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Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome
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PAIN 150 (2010) 485–491
www.elsevier.com/locate/pain
Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome Daniel Ciampi de Andrade a, Belgacem Bendib a,b, Mohammed Hattou b, Yves Keravel b, Jean-Paul Nguyen b, Jean-Pascal Lefaucheur a,* a b
Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, EA 4391, U-PEC, Créteil, France Service de Neurochirurgie, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France
a r t i c l e
i n f o
Article history: Received 4 May 2009 Received in revised form 27 March 2010 Accepted 3 June 2010
Keywords: Dorsal column stimulation F-wave H-reflex Neuromodulation Nociceptive flexion reflex RIII-reflex Somatosensory-evoked potentials Sympathetic skin response
a b s t r a c t Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched ‘ON’ or ‘OFF’ for 1 h. Significant changes in ‘ON’ condition were as follows: SSR amplitude, Hreflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, Hreflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing. Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Spinal cord stimulation (SCS) has been proposed for more than three decades to treat different types of chronic, drug-resistant pain syndromes [8,13]. The mode of action of SCS was initially thought to be an illustration of the ‘‘gate control” theory of pain transmission [18]: the activation of large-diameter non-nociceptive sensory fibers by SCS would decrease the segmental spinal transmission of nociceptive inputs carried by small-diameter afferent fibers. Consistent with this theory, SCS analgesic efficacy was found to correlate with the functional integrity of dorsal columns and large-diameter sensory fibers topographically related to painful territory. The preservation of somatosensory-evoked potentials (SEPs) in preoperative investigation and the production of paresthesiae during the trial screening period are usually considered as prerequisites for SCS success [2,29]. However, the ‘‘gate control” theory should predict a better efficacy of SCS for nociceptive pain that is not confirmed by clinical practice. In addition, this theory * Corresponding author. Tel.: +33 1 4981 2694; fax: +33 1 4981 4660. E-mail address: [email protected] (J.-P. Lefaucheur).
cannot explain a variety of effects induced by SCS in the context of angina pectoris or complex regional pain syndromes. Experimental data support the role played by other mechanisms, including the modulation of supraspinal [1,7,26] or sympathetic [32] neural activities. It is noteworthy that despite the widespread use of SCS to treat chronic pain in thousands of patients, its actual mechanisms of action remain partly unknown [20]. In this study, we have prospectively enrolled 20 patients who were successfully treated by SCS for failed back surgery syndrome (FBSS), which is one of the best indications for SCS [4,14]. Our objective was to better understand the effects produced by SCS on various segmental and suprasegmental neural pathways. For this purpose, we performed neurophysiological testing when the stimulator was switched ‘ON’ or ‘OFF’ and we compared the results between the two conditions. SCS has potential effects on segmental spinal sensory integration. Therefore, segmental sensorimotor reflexes mediated by large- and small-diameter sensory afferents from the painful limb were studied by recording H- and RIII-reflexes, respectively, in S1 territory. In the same spinal segment (but regarding a different pool of motoneurons), spinal motoneuron excitability was assessed by recording F-waves. Suprasegmental ascending
0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2010.06.001
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sensory pathways (dorsal columns) were investigated by recording SEPs to electrical nerve stimulation. Finally, sympathetic skin responses (SSRs) were studied, since various experimental and clinical data suggested that SCS could modulate sympathetic nervous activities.
2. Patients and methods 2.1. Patients and study design The study included 20 patients with FBSS, 8 women and 12 men, aged from 36 to 66 years (mean 49.1 years), who were successfully treated by chronically implanted SCS for more than 1 year. The main pain scores on a 0–100 visual analogue scale (VAS) before surgery and at the time of investigation, as well as the percentage of ‘post/pre’ SCS-induced pain relief [(‘post-SCS’– ‘pre-SCS’ scores)/(‘pre-SCS’ scores)] were calculated. All patients reported pain reduction by more than 40% on VAS scores compared to preoperative baseline in at least three consecutive visits before inclusion. All participants gave their informed consent for this study. SCS had been implanted for unilateral or bilateral sciatica clearly predominating on one side and related to FBSS. The presence of persistent sciatica despite more than two surgical interventions defined FBSS [14]. All patients had previous discectomies with or without laminectomies and foraminotomies. Four patients had arthrodesis. All patients underwent magnetic resonance imaging (MRI) or computed tomography (CT), confirming the absence of recurrent disc herniation and the presence of fibrosis as presumably responsible for the continuing symptoms. A neuropathic pain component was present in all cases because this was considered as a prerequisite for SCS indication. Neuropathic pain was diagnosed according to the presence of radicular pain radiating beyond the knee towards the foot associated with hypoaesthesia in the painful territory in all cases. The other symptoms and signs taken into consideration for supporting that neuropathic mechanisms contributed to patients’ pain were the presence of burning or freezing pain, paroxysmal electrical shocks, dysaesthesia with sensory descriptors such as pricking (‘pins and needles’), tingling or itching sensations, numbness, or evoked pain by rubbing the painful area (dynamic mechanical allodynia). When a typical ‘mechanical’ low back pain was associated with the neuropathic pain in the lower limb, pain was considered as having a ‘mixed’ mechanism of pain. Chronic SCS used a four-contact lead (Resume Model 3587A, Medtronic, Minneapolis, MA, USA) and an implanted pulse generator (Itrel II, Medtronic, MA, USA) delivering monophasic square pulses (standard initial setting: duration: 180 lsec, frequency: 50 Hz, intensity: 3 V) in a cycling mode (3 h of ‘ON’-period alternating with 3 h of ‘OFF’-period). Parameters were individually adapted to the best pain control. The evaluation started in all cases at the end of a 3-h ‘ON’-period and the order of the two recording sets was then randomized. In one half of the patients, the first recording set was started 60 min after the stimulator remained ‘ON’ (‘ON’ condition) and the second recording set was started 60 min after the stimulator was switched ‘OFF’ (‘OFF’ condition). In the other half, the first recording set was started 60 min after the stimulator was switched ‘OFF’ (‘OFF’ condition) and the second recording set was started 60 min after the stimulator was switched ‘ON’ again (‘ON’ condition). The patients were asked to indicate whether the ongoing pain was frankly different (with an estimated difference P20 on a 0–100 VAS) between ‘ON’ and ‘OFF’ conditions. Pain levels were scored just before each recording set, while patients were ‘ON’ or ‘OFF’ since 60 min. Neurophysiological testing was single-blinded,
because investigators were unaware of the ‘ON’ or ‘OFF’ condition, but patients were able to feel paresthesiae in the painful leg when the stimulator was switched ‘ON’. 2.2. Neurophysiological testing Neurophysiological tests were performed in the painful lower limb (or the most painful lower limb) using a Reporter EMG-EP machine (EsaOte Biomedica, Firenze, Italy) and pre-gelled selfadhesive disposable surface electrodes (#9013S0241, Alpine-Biomed, Skovlunde, Denmark), except for the scalp recordings of cortical SEPs, which were made with subcutaneous needle electrodes. Plantar SSRs were recorded (0.1–100 Hz bandpass) with G1 electrode attached to the sole and G2 electrode to the dorsum of the foot. Electrical stimulation (0.2-ms duration pulses) was applied to the left median nerve at the wrist by a bipolar electrode. Three stimuli were delivered at irregular intervals greater than 15 s and increasing intensities between 20 and 40 mA to avoid habituation. The largest amplitude and shortest latency of the SSRs were measured. Motor F-waves to tibial nerve stimulation were recorded (20 Hz–20 kHz bandpass) with G1 electrode on the motor point of the abductor hallucis muscle and G2 electrode on the metatarso-phalangeal joint. Electrical stimulation (0.2-ms duration pulses) was applied at 0.5 Hz to the tibial nerve at the ankle by a bipolar electrode, while the abductor hallucis muscle was at rest as confirmed by auditory feedback. Stimuli were delivered at gradually increasing intensities. Intensity at which F-waves were clearly identifiable (F-wave threshold) and intensity at which M-wave of maximal amplitude was obtained (M-max threshold) were recorded. Then 10 stimuli were delivered with an intensity set at approximately 20% above M-max threshold (supramaximal intensity). The persistence of the F-waves was calculated as the percentage of evoked F-waves among the 10 trials. The largest amplitude and shortest latency of the F-waves were measured. Cortical responses of the