurons and interneurons projecting onto these cells in the motor cortex, and also the excitability of the postsynaptic motor neurons in the spinal cord (Moll et al., 1999). In accordance with our findings, Ziemann et al. (1996) showed that baclofen did not affect TMS threshold. At the spinal level, it has been suggested that MEP amplitude depends on the number of discharging anterior horn cells (Mall et al., 2001). In this respect, Ørsnes et al. (2000) emphasised the postsynaptic site of action of baclofen. Our results suggest a lack of cortical pharmacological action, consistent with the low cisternal-to-lumbar ratio of baclofen following lumbar injection (Mu¨ ller et al., 1988). In this context, the main interest of TMS might therefore be to evaluate the pathways on which remaining voluntary motor function relies. Although some authors found no influence of progabide, another g-aminobutyric acid (GABA) agonist, on Hmax/Mmax
ratio (Mondrup and Pedersen, 1984), we observed a clear depression of the soleus H reflex following ITB in agreement with many previous studies (Milanov, 1992; Capaday, 1995; Azouvi et al., 1996). Ørsnes et al. (2000) proposed that this depression reflects decreased motoneuronal excitability. However, decreased Hmax/Mmax ratio does not imply reduction of spasticity (Pisano et al., 2000). Furthermore, decreased motoneuronal excitability is expected to impair the remaining voluntary motor function (Landau, 1974), although in selected situations, ITB might improve motor control (Latash et al., 1990; Dan and Cheron, 2000a). However, in patients with severe impairment of corticospinal tracts, reflected by TMS abnormalities, deleterious effect of ITB should not be a clinical problem. In this population, the main therapeutic goal is to alleviate discomfort associated with exaggerated reflexes. Among these, flexor spasms are clinically indistinguishable from flexor reflexes produced by electrocutaneous stimulation, i.e. FR (Shahani and Young, 1973). In particular, FR of high magnitude, long duration and low threshold are correlated with patients’ complaints of painful spasms that follow even light stimulation (Parise et al., 1997). Our results show that ITB increases FR threshold values and decreases FR surfaces in spastic children, as previously demonstrated in spastic adults (Parise et al., 1997). This increase in FR threshold is likely related to a specific agonist action of baclofen on GABA-receptor type B, reducing the release by primary afferent terminals in laminae II and III of excitatory neurotransmitters onto ventral horn motoneurons in the spinal cord (Bowery et al., 1980, 1987). The SLR component of FR corresponds to the so-called RA III reflex evoked in normal
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subjects by nociceptive stimulation (Hugon, 1973). In contrast, LLR only occurs in pathological conditions, and has been related to clinical flexor spasms (Shahani and Young, 1973). The undissociated effect of ITB on the SLR and LLR components of the FR and on the H reflex may indicate non-specific action on mono and polysynaptic reflexes at the spinal level (Ørsnes et al., 2000). The clinical interest of FR studies has been previously demonstrated in adults with spasticity of spinal origin (Casale et al., 1995). Our work suggests that this technique can be of value in a paediatric population. 4.3. Conclusions In the present study, we showed that some electrophysiological procedures relevant for the assessment of spasticity and its management may be used in children. This is of particular interest in the current context where the relevance of clinical testing of spasticity and motor dysfunction is limited (Katz et al., 1992; Dan and Cheron, 2000b). The pharmacological action of baclofen concerns multiple levels. Therefore, ITB may have several indications (Ochs et al., 1999). Neurophysiological testing may contribute to objectively assess specific therapeutic objectives of ITB. If the clinical problem is related to flexor spasms, the effect of ITB on FR parameters seems to be useful. However, in spastic patients where functional goals are set, neurophysiological appraisal of the benefit of ITB should also include EMG-biomechanical techniques (Pisano et al., 2000; Dan et al., 2000). References Albright AL. Baclofen in cerebral palsy. J Child Neurol 1996;11:77–83. Andrews K, Fitzgerald M. Flexion reflex responses in biceps femoris and tibialis anterior in human neonates. Early Hum Dev 2000;57:105–110. Ashworth B. Preliminary trial of Carisprodol in multiple sclerosis. Practitioner 1964;192:540–542. Azouvi P, Mane M, Thiebaut JB, Denys P, Remy-Neris O, Bussel B. Intrathecal baclofen administration for control of severe spinal spasticity: functional improvement and long-term follow-up. Arch Phys Med Rehabil 1996;77:35–39. Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M. Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 1980;283:92–94. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987;20: 365–383. Capaday C. The effects of baclofen on the stretch reflex parameters of the cat. Exp Brain Res 1995;104:287–296. Casale R, Glynn CJ, Buonocore M. Reduction of spastic hypertonia in patients with spinal cord injury: a double-blind comparison of intravenous orphenadrine citrate and placebo. Arch Phys Med Rehabil 1995; 76:660–665. Dan B, Cheron G. Intrathecal baclofen normalizes motor strategy for squat-
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