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Laser evoked potentials in amyotrophic lateral sclerosis
Journal of the Neurological Sciences 288 (2010) 106–111
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Laser evoked potentials in amyotrophic lateral sclerosis Isabella Laura Simone ⁎, Rosanna Tortelli, Vito Samarelli, Eustachio D'Errico, Michele Sardaro, Olimpia Difruscolo, Rita Calabrese, Vito De Vito Francesco, Paolo Livrea, Marina de Tommaso Department of Neurological and Psychiatric Sciences, University of Bari, Italy
a r t i c l e
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Article history: Received 12 May 2009 Received in revised form 20 September 2009 Accepted 23 September 2009 Available online 15 October 2009 Keywords: Amyotrophic lateral sclerosis Pain Laser evoked potentials
a b s t r a c t The pathophysiological mechanism of the pain in ALS is still unclear. The aim of the study was to evaluate the laser evoked potentials (LEPs) in ALS patients in relation to their clinical features. Twenty-four ALS patients were selected. Pain features were assessed and their intensity was measured by a 0–10 VAS. LEPs were recorded in all patients and in 23 healthy subjects. The dorsum of both hands was stimulated, at laser stimuli intensity of 7.5 W, with 10 s inter-stimulus interval and 25 ms duration. Four electrodes were placed at Cz, T3, T4 and Fz positions, with the reference electrode at the nasion; T3 and T4 electrodes were referred offline to Fz, in order to detect the N1 component. Latencies of N2, P2 and N1 waves were significantly higher in ALS than in controls. N1 amplitude was significantly increased in ALS patients compared to controls, with a similar trend for the N2–P2 complex. No correlation was found between LEP abnormalities, pain intensity and clinical features. A degeneration of subcortical structures may subtend a delay in the afferent input to the nociceptive cortex in ALS. On the other hand, an increase of pain processing at the cortical level may derive from a potential sensory compensation to motor cortex dysfunction. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Pain is a frequent symptom in chronic neurological diseases as dementia, Parkinson or post stroke complications, and it is also reported by amyotrophic lateral sclerosis (ALS) patients, even if often underestimated [1–4]. Estimates of prevalence of the pain in ALS from case series ranged from 3% to 78% [5–7]. In clinical practice ALS patients refer that sensitive symptoms, including paresthesias, numbness or tingling may be a significant problem, interfering with daily activities and quality of life [6,8]. The pathophysiological mechanism of pain in ALS is not well understood. Pain is usually considered an “indirect” feature of ALS, in particular the musculoskeletal pain, which is the most frequent type of pain in ALS, related to atrophy and altered tone around joints [7]. Nevertheless, it is unclear if a peripheral or central “primary” origin of the pain may be also supposed. Degenerative changes in extra-motor brain areas including basal ganglia and thalamus are known in ALS [9]. On the other hand, recent studies report an impairment of dorsal root ganglion cells and peripheral sensory fibres, mainly of large myelinated fibres 1A, in almost 20% of ALS patients [10,11]. Nerve conduction studies and somatosensory evoked potentials (SEPs) showed abnormal slowing in the peripheral and central sensory pathways, with an elevated thermal threshold, suggesting sub-clinical abnormalities of the sensory system in ALS [12–20]. Furthermore, a recent study by Hamada et al, [21] showed an abnormal amplitude increase of cortical component of SEPs in ALS. The
⁎ Corresponding author. Department of Neurological and Psychiatric Sciences, Piazza Giulio Cesare, 70124, Bari, Italy. Tel.: +39 080 5478519; fax: +39 080 5478532. E-mail address: [email protected] (I.L. Simone). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.09.023