SEPs to tibial nerve stimulation were recorded (20 Hz–20 kHz bandpass) with G1 electrode placed 2 cm behind the vertex and linked G2 electrodes at earlobes. Electrical stimulation (0.2-ms duration pulses) was applied at 2 Hz to the tibial nerve at the ankle by a bipolar electrode with an intensity set at visible motor threshold. Two series of 500 stimuli were averaged. The amplitude and latency of the P40 component were measured. The soleus H-reflex was recorded (20 Hz–20 kHz bandpass) with G1 electrode on the motor point of the soleus muscle and G2 electrode on Achilles tendon. The thigh/leg and leg/foot angles were kept constant at 90°. Electrical stimulation (1-ms duration pulses) was applied at 0.5 Hz to the tibial nerve at the popliteal fossa by a monopolar electrode. Stimuli were delivered at gradually increasing intensities. Intensity at which H-reflex was clearly identifiable (H-reflex threshold) was recorded, and then the intensity was increased to obtain H-reflex of maximal amplitude (H-max). The amplitude and latency of H-max were measured. The nociceptive flexion (RIII) reflex was recorded (20 Hz– 20 kHz bandpass) with G1 electrode on the motor point of the biceps femoris muscle and G2 electrode on its distal tendon. The thigh/leg and leg/foot angles were kept constant at 90°. Electrical stimulation (a train of five 1-ms duration pulses with an inner frequency of 300 Hz) was applied to the sural nerve at the ankle by a bipolar electrode. RIII-reflex threshold was determined by delivering stimuli at gradually increasing and decreasing intensities until a stable reflex response was obtained with a latency ranging between 80 and 180 ms. Then three stimuli were delivered at irregular intervals greater than 15 s to avoid habituation with an intensity set at 20% above RIII-reflex threshold. The maximal area
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and minimal latency of the full-wave rectified and integrated reflex responses were measured. 2.3. Statistical analyses Nonparametric tests were used since not all data passed the normality test as assessed by the Kolmogorov–Smirnov method. Results were compared between ‘ON’ and ‘OFF’ SCS conditions using the Wilcoxon-matched pairs signed rank test. A two-tailed P value of less than 0.05 was considered as significant. However, a stricter threshold of 0.0042 resulting from Holm–Bonferroni correction was also considered as a safeguard against false positives due to multiple testing. In case of significant difference, the percentage of change between ‘ON’ and ‘OFF’ SCS conditions was calculated [(‘ON’–‘OFF’ values)/(‘OFF’ values)]. The relationships between ‘ON/OFF’ neurophysiological changes and between these changes and ‘post/ pre’ SCS-induced pain relief were studied using the Spearman correlation test. A two-tailed P value of less than 0.05 was considered as significant. The respective influence of the ‘ON/OFF’ change in pain level (<20 versus P20 on a 0–100 VAS), the type of pain (mixed versus neuropathic), or the motor deficit (absent versus present) on ‘ON/OFF’ neurophysiological changes was studied using the Mann– Whitney test. A two-tailed P value of less than 0.05 was considered as significant (0.0125 after correction for multiple testing).
3. Results All patients completed the study without adverse events. Demographic and clinical data are presented in Table 1. Pain duration between the last intervention of back surgery and SCS implantation ranged from 1.5 to 10 years (mean 4.5 years). Patients were treated by SCS from 1 to 13 years (mean 5.7 years) before inclusion in this study. Chronic pain relief induced by SCS ranged from 45% to 90% (mean 71.0%). At the time of investigation, remaining pain level in ‘ON’ condition ranged from 10 to 45 (mean 25.6) on a 0–100 VAS. In ‘OFF’ condition, pain level increase was P20 in seven patients and remained <20 in 13 patients, indicating prolonged SCS-induced analgesic after-effects. The painful lower limb was located on the right side in seven patients and on the left side in 13 patients. Nine patients had a pure neuropathic pain located in the lower limb. Eleven patients had mixed pain mechanisms, a typical mechanical low back pain being associated with the neuropathic component in the lower limb. Predominant pain was located in L4/L5 territory in four patients, L5 territory in five patients, L5/S1 territory in five patients, and S1 territory in six patients. Clinically assessed sensory deficit (to light touch, vibration, pin-prick, warm, or cold stimuli) was present in the painful territory, at least moderately, in all patients. Motor deficit was present in nine patients, always in L5 territory and never in S1 territory. Analgesic drug treatment at the time of investigation included benzodiazepins (n = 10), other anticonvulsant drugs (n = 4), antidepressants (n = 10), morphinics (n = 11), and paracetamol (n = 9). Only two patients were not receiving any analgesic drug. According to our normal laboratory values (presented in Table 2), all patients but two, presented at least one abnormal neurophysiological test in ‘OFF’ SCS condition (Table 1). Abnormalities were reduced SSR amplitude (n = 7), increased SSR latency (n = 1), reduced F-wave persistence (n = 2), reduced F-wave amplitude (n = 4), increased F-wave latency (n = 5), reduced P40-SEP amplitude (n = 4), increased P40-SEP latency (n = 12), reduced H-reflex amplitude (n = 9), and increased RIII-reflex threshold (n = 7). Various neurophysiological changes were found between ‘ON’ and ‘OFF’ SCS conditions, as illustrated in Fig. 1. A normalization of
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neurophysiological values in ‘ON’ SCS condition was observed for 4/7 cases of reduced SSR amplitude, 1/2 cases of reduced F-wave persistence, 3/4 cases of reduced F-wave amplitude, 3/5 cases of increased F-wave latency, and 3/12 cases of increased P40-SEP latency. The differences in neurophysiological results between ‘ON’ and ‘OFF’ SCS conditions were significant for nine parameters: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were found to increase in ‘ON’ condition, whereas SSR latency, F-wave latency, P40-SEP amplitude, H-reflex amplitude, and RIII-reflex area were found to decrease in ‘ON’ condition (Table 2). The difference between ‘ON’ and ‘OFF’ SCS conditions remained significant after adjustment for multiple comparisons for only four parameters: P40-SEP amplitude, H-reflex amplitude, RIII-reflex threshold, and RIII-reflex area. The percentage of change between ‘ON’ and ‘OFF’ SCS conditions was then calculated for these four parameters. A positive correlation was found between ‘ON/OFF’ changes in H-reflex amplitude and RIII-reflex area (r = 0.56, P = 0.01, Spearman test) (Fig. 2). There were no correlations between the other ‘ON/OFF’ neurophysiological changes. The ‘post/pre’ SCS-induced pain relief correlated negatively with ‘ON/OFF’ changes in RIII-reflex threshold (r = 0.52, P = 0.02) and positively with ‘ON/OFF’ changes in RIII-reflex area (r = 0.46, P = 0.04) (Fig. 2). There were no correlations between ‘post/pre’ SCS-induced pain relief and the other ‘ON/OFF’ neurophysiological changes. The ‘ON/OFF’ change in RIII-reflex threshold varied with the ‘ON/OFF’ change in pain level: RIII-reflex threshold increased in ‘ON’ SCS condition, but more when pain level decrease was P20 than when it remained <20 (mean (SEM): +49.4 (16.1)% versus +16.3 (9.1)%, P = 0.04, Mann–Whitney test) (Fig. 2). The ‘ON/OFF’ change in P40-SEP amplitude varied with the type of pain: P40SEP amplitude decreased in ‘ON’ SCS condition, but more in patients with mixed pain than in patients with pure neuropathic pain ( 35.9 (6.3)% versus 17.2 (7.4)%, P = 0.03) (Fig. 2). No other ‘ON/ OFF’ neurophysiological changes varied with the ‘ON/OFF’ change in pain level, the type of pain, or the motor deficit. The significant differences between neurophysiological changes and ‘ON/OFF’ analgesic effects or the type of pain did not persist after statistical correction for multiple testing.
4. Discussion This study shows that SCS may influence various neural pathways. Inhibitory effects on P40-SEP, H-reflex, and RIII-reflex were the most significant results. Attenuation of RIII-reflex by SCS has previously been reported and associated with a good efficacy of the procedure [9,10]. In the present study, SCS was found to increase RIII-reflex threshold and to reduce RIII-reflex area and this was correlated with the magnitude of SCS-induced pain relief. Attenuation of RIII-reflex also correlated with the decrease in H-reflex amplitude. The RIII-reflex assesses a polysynaptic pathway between A-delta cutaneous afferents and alpha-motoneuron efferents, while the H-reflex assesses a monosynaptic pathway between Ia proprioceptive afferents and alpha-motoneuron efferents. The correlated inhibition induced by SCS on RIII- and H-reflexes probably did not result from a reduction of alpha-motoneuron excitability, because F-wave amplitude and persistence would have declined in case of reduced motoneuron excitability [16], whereas these parameters did not change with stimulation condition in our study. In addition, F-wave latency was found to be shortened in ‘ON’ SCS condition, whereas it should increase in case of reduced motoneuron excitability [19]. If we hypothesize that SCS exerts its inhibitory influence on segmental spinal level, the correlated inhibition of RIII- and H-reflexes should have occurred in the lumbar dorsal horns, presynaptic to the motoneurons [11].
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Table 1 Demographic, clinical and neurophysiological data of the 20 patients treated by spinal cord stimulation (SCS). No.
Sex
Age (years)
Pain duration before SCS implant (years)
Time after SCS implant (years)
Mean SCSinduced pain relief (%)
Mean ongoing pain intensity (SCS-ON) (VAS/ 100)
SCS aftereffects (when switched ‘OFF’)
Motor deficit location
Sensory deficit location
Pain location
Pain mechanism
Abnormal electrophysiological results (SCS-OFF)
Analgesic drug treatment at the time of investigation
1
W
53
5
4.5
85
12
Yes
l. L5
l. L5
l. L5/S1
Neuropathic
Increased SSR and P40-SEP latencies
2
M
47
2
13
60
40
Yes
No
r. L5
r. L5
Mixed
3
M
41
1.5
4.5
65
25
No
l. L5
l. L5
l. L5/S1
Neuropathic
4
W
53
3.5
9
70
20
No
r. L5
r. L5/S1
r. L5/S1
Mixed
5
W
49
6.5
13
60
45
Yes
No
l. S1
l. S1
Neuropathic
Reduced SSR and F-wave amplitudes, increased F-wave and P40-SEP latencies, and increased RIII threshold Increased P40-SEP latency and RIII threshold Reduced SSR, F-wave, and H-reflex amplitudes, reduced F-wave persistence, and increased RIII threshold Increased P40-SEP latency
Aceprometazine, bromazepam, dextropropoxyphene, mianserine, and paracetamol Citalopram and clonazepam
6
M
48
6.5
11
65
32
Yes
r. L5
r. L5/S1
r. L5/S1
Mixed
7
M
53
3
2
65
28
Yes
No
l. S1
l. S1
Mixed
8 9
W M
39 65
5 4
11.5 4
80 55
14 40
Yes Yes
l. L5 No
l. L5/S1 r. L5
l. L5/S1 r. L5
Mixed Mixed
10
M
49
5
4
55
45
Yes
l. L5
l. L4/L5
l. L4/L5
Mixed
11 12
M W
46 42
4 3.5
4 4
65 70
25 30
Yes Yes
No No
l. L5 r. S1
l. L4/L5 r. S1
Mixed Mixed
Reduced H-reflex amplitude Reduced P40-SEP amplitude and increased P40-SEP latency
13
M
38
2
1
90
10
No
r. L5
r. L5
r. L5
Neuropathic
14
W
66
1.5
3
80
15
No
l. L5
l. L5
l. L5
Mixed
15
W
48
5.5
1.5
70
25
Yes
No
r. L5
r. L5
Mixed
Reduced SSR and H-reflex amplitudes and increased P40-SEP latency Reduced SSR amplitude and F-wave persistence and increased F-wave latency None
16
M
51
6
1
75
25
No
No
l. S1
l. S1
Neuropathic
17 18 19
W M M
36 38 61
5 10 8
9 1 1
85 45 90
15 45 10
No Yes Yes
No No l. L5
l. S1 l. S1 l. L5
l. S1 l. S1 l. L4/L5
Neuropathic Neuropathic Neuropathic
20
M
59
3
11
90
10
No
No
l. L5
l. L4/L5
Neuropathic
Clonazepam and fluoxetine
Codeine and paracetamol Dextropropoxyphene, gabapentine, and paracetamol Carbamazepine, clomipramine, and Tramadol Clonazepam and mianserine Citalopram, dextropropoxyphene, and paracetamol Amitriptyiline Clonazepam, codeine, and paracetamol Carbamazepine and clomipramine Clonazepam, codeine, and paracetamol Clonazepam Buprenorphine Amitriptyline and gabapentine None
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Reduced H-reflex amplitude and increased P40-SEP latency and RIII threshold Increased P40-SEP latency Reduced SSR and H-reflex amplitudes Reduced P40-SEP amplitude, increased F-wave and P40-SEP latencies, and increased RIII threshold Reduced P40-SEP and H-reflex amplitudes and increased P40-SEP latency
Dextropropoxyphene, lorazepam, and paracetamol Alprazolam, paracetamol, and tramadol
D.C. de Andrade et al. / PAIN 150 (2010) 485–491
Increased P40-SEP latency and RIII threshold, and reduced H-reflex amplitude Reduced SSR, P40-SEP, and F-wave amplitudes and increased F-wave and P40-SEP latencies Reduced SSR and H-reflex amplitudes Reduced F-wave and H-reflex amplitudes and increased F-wave latency and RIII threshold None
Amitriptyiline, clonazepam, codeine, and paracetamol None
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D.C. de Andrade et al. / PAIN 150 (2010) 485–491 Table 2 Neurophysiological results in ‘OFF’ and ‘ON’ conditions of spinal cord stimulation. Normal limits
OFF-stimulation
ON-stimulation
Wilcoxon test (P value)
SSR amplitude (mV) Range
P0.6
1.4 (2.1, 0.4) 0.1–6.0
2.0 (2.4, 0.4) 0.4–6.3
0.0484
SSR latency (s) Range
62.5
2.0 (2.1, 0.1) 1.8–2.8
1.9 (1.9, 0.1) 1.3–3.0
0.0267
M-max threshold (mA) Range
NA
45.0 (46.0, 2.0) 30–60
45.0 (47.8, 1.8) 35–65
0.1726
M-max amplitude (mV) Range
P5
9.3 (9.2, 0.4) 6.5–12.0
9.8 (9.3, 0.4) 6.0–12.0
0.5966
F-wave threshold (mA) Range
NA
16.5 (18.6, 1.4) 12–33
20.0 (18.9, 1.3) 11–29
0.6788
F-wave amplitude (lV) Range
P60
160 (207.0, 38.4) 30–650
170 (220.5, 36.2) 30–580
0.6226
F-wave latency (ms) Range
656
51.5 (52.7, 0.9) 48–65
51.0 (51.0, 1.1) 45–65
0.0092
F-wave persistence (%) Range
P20
100 (80.0, 6.8) 10–100
100 (86.5, 5.6) 10–100
0.3750
P40-SEP amplitude (lV)
0.6
0.0017
Range
1.9 (1.8, 0.2)
1.3 (1.3, 0.2)
0.4–3.4
0.2–2.9
P40-SEP latency (ms) Range
45
46.0 (45.8, 0.6) 41.0–52.0
45.0 (45.9, 0.7) 40.5–51.5
0.8904
H-reflex threshold (mA) Range H-reflex amplitude (mV)
NA
15.5 (16.4, 1.2) 9–28 2.7 (2.4, 0.4)
18.0 (17.9, 1.2) 10–30 1.2 (1.7, 0.3)
0.0166
0.1–5.6
0.1–5.4
0.8
Range
0.0007
H-reflex latency (ms) Range
36
31.9 (31.3, 0.5) 26.4–34.4
31.1 (31.4, 0.5) 27.2–34.9
0.6477
RIII-reflex threshold (mA)
12
7.3 (9.2, 0.8)
10.8 (11.0, 0.7)
0.0039
5.5–16
6.5–17
Range RIII-reflex area (mV/ms)
0.8
Range RIII-reflex latency (ms) Range
180
3.7 (3.5, 0.3)
1.8 (2.1, 0.2)
1.5–5.8
0.6–4.8
113.5 (113.5, 5.2) 82–165
121.5 (123.2, 7.2) 80–176
0.0005 0.0290
Normal limits are upper or lower limits of our normative laboratory values (established on 60 healthy subjects aged 20–80 years (sex ratio 1:1) without symptoms or signs of peripheral neuropathies or other neurological illness; NA: not available value). In OFF- and ON-stimulation columns median values (mean and standard error of the mean) are presented. SSR: sympathetic skin response. SEPs: somatosensory-evoked potentials. Significant P values of the Wilcoxon-matched pairs signed rank test are in bold, and underlined when the significance persisted after correction for multiple testing.