authors suggested an over-expression of the sensory cortex as a possible compensation to motor cortex disturbances [21]. Many reports indicate a reciprocal interaction between motor and nociceptive cortex. Studies by transcranial magnetic stimulation (TMS) showed that chronic neuropathic pain is associated with changes in motor cortex excitability, and the stimulation of motor cortex by repetitive TMS reduces pain perception, probably by a restore of GABAergic inhibition on the nociceptive cortex [22]. In ALS patients, a loss of GABAergic interneurones, found by histopathological and PET studies [23–25], might account for an overexpression of the nociceptive cortex. The introduction of laser stimuli in neurophysiology has enabled the functional evaluation of pain pathways and their cortical projections [26– 28]. In normal subjects, voluntary movement reduces laser evoked potentials (LEPs), suggesting that a physiological activation of the motor cortex inhibits cortical pain processing by a centrifugal mechanism [29– 31]; on the other hand, an inverse phenomenon of nociceptive cortex activation may be supposed in the presence of a central motor deficit. In the last years, LEPs have been applied to study pain in degenerative disorders of central nervous system (CNS), not directly affecting the sensory and nociceptive systems [27,32–35]. In Parkinson's disease, both patterns of enhanced and reduced LEP amplitude have been described, suggesting that in these patients pain may be partly subtended by an abnormal basal ganglia modulation of sensory cortex [36,37]. To our knowledge, the LEPs have not been evaluated yet in ALS patients. In order to test the hypothesis that a dysfunction of cortical and/or subcortical structures may be involved in the pain pathways of ALS, we performed an evaluation of LEP patterns in relation to the frequency, the type and the severity of the pain in ALS patients.
I.L. Simone et al. / Journal of the Neurological Sciences 288 (2010) 106–111
2. Materials and methods 2.1. Patients Twenty-four ALS patients (n. 12 definite, n. 8 probable and n. 4 possible, according to revised El Escorial criteria [38]), were examined. All patients had a sporadic form of the disease. The mean age at observation was 66.6 (9.22 SD) and the disease duration was 24.8 (17.5 SD) months. Twenty-three healthy subjects (12 women and 11 men, mean age 65.4± 4.5, range 58–72 years) were assumed as controls. The exclusion criteria for LEP examination were the presence of any other neurological, psychiatric and general medical disease, past history possibly associated with peripheral neuropathy, or any CNS acting drug assumption in the last 2 months and analgesics in the last 48 h. All patients agreed to the study after a signed informed consent. 2.2. Measures The motor functional status in ALS patients was assessed using both the ALS Functional Rating Scale (ALSFRS) [39] and the Manual Muscle Testing (MMT) [40]. The sensory functional status was assessed by a standard clinical neurological method to explore touch, pinprick, cold/heat and vibration sense. Tactile sense was assessed by a piece of cotton wool, pinprick by blunted needles, thermal sense by hot/cold tubes and vibration sense by 128 Hz tuning fork. Quantitative sensory testing was not performed, since it was much time consuming for our patients with limited compliance. Moreover, the duration of LEP analysis was very long as well. Quality, location and intensity of pain were assessed in all patients. Patients were asked to define the type of pain, as muscular cramps, musculoskeletal pain (artralgic pain related to immobility or to motion) and neuropathic pain (burning or lancinating sensation or intermittent shooting pain). According to established clinical criteria, we defined central neuropathic pain a pain without a distribution in the territory of a route or nerve [41]. Pain intensity was recorded by Visual Analog scale (VAS) with numerical rating ranging from 0 (no pain) to 10 (pain as bad as it could be) [42]. Depression was evaluated using the Beck Depression Inventory (BDI) scale [43]. Demographic and clinical features of ALS patients are shown in Table 1. 2.3. Neurophysiological study All patients were submitted to standardized electromyography and electroneurography, according to El Escorial guidelines [38]. SEPs were also recorded, in line with the recent recommendations [44], in 18 out of 24 patients, stimulating both the median and tibial nerve. They were compared with those recorded in a group of 30 healthy age and sex matched controls. In 12 patients abnormal prolonged N13–N20 and N22– P39 times were found, concurring with an amplitude reduction of cortical N20 in 5 patients and abnormal P39 duration in three patients. 2.3.1. CO2 laser stimulation and LEP recording Each subject was seated in a comfortable chair, positioned in a quiet room with a temperature of 21–23 °C, in an awake and relaxed Table 1 Clinical and demographic features in ALS patients. ALS patients