Fig. 1. Representative traces of neurophysiological recordings performed in ‘ON’ and ‘OFF’ conditions of spinal cord stimulation (SCS). SSR: sympathetic skin response and SEPs: somatosensory-evoked potentials.
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Fig. 2. Correlation between changes in H-reflex amplitude and RIII-reflex area observed ‘ON/OFF’ spinal cord stimulation. Correlations between pain level changes observed ‘post/pre’ spinal cord stimulation and changes in RIII-reflex threshold or area observed ‘ON/OFF’ spinal cord stimulation. Differences in RIII-reflex threshold and P40-SEP amplitude changes observed ‘ON/OFF’ spinal cord stimulation according to ‘ON/OFF’ pain level changes and pain mechanisms, respectively. SCS: spinal cord stimulation and SEPs: somatosensory-evoked potentials. Correlation coefficient (r) and P values of the Spearman or Mann–Whitney test are presented.
Experimental studies have demonstrated a suppressive action of SCS on neuronal hyperexcitability or long-term synaptic potentiation in the dorsal horns [31,33]. At this level, SCS may concomitantly depress segmental transmission of both nociceptive and non-nociceptive (e.g., proprioceptive) information. Neuropathic pain has been associated with an augmented responsiveness of the wide-dynamic range (WDR) neurons of the dorsal horns. SCS could especially reduce WDR neuronal hyperactivity in response to innocuous stimuli. Regarding potentially involved neurotransmitters, experimental data showed that SCS could increase the release of extracellular GABA, but decrease that of glutamate and aspartate in the dorsal horns [5]. The analgesic effect of SCS has also been associated with cholinergic activation in the dorsal horns via muscarinic receptors [28].
Supraspinal mechanisms probably also contribute to SCS efficacy. The finding that SCS decreased P40-SEP amplitude, independently from changes in RIII- and H-reflexes, favored this hypothesis. The SEPs assess A-beta cutaneous afferents, spinal dorsal columns, and intraencephalic lemniscal pathways, including thalamic relay and cortical integration. The reduction of short-latency SEP amplitude by SCS has previously been observed [6,15]. One possible cause of SEP attenuation refers to spike collision in the dorsal columns between the ascending volleys triggered by tibial nerve stimulation and action potentials triggered by SCS. Whatever the underlying mechanism, a recent source dipole analysis showed that SCS was able to attenuate SEP processing in both primary (SI) and secondary (SII) somatosensory cortices [24]. In contrast, other neuroimaging studies revealed an increased activation
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of SI, SII and posterior insula during SCS [12,25,30]. SCS likely produces complex changes in cortical processing of both innocuous and noxious sensory information. It is also conceivable that descending inhibitory controls play a role in the modulation of spinal activities by SCS. In contrast to its inhibitory effects on sensory processing, SCS was found to enhance plantar SSRs (increased amplitude and shortened latency). This was surprising because the sympathetic nervous system is thought to be inhibited by SCS, providing peripheral vasodilatation for the treatment of vaso-occlusive diseases. However, the vasodilatation induced by SCS is mostly mediated by adrenergic pathways [32], whereas SSRs assess sympathetic cholinergic innervation of the sweat glands. Sudomotor and vasomotor activities can be differentiated within the sympathetic nervous system, e.g., regarding the location of the central control in the rostral medulla, that is ventromedial for cholinergic sudation and ventrolateral for adrenergic vasoconstriction [17]. Thus, SCS could facilitate sympathetic sudomotor activities in parallel with a reduction of sympathetic vasomotor activities, possibly reflecting compensatory mechanisms. Finally, several limitations of this study should be acknowledged. First, unilateral recordings were performed, although SCS could lead to bilateral effects. Second, almost all patients were taking analgesic drugs at the time of investigation. These drugs could interfere with neurophysiological results, but it was not possible to satisfactorily address this question in this study. Third, pain level did not return to pre-implantation level in a majority of patients of this series, although SCS was stopped for 1 hour. SCS is able to induce prolonged analgesic after-effects beyond the time of stimulation, especially in good responders. This may have reduced the magnitude of neurophysiological changes, if related to pain relief, in this study. In conclusion, the present results suggest that SCS is able to produce a broad inhibition of sensory afferent inputs mediated by Ia, Abeta and A-delta myelinated fibers at either spinal segmental or supraspinal level in FBSS patients. Segmental spinal motor output remained unchanged or was even facilitated, according to previous data [11], as well as sudomotor cholinergic activities in the sympathetic nervous system. The modulation of Ia fiber activity, suggested by the increased threshold and decreased amplitude of the H-reflex, did not appear to be directly related to pain relief. H-reflex attenuation mediated by SCS could support the value of this procedure to treat spasticity [3,21,23]. The effect of SCS on P40-SEP was more pronounced in patients with mixed rather than pure neuropathic pain. However, SCS was found to yield better results in patients with primary complaints of neuropathic pain in lower limbs rather than in those with predominant mechanical low back pain, although this assertion remains a matter of debate [22]. Finally, RIII-reflex attenuation was the main neurophysiological change related to SCS-induced pain relief observed either ‘post/pre’ implantation or ‘ON/OFF’ stimulation. This was a strong objective evidence of a real analgesic efficacy of the procedure [27] correlated to the fact that only good responders to SCS have been included. This study showed a variety of neurophysiological effects induced by SCS at both segmental and suprasegmental levels. These results upport the possible application of SCS to act on sensory, autonomic, or motor disturbances in various neurological conditions. Acknowledgment The authors would like to state that there are no conflicts of interest regarding this work. References [1] Bantli H, Bloedel JR, Thienprasit P. Supraspinal interactions resulting from experimental dorsal column stimulation. J Neurosurg 1975;42:296–300.
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[2] Barolat G, Ketcik B, He J. Long-term outcome of spinal cord stimulation for chronic pain management. Neuromodulation 1998;1:19–29. [3] Cioni B, Meglio M, Prezioso A, Talamonti G, Tirendi M. Spinal cord stimulation (SCS) in spastic hemiparesis. Pacing Clin Electrophysiol 1989;12:739–42. [4] Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jensen TS, Lefaucheur JP, Simpson BA, Taylor RS. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007;14:952–70. [5] Cui JG, O’ Connor WT, Ungerstedt U, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory aminoacids in mononeuropathy via a GABAergic mechanism. Pain 1997;73:87–95. [6] Doerr M, Krainick JU, Thoden U. Pain perception in man after long term spinal cord stimulation. J Neurol 1978;217:261–70. [7] El-Khoury C, Hawwa N, Baliki M, Atweh SF, Jabbur SJ, Saadé NE. Attenuation of neuropathic pain by segmental and supraspinal activation of the dorsal column system in awake rats. Neuroscience 2002;112:541–53. [8] Falowski S, Celii A, Sharan A. Spinal cord stimulation: an update. Neurotherapeutics 2008;5:86–99. [9] García-Larrea L, Sindou M, Mauguière F. Nociceptive flexion reflexes during analgesic neurostimulation in man. Pain 1989;39:145–56. [10] García-Larrea L, Peyron R, Mertens P, Laurent B, Mauguière F, Sindou M. Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans. Arch Med Res 2000;31:248–57. [11] Hunter JP, Ashby P. Segmental effects of epidural spinal cord stimulation in humans. J Physiol (London) 1994;474:407–19. [12] Kiriakopoulos ET, Tasker RT, Nicosia S, Wood ML, Mikulis DJ. Functional magnetic resonance imaging: a potential tool for the evaluation of spinal cord stimulation: technical case report. Neurosurgery 1997;41:501–4. [13] Kumar K, Hunter G, Demeria D. Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22 year experience. Neurosurgery 2006;58:481–96. [14] Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Thomson S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 2007;132:179–88. [15] Larson SJ, Sances Jr A, Riegel DH, Meyer GA, Dallmann DE, Swiontek T. Neurophysiological effects of dorsal column stimulation in man and monkey. J Neurosurg 1974;41:217–23. [16] Lin JZ, Floeter MK. Do F-wave measurements detect changes in motor neuron excitability? Muscle Nerve 2004;30:289–94. [17] McAllen RM, May CN, Shafton AD. Functional anatomy of sympathetic premotor cell groups in the medulla. Clin Exp Hypertens 1995;17:209–21. [18] Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971–9. [19] Mesrati F, Vecchierini MF. F-waves: neurophysiology and clinical value. Neurophysiol Clin 2004;34:217–43. [20] Meyerson BA, Linderoth B. Mode of action of spinal cord stimulation in neuropathic pain. J Pain Symptom Manage 2006;31:S6–S12. [21] Nakamura S, Tsubokawa T. Evaluation of spinal cord stimulation for postapoplectic spastic hemiplegia. Neurosurgery 1985;17:253–9. [22] Ohnmeiss DD, Rashbaum RF. Patient satisfaction with spinal cord stimulation for predominant complaints of chronic, intractable low back pain. Spine J 2001;1:358–63. [23] Pinter MM, Gerstenbrand F, Dimitrijevic MR. Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control of spasticity. Spinal Cord 2000;38:524–31. [24] Polácek H, Kozák J, Vrba I, Vrána J, Stancák A. Effects of spinal cord stimulation on the cortical somatosensory evoked potentials in failed back surgery syndrome patients. Clin Neurophysiol 2007;118:1291–302. [25] Rasche D, Siebert S, Stippich C, Kress B, Nennig E, Sartor K, Tronnier VM. Spinal cord stimulation in Failed-Back-Surgery-Syndrome. Preliminary study for the evaluation of therapy by functional magnetic resonance imaging (fMRI). Schmerz 2005;19:497–505. [26] Rees H, Roberts MH. Antinociceptive effects of dorsal column stimulation in the rat: involvement of the anterior pretectal nucleus. J Physiol (London) 1989;417:375–88. [27] Sandrini G, Serrao M, Rossi P, Romaniello A, Cruccu G, Willer JC. The lower limb flexion reflex in humans. Prog Neurobiol 2005;77:353–95. [28] Schechtmann G, Song Z, Ultenius C, Meyerson BA, Linderoth B. Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy. Pain 2008;139:136–45. [29] Sindou MP, Mertens P, Bendavid U, García-Larrea L, Mauguière F. Predictive value of somatosensory evoked potentials for long-lasting pain relief after spinal cord stimulation: practical use for patient selection. Neurosurgery 2003;52:1374–83. [30] Stancák A, Kozák J, Vrba I, Tintera J, Vrána J, Polácek H, Stancák M. Functional magnetic resonance imaging of cerebral activation during spinal cord stimulation in failed back surgery syndrome patients. Eur J Pain 2008;12:137–48. [31] Wallin J, Fiskå A, Tjølsen A, Linderoth B, Hole K. Spinal cord stimulation inhibits long-term potentiation of spinal wide dynamic range neurons. Brain Res 2003;973:39–43. [32] Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008;138:9–23. [33] Yakhnitsa V, Linderoth B, Meyerson BA. Effects of spinal cord stimulation on dorsal horn neuronal activity in a rat model of mononeuropathy. Pain 1999;79:223–33.
PAIN 150 (2010) 485–491
www.elsevier.com/locate/pain
Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome Daniel Ciampi de Andrade a, Belgacem Bendib a,b, Mohammed Hattou b, Yves Keravel b, Jean-Paul Nguyen b, Jean-Pascal Lefaucheur a,* a b
Service de Physiologie – Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, EA 4391, U-PEC, Créteil, France Service de Neurochirurgie, Hôpital Henri Mondor, Assistance Publique – Hôpitaux de Paris, Créteil, France
a r t i c l e
i n f o
Article history: Received 4 May 2009 Received in revised form 27 March 2010 Accepted 3 June 2010
Keywords: Dorsal column stimulation F-wave H-reflex Neuromodulation Nociceptive flexion reflex RIII-reflex Somatosensory-evoked potentials Sympathetic skin response
a b s t r a c t Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched ‘ON’ or ‘OFF’ for 1 h. Significant changes in ‘ON’ condition were as follows: SSR amplitude, Hreflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, Hreflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing. Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction Spinal cord stimulation (SCS) has been proposed for more than three decades to treat different types of chronic, drug-resistant pain syndromes [8,13]. The mode of action of SCS was initially thought to be an illustration of the ‘‘gate control” theory of pain transmission [18]: the activation of large-diameter non-nociceptive sensory fibers by SCS would decrease the segmental spinal transmission of nociceptive inputs carried by small-diameter afferent fibers. Consistent with this theory, SCS analgesic efficacy was found to correlate with the functional integrity of dorsal columns and large-diameter sensory fibers topographically related to painful territory. The preservation of somatosensory-evoked potentials (SEPs) in preoperative investigation and the production of paresthesiae during the trial screening period are usually considered as prerequisites for SCS success [2,29]. However, the ‘‘gate control” theory should predict a better efficacy of SCS for nociceptive pain that is not confirmed by clinical practice. In addition, this theory * Corresponding author. Tel.: +33 1 4981 2694; fax: +33 1 4981 4660. E-mail address: [email protected] (J.-P. Lefaucheur).
cannot explain a variety of effects induced by SCS in the context of angina pectoris or complex regional pain syndromes. Experimental data support the role played by other mechanisms, including the modulation of supraspinal [1,7,26] or sympathetic [32] neural activities. It is noteworthy that despite the widespread use of SCS to treat chronic pain in thousands of patients, its actual mechanisms of action remain partly unknown [20]. In this study, we have prospectively enrolled 20 patients who were successfully treated by SCS for failed back surgery syndrome (FBSS), which is one of the best indications for SCS [4,14]. Our objective was to better understand the effects produced by SCS on various segmental and suprasegmental neural pathways. For this purpose, we performed neurophysiological testing when the stimulator was switched ‘ON’ or ‘OFF’ and we compared the results between the two conditions. SCS has potential effects on segmental spinal sensory integration. Therefore, segmental sensorimotor reflexes mediated by large- and small-diameter sensory afferents from the painful limb were studied by recording H- and RIII-reflexes, respectively, in S1 territory. In the same spinal segment (but regarding a different pool of motoneurons), spinal motoneuron excitability was assessed by recording F-waves. Suprasegmental ascending
0304-3959/$36.00 Ó 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2010.06.001
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sensory pathways (dorsal columns) were investigated by recording SEPs to electrical nerve stimulation. Finally, sympathetic skin responses (SSRs) were studied, since various experimental and clinical data suggested that SCS could modulate sympathetic nervous activities.