n.24
Sex ratio (M/F) Age at observation (mean ± SD) El Escorial criteria diagnosis Site of onset Disease duration (mean ± SD) ALSFRS (mean ± SD) MMT (mean ± SD) BDI (mean ± SD)
11/13 66.6 ± 9.22 years n. 12 definite, n. 8 probable, n. 4 possible n. 19 spinal, n. 5 bulbar 24.8 ± 17.54 months 29.37 ± 6.8 8.7 ± 1.13 8.4 ± 6.6
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state. Subjects and experimenters wore protective goggles during data acquisition. The pain stimulus was a laser pulse (wavelength 10.6 µm) generated by a CO2 laser (Neurolas; Electronic Engineering, Florence, Italy; www.elengroup.com). The beam diameter was 2.5 mm and the stimulus duration was 25 ms. All laser stimuli were adjusted at an intensity of 7.5 W, with an inter-stimulus interval of 10 s, preceded by a verbal warning. We placed four electrodes at Cz, T3, T4 and Fz positions, with the reference electrode at the nasion; the T3 and T4 electrodes were referred off-line to Fz, in order to detect the N1 component [45]. Another electrode was placed above the right eye to record the electroculogram. Signals were amplified, filtered (0.5– 80 Hz) and stored on a biopotential analyzer (MICROMED System Plus, Italy). Four series of 20 laser pulses each were applied to both right and left hands in a random order, with an inter-series interval of at least 5 min. Patients and healthy controls were asked to pay attention to the stimuli and to count them. At the end of each stimulation series, all subjects were requested to rate the pain induced by the laser stimuli, using a 0–100 visual analog pain scale (laser-VAS), in which 0 indicated no pain (white) and 100 (red) indicated the most severe pain imaginable. 2.3.2. LEP analysis An investigator blind to the clinical condition analyzed the LEPs for 1 s, with a 100 ms pre-stimulus time, at a sampling rate of 512 Hz. All runs that contained transient activities that exceeded 65 μV at each recording channel were excluded from the average by an automatic artefact rejection algorithm. In addition, further artefacts were visually inspected and an average of at least 15 artefact-free responses was obtained off-line. For each stimulation site, an average across the two series of stimuli was obtained for the right and left hands. LEPs were identified based on their latency and distribution, and three responses were labelled according to Valeriani et al. [45]. The N2a (namely N2) and P2 components were analyzed at the vertex (Cz), and the N1 component was analyzed at T3–Fz for right-hand stimulation and T4–Fz for lefthand stimulation. Absolute latencies of the scalp potentials were measured at the highest peak of each response component, and the amplitude of each wave was measured from the baseline. We examined the amplitude of the N1 wave and N2–P2 complex. The mean values of laser-VAS and LEP latencies and amplitudes were computed across the two sides for patients and normal subjects. The asymmetry of LEP amplitudes and latencies was computed considering the absolute interside difference in patients and controls. LEPs were considered abnormal when the values of latencies and amplitudes differed for over 2 SD from the mean normal values. 3. Statistical analysis The Student's t test for unpaired data was used to compare LEP features, laser-VAS values and asymmetry indexes between patients and controls, between patients referring and not referring pain, and patients with and without SEP abnormalities. The one-way ANOVA test with Bonferroni correction was applied to compare LEPs and laser-VAS across ALS patients with different types of pain. The Pearson χ2 square and Fisher exact test were employed to evaluate the correspondence between SEP and LEP abnormalities. The Spearman correlation was employed to test the correlations between LEPs, pain
Table 2 Pain features in ALS patients. Presence of pain
n.18 patients (75%)
Mean pain severity (mean ± SD) Muscular cramps Musculoskeletal pain Central neuropathic pain
4.4 ± 1.91 n.2 (11%) n.13 (72%) n.3 (16.6%)
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Table 3 Laser evoked potentials and laser-VAS in ALS patients and controls.