2. Patients and methods 2.1. Patients and study design The study included 20 patients with FBSS, 8 women and 12 men, aged from 36 to 66 years (mean 49.1 years), who were successfully treated by chronically implanted SCS for more than 1 year. The main pain scores on a 0–100 visual analogue scale (VAS) before surgery and at the time of investigation, as well as the percentage of ‘post/pre’ SCS-induced pain relief [(‘post-SCS’– ‘pre-SCS’ scores)/(‘pre-SCS’ scores)] were calculated. All patients reported pain reduction by more than 40% on VAS scores compared to preoperative baseline in at least three consecutive visits before inclusion. All participants gave their informed consent for this study. SCS had been implanted for unilateral or bilateral sciatica clearly predominating on one side and related to FBSS. The presence of persistent sciatica despite more than two surgical interventions defined FBSS [14]. All patients had previous discectomies with or without laminectomies and foraminotomies. Four patients had arthrodesis. All patients underwent magnetic resonance imaging (MRI) or computed tomography (CT), confirming the absence of recurrent disc herniation and the presence of fibrosis as presumably responsible for the continuing symptoms. A neuropathic pain component was present in all cases because this was considered as a prerequisite for SCS indication. Neuropathic pain was diagnosed according to the presence of radicular pain radiating beyond the knee towards the foot associated with hypoaesthesia in the painful territory in all cases. The other symptoms and signs taken into consideration for supporting that neuropathic mechanisms contributed to patients’ pain were the presence of burning or freezing pain, paroxysmal electrical shocks, dysaesthesia with sensory descriptors such as pricking (‘pins and needles’), tingling or itching sensations, numbness, or evoked pain by rubbing the painful area (dynamic mechanical allodynia). When a typical ‘mechanical’ low back pain was associated with the neuropathic pain in the lower limb, pain was considered as having a ‘mixed’ mechanism of pain. Chronic SCS used a four-contact lead (Resume Model 3587A, Medtronic, Minneapolis, MA, USA) and an implanted pulse generator (Itrel II, Medtronic, MA, USA) delivering monophasic square pulses (standard initial setting: duration: 180 lsec, frequency: 50 Hz, intensity: 3 V) in a cycling mode (3 h of ‘ON’-period alternating with 3 h of ‘OFF’-period). Parameters were individually adapted to the best pain control. The evaluation started in all cases at the end of a 3-h ‘ON’-period and the order of the two recording sets was then randomized. In one half of the patients, the first recording set was started 60 min after the stimulator remained ‘ON’ (‘ON’ condition) and the second recording set was started 60 min after the stimulator was switched ‘OFF’ (‘OFF’ condition). In the other half, the first recording set was started 60 min after the stimulator was switched ‘OFF’ (‘OFF’ condition) and the second recording set was started 60 min after the stimulator was switched ‘ON’ again (‘ON’ condition). The patients were asked to indicate whether the ongoing pain was frankly different (with an estimated difference P20 on a 0–100 VAS) between ‘ON’ and ‘OFF’ conditions. Pain levels were scored just before each recording set, while patients were ‘ON’ or ‘OFF’ since 60 min. Neurophysiological testing was single-blinded,
because investigators were unaware of the ‘ON’ or ‘OFF’ condition, but patients were able to feel paresthesiae in the painful leg when the stimulator was switched ‘ON’. 2.2. Neurophysiological testing Neurophysiological tests were performed in the painful lower limb (or the most painful lower limb) using a Reporter EMG-EP machine (EsaOte Biomedica, Firenze, Italy) and pre-gelled selfadhesive disposable surface electrodes (#9013S0241, Alpine-Biomed, Skovlunde, Denmark), except for the scalp recordings of cortical SEPs, which were made with subcutaneous needle electrodes. Plantar SSRs were recorded (0.1–100 Hz bandpass) with G1 electrode attached to the sole and G2 electrode to the dorsum of the foot. Electrical stimulation (0.2-ms duration pulses) was applied to the left median nerve at the wrist by a bipolar electrode. Three stimuli were delivered at irregular intervals greater than 15 s and increasing intensities between 20 and 40 mA to avoid habituation. The largest amplitude and shortest latency of the SSRs were measured. Motor F-waves to tibial nerve stimulation were recorded (20 Hz–20 kHz bandpass) with G1 electrode on the motor point of the abductor hallucis muscle and G2 electrode on the metatarso-phalangeal joint. Electrical stimulation (0.2-ms duration pulses) was applied at 0.5 Hz to the tibial nerve at the ankle by a bipolar electrode, while the abductor hallucis muscle was at rest as confirmed by auditory feedback. Stimuli were delivered at gradually increasing intensities. Intensity at which F-waves were clearly identifiable (F-wave threshold) and intensity at which M-wave of maximal amplitude was obtained (M-max threshold) were recorded. Then 10 stimuli were delivered with an intensity set at approximately 20% above M-max threshold (supramaximal intensity). The persistence of the F-waves was calculated as the percentage of evoked F-waves among the 10 trials. The largest amplitude and shortest latency of the F-waves were measured. Cortical responses of the SEPs to tibial nerve stimulation were recorded (20 Hz–20 kHz bandpass) with G1 electrode placed 2 cm behind the vertex and linked G2 electrodes at earlobes. Electrical stimulation (0.2-ms duration pulses) was applied at 2 Hz to the tibial nerve at the ankle by a bipolar electrode with an intensity set at visible motor threshold. Two series of 500 stimuli were averaged. The amplitude and latency of the P40 component were measured. The soleus H-reflex was recorded (20 Hz–20 kHz bandpass) with G1 electrode on the motor point of the soleus muscle and G2 electrode on Achilles tendon. The thigh/leg and leg/foot angles were kept constant at 90°. Electrical stimulation (1-ms duration pulses) was applied at 0.5 Hz to the tibial nerve at the popliteal fossa by a monopolar electrode. Stimuli were delivered at gradually increasing intensities. Intensity at which H-reflex was clearly identifiable (H-reflex threshold) was recorded, and then the intensity was increased to obtain H-reflex of maximal amplitude (H-max). The amplitude and latency of H-max were measured. The nociceptive flexion (RIII) reflex was recorded (20 Hz– 20 kHz bandpass) with G1 electrode on the motor point of the biceps femoris muscle and G2 electrode on its distal tendon. The thigh/leg and leg/foot angles were kept constant at 90°. Electrical stimulation (a train of five 1-ms duration pulses with an inner frequency of 300 Hz) was applied to the sural nerve at the ankle by a bipolar electrode. RIII-reflex threshold was determined by delivering stimuli at gradually increasing and decreasing intensities until a stable reflex response was obtained with a latency ranging between 80 and 180 ms. Then three stimuli were delivered at irregular intervals greater than 15 s to avoid habituation with an intensity set at 20% above RIII-reflex threshold. The maximal area
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and minimal latency of the full-wave rectified and integrated reflex responses were measured. 2.3. Statistical analyses Nonparametric tests were used since not all data passed the normality test as assessed by the Kolmogorov–Smirnov method. Results were compared between ‘ON’ and ‘OFF’ SCS conditions using the Wilcoxon-matched pairs signed rank test. A two-tailed P value of less than 0.05 was considered as significant. However, a stricter threshold of 0.0042 resulting from Holm–Bonferroni correction was also considered as a safeguard against false positives due to multiple testing. In case of significant difference, the percentage of change between ‘ON’ and ‘OFF’ SCS conditions was calculated [(‘ON’–‘OFF’ values)/(‘OFF’ values)]. The relationships between ‘ON/OFF’ neurophysiological changes and between these changes and ‘post/ pre’ SCS-induced pain relief were studied using the Spearman correlation test. A two-tailed P value of less than 0.05 was considered as significant. The respective influence of the ‘ON/OFF’ change in pain level (<20 versus P20 on a 0–100 VAS), the type of pain (mixed versus neuropathic), or the motor deficit (absent versus present) on ‘ON/OFF’ neurophysiological changes was studied using the Mann– Whitney test. A two-tailed P value of less than 0.05 was considered as significant (0.0125 after correction for multiple testing).
3. Results All patients completed the study without adverse events. Demographic and clinical data are presented in Table 1. Pain duration between the last intervention of back surgery and SCS implantation ranged from 1.5 to 10 years (mean 4.5 years). Patients were treated by SCS from 1 to 13 years (mean 5.7 years) before inclusion in this study. Chronic pain relief induced by SCS ranged from 45% to 90% (mean 71.0%). At the time of investigation, remaining pain level in ‘ON’ condition ranged from 10 to 45 (mean 25.6) on a 0–100 VAS. In ‘OFF’ condition, pain level increase was P20 in seven patients and remained <20 in 13 patients, indicating prolonged SCS-induced analgesic after-effects. The painful lower limb was located on the right side in seven patients and on the left side in 13 patients. Nine patients had a pure neuropathic pain located in the lower limb. Eleven patients had mixed pain mechanisms, a typical mechanical low back pain being associated with the neuropathic component in the lower limb. Predominant pain was located in L4/L5 territory in four patients, L5 territory in five patients, L5/S1 territory in five patients, and S1 territory in six patients. Clinically assessed sensory deficit (to light touch, vibration, pin-prick, warm, or cold stimuli) was present in the painful territory, at least moderately, in all patients. Motor deficit was present in nine patients, always in L5 territory and never in S1 territory. Analgesic drug treatment at the time of investigation included benzodiazepins (n = 10), other anticonvulsant drugs (n = 4), antidepressants (n = 10), morphinics (n = 11), and paracetamol (n = 9). Only two patients were not receiving any analgesic drug. According to our normal laboratory values (presented in Table 2), all patients but two, presented at least one abnormal neurophysiological test in ‘OFF’ SCS condition (Table 1). Abnormalities were reduced SSR amplitude (n = 7), increased SSR latency (n = 1), reduced F-wave persistence (n = 2), reduced F-wave amplitude (n = 4), increased F-wave latency (n = 5), reduced P40-SEP amplitude (n = 4), increased P40-SEP latency (n = 12), reduced H-reflex amplitude (n = 9), and increased RIII-reflex threshold (n = 7). Various neurophysiological changes were found between ‘ON’ and ‘OFF’ SCS conditions, as illustrated in Fig. 1. A normalization of
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neurophysiological values in ‘ON’ SCS condition was observed for 4/7 cases of reduced SSR amplitude, 1/2 cases of reduced F-wave persistence, 3/4 cases of reduced F-wave amplitude, 3/5 cases of increased F-wave latency, and 3/12 cases of increased P40-SEP latency. The differences in neurophysiological results between ‘ON’ and ‘OFF’ SCS conditions were significant for nine parameters: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were found to increase in ‘ON’ condition, whereas SSR latency, F-wave latency, P40-SEP amplitude, H-reflex amplitude, and RIII-reflex area were found to decrease in ‘ON’ condition (Table 2). The difference between ‘ON’ and ‘OFF’ SCS conditions remained significant after adjustment for multiple comparisons for only four parameters: P40-SEP amplitude, H-reflex amplitude, RIII-reflex threshold, and RIII-reflex area. The percentage of change between ‘ON’ and ‘OFF’ SCS conditions was then calculated for these four parameters. A positive correlation was found between ‘ON/OFF’ changes in H-reflex amplitude and RIII-reflex area (r = 0.56, P = 0.01, Spearman test) (Fig. 2). There were no correlations between the other ‘ON/OFF’ neurophysiological changes. The ‘post/pre’ SCS-induced pain relief correlated negatively with ‘ON/OFF’ changes in RIII-reflex threshold (r = 0.52, P = 0.02) and positively with ‘ON/OFF’ changes in RIII-reflex area (r = 0.46, P = 0.04) (Fig. 2). There were no correlations between ‘post/pre’ SCS-induced pain relief and the other ‘ON/OFF’ neurophysiological changes. The ‘ON/OFF’ change in RIII-reflex threshold varied with the ‘ON/OFF’ change in pain level: RIII-reflex threshold increased in ‘ON’ SCS condition, but more when pain level decrease was P20 than when it remained <20 (mean (SEM): +49.4 (16.1)% versus +16.3 (9.1)%, P = 0.04, Mann–Whitney test) (Fig. 2). The ‘ON/OFF’ change in P40-SEP amplitude varied with the type of pain: P40SEP amplitude decreased in ‘ON’ SCS condition, but more in patients with mixed pain than in patients with pure neuropathic pain ( 35.9 (6.3)% versus 17.2 (7.4)%, P = 0.03) (Fig. 2). No other ‘ON/ OFF’ neurophysiological changes varied with the ‘ON/OFF’ change in pain level, the type of pain, or the motor deficit. The significant differences between neurophysiological changes and ‘ON/OFF’ analgesic effects or the type of pain did not persist after statistical correction for multiple testing.