ALS patients n. 24 Control subjects n. 23
ALS patients n. 24 Control subjects n. 23
Latencies
N1(ms)
N2(ms)
P2 (ms)
VAS(0–100)
Mean ± SD Asymmetry Mean ± SD Asymmetry
199.6 ± 22.5⁎⁎ 31.9 ± 31.6 160.4 ± 21.3 29.7 ± 17.4
257.6 ± 32.4⁎⁎ 30 ± 27.6 221.8 ± 28.45 25.4 ± 21
379.9 ± 58⁎⁎ 33.9 ± 23.7 303.8 ± 21.2 21.9 ± 22.3
44 ± 26.7 10.8 ± 9.2 37.6 ± 22.2 12.4 ± 10
Amplitudes
N1 (uV)
N2–P2 (uV)
Mean ± SD Asymmetry Mean ± SD Asymmetry
7.3 ± 6⁎ 5 ± 3.6⁎ 4.1 ± 1.3 1.9 ± 1.6
15.4 ± 9.8 5.9 ± 4.6 11.4 ± 6.8 3.7 ± 3.5
For latency, amplitude and laser-VAS, the average values across right and left sides are considered. Results of the unpaired Student's t test are reported: ⁎p < 0.05; ⁎⁎p < 0.001.
intensity and demographic and clinical features. All the analyses were performed using SPSS version 8. 4. Results 4.1. Pain features in ALS On clinical examination, all ALS patients did not refer subjective negative signs of sensory impairment, as thermal and touch hypoesthesia or vibration and sense position hypoesthesia. Six patients did not refer any kind of pain, 13 patients reported musculoskeletal pain, two had muscular cramps and three referred symptoms of central neuropathic pain. The mean intensity of pain was 4.44 (1.91 SD) (Table 2) and the pain was most frequently located in patients' legs (65%) and arms (43%). Patients with and without pain did not differ for demographic and clinical features, including neurological status and disease duration. Intensity of pain did not correlate with age at observation, ALSFRS, BDI and disease duration. Nevertheless, patients with longer disease duration had a significantly more intense pain (Student's t test, p = 0.019). A significant negative correlation was found with MMT (rs = −0.443; p = 0.03).
4.2. LEPs ALS patients showed a significant increase in latency of all LEPs compared with healthy controls. In addition, the N1 amplitude was significantly higher in ALS, and the N2–P2 amplitude showed a similar, though not significant, trend (Table 3, Figs. 1, 2). In 19 patients (79%) the N1, N2 and P2 latencies exceeded for more than 2 SD the normal range, and among these, 8 patients had also an increase of N1 amplitude, and 7 patients of N2–P2 amplitude. The laser-VAS values were similar between patients and controls. The asymmetry indexes did not differ between groups, either for latencies or for amplitudes (Table 3). The LEPs and the laser-VAS values did not differ between patients who complained or did not complain of the pain, although there was a trend towards an increase of latencies and amplitudes of LEP waves in patients with pain (Fig. 3). Moreover, no differences were found between LEPs and laser-VAS values in patients referring various kinds of pain, as well as in patients with and without SEP abnormalities. There was no correspondence between LEP and SEP abnormalities (χ2 test 2.21, Fisher exact test 0.26, n.s.) (Fig. 4). LEP latencies and amplitudes did not correlate with age at observation, disease duration, pain intensity, ALSFRS and MMT.
Fig. 1. An example of LEPs by the right-hand stimulation in a representative ALS patient, a 65-year-old male (on the right) and in a 62-year-old healthy male (on the left). A latency increase of the main waves is visible in ALS patient, who also shows an increase of N1 and N2–P2 amplitude. Each trace is the average of 15 artefact-free tracks.
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Fig. 3. Mean values ± SD of LEP latencies and amplitudes in ALS patients complaining and not complaining of pain. The increase of LEP amplitudes and latencies in patients with painful symptoms was not significant at the Student's t test.