4. Discussion This study shows that SCS may influence various neural pathways. Inhibitory effects on P40-SEP, H-reflex, and RIII-reflex were the most significant results. Attenuation of RIII-reflex by SCS has previously been reported and associated with a good efficacy of the procedure [9,10]. In the present study, SCS was found to increase RIII-reflex threshold and to reduce RIII-reflex area and this was correlated with the magnitude of SCS-induced pain relief. Attenuation of RIII-reflex also correlated with the decrease in H-reflex amplitude. The RIII-reflex assesses a polysynaptic pathway between A-delta cutaneous afferents and alpha-motoneuron efferents, while the H-reflex assesses a monosynaptic pathway between Ia proprioceptive afferents and alpha-motoneuron efferents. The correlated inhibition induced by SCS on RIII- and H-reflexes probably did not result from a reduction of alpha-motoneuron excitability, because F-wave amplitude and persistence would have declined in case of reduced motoneuron excitability [16], whereas these parameters did not change with stimulation condition in our study. In addition, F-wave latency was found to be shortened in ‘ON’ SCS condition, whereas it should increase in case of reduced motoneuron excitability [19]. If we hypothesize that SCS exerts its inhibitory influence on segmental spinal level, the correlated inhibition of RIII- and H-reflexes should have occurred in the lumbar dorsal horns, presynaptic to the motoneurons [11].
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Table 1 Demographic, clinical and neurophysiological data of the 20 patients treated by spinal cord stimulation (SCS). No.
Sex
Age (years)
Pain duration before SCS implant (years)
Time after SCS implant (years)
Mean SCSinduced pain relief (%)
Mean ongoing pain intensity (SCS-ON) (VAS/ 100)
SCS aftereffects (when switched ‘OFF’)
Motor deficit location
Sensory deficit location
Pain location
Pain mechanism
Abnormal electrophysiological results (SCS-OFF)
Analgesic drug treatment at the time of investigation
1
W
53
5
4.5
85
12
Yes
l. L5
l. L5
l. L5/S1
Neuropathic
Increased SSR and P40-SEP latencies
2
M
47
2
13
60
40
Yes
No
r. L5
r. L5
Mixed
3
M
41
1.5
4.5
65
25
No
l. L5
l. L5
l. L5/S1
Neuropathic
4
W
53
3.5
9
70
20
No
r. L5
r. L5/S1
r. L5/S1
Mixed
5
W
49
6.5
13
60
45
Yes
No
l. S1
l. S1
Neuropathic
Reduced SSR and F-wave amplitudes, increased F-wave and P40-SEP latencies, and increased RIII threshold Increased P40-SEP latency and RIII threshold Reduced SSR, F-wave, and H-reflex amplitudes, reduced F-wave persistence, and increased RIII threshold Increased P40-SEP latency
Aceprometazine, bromazepam, dextropropoxyphene, mianserine, and paracetamol Citalopram and clonazepam
6
M
48
6.5
11
65
32
Yes
r. L5
r. L5/S1
r. L5/S1
Mixed
7
M
53
3
2
65
28
Yes
No
l. S1
l. S1
Mixed
8 9
W M
39 65
5 4
11.5 4
80 55
14 40
Yes Yes
l. L5 No
l. L5/S1 r. L5
l. L5/S1 r. L5
Mixed Mixed
10
M
49
5
4
55
45
Yes
l. L5
l. L4/L5
l. L4/L5
Mixed
11 12
M W
46 42
4 3.5
4 4
65 70
25 30
Yes Yes
No No
l. L5 r. S1
l. L4/L5 r. S1
Mixed Mixed
Reduced H-reflex amplitude Reduced P40-SEP amplitude and increased P40-SEP latency
13
M
38
2
1
90
10
No
r. L5
r. L5
r. L5
Neuropathic
14
W
66
1.5
3
80
15
No
l. L5
l. L5
l. L5
Mixed
15
W
48
5.5
1.5
70
25
Yes
No
r. L5
r. L5
Mixed
Reduced SSR and H-reflex amplitudes and increased P40-SEP latency Reduced SSR amplitude and F-wave persistence and increased F-wave latency None
16
M
51
6
1
75
25
No
No
l. S1
l. S1
Neuropathic
17 18 19
W M M
36 38 61
5 10 8
9 1 1
85 45 90
15 45 10
No Yes Yes
No No l. L5
l. S1 l. S1 l. L5
l. S1 l. S1 l. L4/L5
Neuropathic Neuropathic Neuropathic
20
M
59
3
11
90
10
No
No
l. L5
l. L4/L5
Neuropathic
Clonazepam and fluoxetine
Codeine and paracetamol Dextropropoxyphene, gabapentine, and paracetamol Carbamazepine, clomipramine, and Tramadol Clonazepam and mianserine Citalopram, dextropropoxyphene, and paracetamol Amitriptyiline Clonazepam, codeine, and paracetamol Carbamazepine and clomipramine Clonazepam, codeine, and paracetamol Clonazepam Buprenorphine Amitriptyline and gabapentine None
Ò
Reduced H-reflex amplitude and increased P40-SEP latency and RIII threshold Increased P40-SEP latency Reduced SSR and H-reflex amplitudes Reduced P40-SEP amplitude, increased F-wave and P40-SEP latencies, and increased RIII threshold Reduced P40-SEP and H-reflex amplitudes and increased P40-SEP latency
Dextropropoxyphene, lorazepam, and paracetamol Alprazolam, paracetamol, and tramadol
D.C. de Andrade et al. / PAIN 150 (2010) 485–491
Increased P40-SEP latency and RIII threshold, and reduced H-reflex amplitude Reduced SSR, P40-SEP, and F-wave amplitudes and increased F-wave and P40-SEP latencies Reduced SSR and H-reflex amplitudes Reduced F-wave and H-reflex amplitudes and increased F-wave latency and RIII threshold None
Amitriptyiline, clonazepam, codeine, and paracetamol None
Ò
489
D.C. de Andrade et al. / PAIN 150 (2010) 485–491 Table 2 Neurophysiological results in ‘OFF’ and ‘ON’ conditions of spinal cord stimulation. Normal limits
OFF-stimulation
ON-stimulation
Wilcoxon test (P value)
SSR amplitude (mV) Range
P0.6
1.4 (2.1, 0.4) 0.1–6.0
2.0 (2.4, 0.4) 0.4–6.3
0.0484
SSR latency (s) Range
62.5
2.0 (2.1, 0.1) 1.8–2.8
1.9 (1.9, 0.1) 1.3–3.0
0.0267
M-max threshold (mA) Range
NA
45.0 (46.0, 2.0) 30–60
45.0 (47.8, 1.8) 35–65
0.1726
M-max amplitude (mV) Range
P5
9.3 (9.2, 0.4) 6.5–12.0
9.8 (9.3, 0.4) 6.0–12.0
0.5966
F-wave threshold (mA) Range
NA
16.5 (18.6, 1.4) 12–33
20.0 (18.9, 1.3) 11–29
0.6788
F-wave amplitude (lV) Range
P60
160 (207.0, 38.4) 30–650
170 (220.5, 36.2) 30–580
0.6226
F-wave latency (ms) Range
656
51.5 (52.7, 0.9) 48–65
51.0 (51.0, 1.1) 45–65
0.0092
F-wave persistence (%) Range
P20
100 (80.0, 6.8) 10–100
100 (86.5, 5.6) 10–100
0.3750
P40-SEP amplitude (lV)
0.6
0.0017
Range
1.9 (1.8, 0.2)
1.3 (1.3, 0.2)
0.4–3.4
0.2–2.9
P40-SEP latency (ms) Range
45
46.0 (45.8, 0.6) 41.0–52.0
45.0 (45.9, 0.7) 40.5–51.5
0.8904
H-reflex threshold (mA) Range H-reflex amplitude (mV)
NA
15.5 (16.4, 1.2) 9–28 2.7 (2.4, 0.4)
18.0 (17.9, 1.2) 10–30 1.2 (1.7, 0.3)
0.0166
0.1–5.6
0.1–5.4
0.8
Range
0.0007
H-reflex latency (ms) Range
36
31.9 (31.3, 0.5) 26.4–34.4
31.1 (31.4, 0.5) 27.2–34.9
0.6477
RIII-reflex threshold (mA)
12
7.3 (9.2, 0.8)
10.8 (11.0, 0.7)
0.0039
5.5–16
6.5–17
Range RIII-reflex area (mV/ms)
0.8
Range RIII-reflex latency (ms) Range
180
3.7 (3.5, 0.3)
1.8 (2.1, 0.2)
1.5–5.8
0.6–4.8
113.5 (113.5, 5.2) 82–165
121.5 (123.2, 7.2) 80–176
0.0005 0.0290
Normal limits are upper or lower limits of our normative laboratory values (established on 60 healthy subjects aged 20–80 years (sex ratio 1:1) without symptoms or signs of peripheral neuropathies or other neurological illness; NA: not available value). In OFF- and ON-stimulation columns median values (mean and standard error of the mean) are presented. SSR: sympathetic skin response. SEPs: somatosensory-evoked potentials. Significant P values of the Wilcoxon-matched pairs signed rank test are in bold, and underlined when the significance persisted after correction for multiple testing.