Fig. 2. Mean values ± SD of LEP latencies and amplitudes in ALS patients and controls. Results of Student's t test for unpaired data are shown: *p < 0.05 **p < 0.01.
5. Discussion Interest in pain in neuromuscular diseases, particularly ALS, has been on the increase in recent years. Pain in ALS could arise from different causes including mechanisms related to muscular cramps or musculoskeletal problems, as confirmed in our patients, who exhibited in large majority pain of musculoskeletal origin. Consistent with the previous results, we found that intensity of pain was significantly higher in patients with longer disease duration [8]. In addition, the negative correlation between pain intensity and muscular strength suggests that pain may be an – indirect – symptom of the disease, largely caused by motor and postural deficits. Nevertheless, an abnormal LEP pattern was found in our ALS series. All cortical components showed a significant latency increase in ALS patients compared to controls, suggesting a conduction slowing due to an impairment of nociceptive pathways. This finding concurs with most of the studies on SEPs, showing a prolonged central conduction time [12,17,19–21], though our LEP method did not allow us to discriminate a peripheral from a central delay. In ALS degeneration of subcortical structures, including the thalamus, has been reported [9], and this may subtend the delay in the afferent input to the nociceptive cortex; on the other hand no study has described peripheral involvement of nociceptive afferents. In our patients, there was no correspondence between LEP and SEP abnormalities, nor LEP latencies were more prolonged in patients with SEP central delay, suggesting a specific involvement of nociceptive pathways in most of the patients.
Another data emerging from our results, was the amplitude increase of N1 wave, with a similar trend for the N2–P2 complex. The LEP amplitude abnormalities were less represented in our series than the LEP latency increase. Nevertheless, this result concurs with recent findings about SEPs, which were found to be increased in amplitude in the moderate weakness ALS group, and reduced in the severe weakness group [21]. Those authors interpreted their data in light of sensory cortical compensation for motor disturbances. Considering that the N1 component is supposed to be generated from the SII cortex, mainly devoted to the discriminative aspects of the pain [45], the hypothesis of an increase of cortical sensory performances in order to compensate for the motor
Fig. 4. Distribution of patients with SEP and LEP abnormalities. Results of Pearson χ2 test: n.s.
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deficit might be coherent with our results. Sensory input can facilitate motor cortex (MI) [46–48], and we also suppose that the same type of facilitation occurs through painful stimuli. The LEP amplitude enhancement may be a consequence of motor cortex hypofunction, as suggested by the studies showing that the activation of nociceptive cortex is modulated by the state of cortical motor excitation. Voluntary movement and motor cortex excitation inhibit LEPs and laser pain perception in healthy subjects [29–31]. Another possible explanation for LEP amplitude increase in ALS is a diffuse decrease of intra-cortical inhibition, with neuro-excitotoxic changes in the motor and non-motor cortex, as indicated by previous SEP results [21]. To support this hypothesis, a decrease of 5-HT and 5 hydroxyindolacetic acid was found in cerebrospinal fluid, plasma as well as in post-mortem spinal cord of ALS patients [49]. Furthermore, histopathological and PET studies showed a loss of inhibitory GABAergic interneurons in motor, extra-motor cortex and spinal cord of ALS patients [23–25]. In this context it is also interesting to note that a decrease of GABA was found in the spinal cord of a mouse model of ALS over expressing the mutated G93A-SOD1 [50]. Therefore, all these data might suggest a loss of function in the central and peripheral inhibitory pain pathways, both in descending serotonergic dorsolateral funiculus, and in GABA-releasing interneurons. In fibromyalgia the finding of a generalized amplitude increase of LEPs, even if reported in few conditions, suggested a greater activation of the CNS under nociceptive stimulation [51], concurring with a phenomenon of “hyperattention” to laser pain [52]. According to Garcia-Larrea et al. [53], normal or enhanced LEPs to stimulation of a painful territory suggest the integrity of pain pathways, and