Fig. 1. Representative traces of neurophysiological recordings performed in ‘ON’ and ‘OFF’ conditions of spinal cord stimulation (SCS). SSR: sympathetic skin response and SEPs: somatosensory-evoked potentials.
490
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Fig. 2. Correlation between changes in H-reflex amplitude and RIII-reflex area observed ‘ON/OFF’ spinal cord stimulation. Correlations between pain level changes observed ‘post/pre’ spinal cord stimulation and changes in RIII-reflex threshold or area observed ‘ON/OFF’ spinal cord stimulation. Differences in RIII-reflex threshold and P40-SEP amplitude changes observed ‘ON/OFF’ spinal cord stimulation according to ‘ON/OFF’ pain level changes and pain mechanisms, respectively. SCS: spinal cord stimulation and SEPs: somatosensory-evoked potentials. Correlation coefficient (r) and P values of the Spearman or Mann–Whitney test are presented.
Experimental studies have demonstrated a suppressive action of SCS on neuronal hyperexcitability or long-term synaptic potentiation in the dorsal horns [31,33]. At this level, SCS may concomitantly depress segmental transmission of both nociceptive and non-nociceptive (e.g., proprioceptive) information. Neuropathic pain has been associated with an augmented responsiveness of the wide-dynamic range (WDR) neurons of the dorsal horns. SCS could especially reduce WDR neuronal hyperactivity in response to innocuous stimuli. Regarding potentially involved neurotransmitters, experimental data showed that SCS could increase the release of extracellular GABA, but decrease that of glutamate and aspartate in the dorsal horns [5]. The analgesic effect of SCS has also been associated with cholinergic activation in the dorsal horns via muscarinic receptors [28].
Supraspinal mechanisms probably also contribute to SCS efficacy. The finding that SCS decreased P40-SEP amplitude, independently from changes in RIII- and H-reflexes, favored this hypothesis. The SEPs assess A-beta cutaneous afferents, spinal dorsal columns, and intraencephalic lemniscal pathways, including thalamic relay and cortical integration. The reduction of short-latency SEP amplitude by SCS has previously been observed [6,15]. One possible cause of SEP attenuation refers to spike collision in the dorsal columns between the ascending volleys triggered by tibial nerve stimulation and action potentials triggered by SCS. Whatever the underlying mechanism, a recent source dipole analysis showed that SCS was able to attenuate SEP processing in both primary (SI) and secondary (SII) somatosensory cortices [24]. In contrast, other neuroimaging studies revealed an increased activation
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D.C. de Andrade et al. / PAIN 150 (2010) 485–491
of SI, SII and posterior insula during SCS [12,25,30]. SCS likely produces complex changes in cortical processing of both innocuous and noxious sensory information. It is also conceivable that descending inhibitory controls play a role in the modulation of spinal activities by SCS. In contrast to its inhibitory effects on sensory processing, SCS was found to enhance plantar SSRs (increased amplitude and shortened latency). This was surprising because the sympathetic nervous system is thought to be inhibited by SCS, providing peripheral vasodilatation for the treatment of vaso-occlusive diseases. However, the vasodilatation induced by SCS is mostly mediated by adrenergic pathways [32], whereas SSRs assess sympathetic cholinergic innervation of the sweat glands. Sudomotor and vasomotor activities can be differentiated within the sympathetic nervous system, e.g., regarding the location of the central control in the rostral medulla, that is ventromedial for cholinergic sudation and ventrolateral for adrenergic vasoconstriction [17]. Thus, SCS could facilitate sympathetic sudomotor activities in parallel with a reduction of sympathetic vasomotor activities, possibly reflecting compensatory mechanisms. Finally, several limitations of this study should be acknowledged. First, unilateral recordings were performed, although SCS could lead to bilateral effects. Second, almost all patients were taking analgesic drugs at the time of investigation. These drugs could interfere with neurophysiological results, but it was not possible to satisfactorily address this question in this study. Third, pain level did not return to pre-implantation level in a majority of patients of this series, although SCS was stopped for 1 hour. SCS is able to induce prolonged analgesic after-effects beyond the time of stimulation, especially in good responders. This may have reduced the magnitude of neurophysiological changes, if related to pain relief, in this study. In conclusion, the present results suggest that SCS is able to produce a broad inhibition of sensory afferent inputs mediated by Ia, Abeta and A-delta myelinated fibers at either spinal segmental or supraspinal level in FBSS patients. Segmental spinal motor output remained unchanged or was even facilitated, according to previous data [11], as well as sudomotor cholinergic activities in the sympathetic nervous system. The modulation of Ia fiber activity, suggested by the increased threshold and decreased amplitude of the H-reflex, did not appear to be directly related to pain relief. H-reflex attenuation mediated by SCS could support the value of this procedure to treat spasticity [3,21,23]. The effect of SCS on P40-SEP was more pronounced in patients with mixed rather than pure neuropathic pain. However, SCS was found to yield better results in patients with primary complaints of neuropathic pain in lower limbs rather than in those with predominant mechanical low back pain, although this assertion remains a matter of debate [22]. Finally, RIII-reflex attenuation was the main neurophysiological change related to SCS-induced pain relief observed either ‘post/pre’ implantation or ‘ON/OFF’ stimulation. This was a strong objective evidence of a real analgesic efficacy of the procedure [27] correlated to the fact that only good responders to SCS have been included. This study showed a variety of neurophysiological effects induced by SCS at both segmental and suprasegmental levels. These results upport the possible application of SCS to act on sensory, autonomic, or motor disturbances in various neurological conditions. Acknowledgment The authors would like to state that there are no conflicts of interest regarding this work. References [1] Bantli H, Bloedel JR, Thienprasit P. Supraspinal interactions resulting from experimental dorsal column stimulation. J Neurosurg 1975;42:296–300.
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