do not support a neuropathic pathophysiology. We can suppose that ALS may represent a peculiar condition where LEPs enhancement may be subtended by a dysfunction of structures involved in pain processing. In fact, in our ALS series, the N1 amplitude increase contrasts with latency prolongation. Similarly, Hamada et al. showed an increase of amplitude and a N20 conduction delay and explained this delay as a phenomenon correlated to a prolongation of sensory cortex production processes [21]. In our study, this hypothesis does not seem appropriate for the whole group of ALS patients, since the LEP latency prolongation did not constantly match with LEP amplitude increase. It is likely that the facilitation of the nociceptive cortex, induced by motor cortex hypofunction and determining LEP amplitude enhancement, may co-exist with initial degeneration of subcortical structures, including the thalamus [9], with a subsequent delay in the afferent input to the nociceptive cortex. In conclusion the present LEP findings may be a result of concurrent phenomena, which consist of an initial degeneration of subcortical structures and a hyper-activation of the cortical nociceptive zones mainly devoted to the discriminative aspects of pain, induced by motor cortex dysfunction and loss of intra-cortical inhibition. LEP findings did not correlate with disease duration, severity and pain intensity. Therefore, nociceptive pathway dysfunction does not seem to be associated with or causative of the pain in ALS and the changes in nociceptive pathways do not seem to influence the clinical outcome of ALS patients, whose painful symptoms are confirmed to be mainly an “indirect” feature, prevalently of muscular–skeletal origin. Nevertheless, there was a trend towards an increase of LEP abnormalities in patients reporting pain symptoms, when compared to patients with no pain. Further evidence in ALS animal models and longitudinal observation in larger number of ASL patients may be useful to clarify if the pain may be enhanced by mechanisms which are intrinsic to the disease and/or linked with functional and degenerative changes of nociceptive pathways. References [1] Gibson SJ, Voukelatos X, Ames D, Flicker L, Helme RD. An examination of pain perception and cerebral event-related potentials following carbon dioxide laser stimulation in patients with Alzheimer's disease and age-matched control volunteers. Pain Res Manag 2001;6:126–32. [2] Benedetti F, Arduino C, Vighetti S, Asteggiano G, Tarenzi L, Rainero I. Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration. Pain 2004;111:22–9.
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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Laser evoked potentials in amyotrophic lateral sclerosis Isabella Laura Simone ⁎, Rosanna Tortelli, Vito Samarelli, Eustachio D'Errico, Michele Sardaro, Olimpia Difruscolo, Rita Calabrese, Vito De Vito Francesco, Paolo Livrea, Marina de Tommaso Department of Neurological and Psychiatric Sciences, University of Bari, Italy
a r t i c l e
i n f o
Article history: Received 12 May 2009 Received in revised form 20 September 2009 Accepted 23 September 2009 Available online 15 October 2009 Keywords: Amyotrophic lateral sclerosis Pain Laser evoked potentials
a b s t r a c t The pathophysiological mechanism of the pain in ALS is still unclear. The aim of the study was to evaluate the laser evoked potentials (LEPs) in ALS patients in relation to their clinical features. Twenty-four ALS patients were selected. Pain features were assessed and their intensity was measured by a 0–10 VAS. LEPs were recorded in all patients and in 23 healthy subjects. The dorsum of both hands was stimulated, at laser stimuli intensity of 7.5 W, with 10 s inter-stimulus interval and 25 ms duration. Four electrodes were placed at Cz, T3, T4 and Fz positions, with the reference electrode at the nasion; T3 and T4 electrodes were referred offline to Fz, in order to detect the N1 component. Latencies of N2, P2 and N1 waves were significantly higher in ALS than in controls. N1 amplitude was significantly increased in ALS patients compared to controls, with a similar trend for the N2–P2 complex. No correlation was found between LEP abnormalities, pain intensity and clinical features. A degeneration of subcortical structures may subtend a delay in the afferent input to the nociceptive cortex in ALS. On the other hand, an increase of pain processing at the cortical level may derive from a potential sensory compensation to motor cortex dysfunction. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Pain is a frequent symptom in chronic neurological diseases as dementia, Parkinson or post stroke complications, and it is also reported by amyotrophic lateral sclerosis (ALS) patients, even if often underestimated [1–4]. Estimates of prevalence of the pain in ALS from case series ranged from 3% to 78% [5–7]. In clinical practice ALS patients refer that sensitive symptoms, including paresthesias, numbness or tingling may be a significant problem, interfering with daily activities and quality of life [6,8]. The pathophysiological mechanism of pain in ALS is not well understood. Pain is usually considered an “indirect” feature of ALS, in particular the musculoskeletal pain, which is the most frequent type of pain in ALS, related to atrophy and altered tone around joints [7]. Nevertheless, it is unclear if a peripheral or central “primary” origin of the pain may be also supposed. Degenerative changes in extra-motor brain areas including basal ganglia and thalamus are known in ALS [9]. On the other hand, recent studies report an impairment of dorsal root ganglion cells and peripheral sensory fibres, mainly of large myelinated fibres 1A, in almost 20% of ALS patients [10,11]. Nerve conduction studies and somatosensory evoked potentials (SEPs) showed abnormal slowing in the peripheral and central sensory pathways, with an elevated thermal threshold, suggesting sub-clinical abnormalities of the sensory system in ALS [12–20]. Furthermore, a recent study by Hamada et al, [21] showed an abnormal amplitude increase of cortical component of SEPs in ALS. The
⁎ Corresponding author. Department of Neurological and Psychiatric Sciences, Piazza Giulio Cesare, 70124, Bari, Italy. Tel.: +39 080 5478519; fax: +39 080 5478532. E-mail address: [email protected] (I.L. Simone). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.09.023
authors suggested an over-expression of the sensory cortex as a possible compensation to motor cortex disturbances [21]. Many reports indicate a reciprocal interaction between motor and nociceptive cortex. Studies by transcranial magnetic stimulation (TMS) showed that chronic neuropathic pain is associated with changes in motor cortex excitability, and the stimulation of motor cortex by repetitive TMS reduces pain perception, probably by a restore of GABAergic inhibition on the nociceptive cortex [22]. In ALS patients, a loss of GABAergic interneurones, found by histopathological and PET studies [23–25], might account for an overexpression of the nociceptive cortex. The introduction of laser stimuli in neurophysiology has enabled the functional evaluation of pain pathways and their cortical projections [26– 28]. In normal subjects, voluntary movement reduces laser evoked potentials (LEPs), suggesting that a physiological activation of the motor cortex inhibits cortical pain processing by a centrifugal mechanism [29– 31]; on the other hand, an inverse phenomenon of nociceptive cortex activation may be supposed in the presence of a central motor deficit. In the last years, LEPs have been applied to study pain in degenerative disorders of central nervous system (CNS), not directly affecting the sensory and nociceptive systems [27,32–35]. In Parkinson's disease, both patterns of enhanced and reduced LEP amplitude have been described, suggesting that in these patients pain may be partly subtended by an abnormal basal ganglia modulation of sensory cortex [36,37]. To our knowledge, the LEPs have not been evaluated yet in ALS patients. In order to test the hypothesis that a dysfunction of cortical and/or subcortical structures may be involved in the pain pathways of ALS, we performed an evaluation of LEP patterns in relation to the frequency, the type and the severity of the pain in ALS patients.
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2. Materials and methods 2.1. Patients Twenty-four ALS patients (n. 12 definite, n. 8 probable and n. 4 possible, according to revised El Escorial criteria [38]), were examined. All patients had a sporadic form of the disease. The mean age at observation was 66.6 (9.22 SD) and the disease duration was 24.8 (17.5 SD) months. Twenty-three healthy subjects (12 women and 11 men, mean age 65.4± 4.5, range 58–72 years) were assumed as controls. The exclusion criteria for LEP examination were the presence of any other neurological, psychiatric and general medical disease, past history possibly associated with peripheral neuropathy, or any CNS acting drug assumption in the last 2 months and analgesics in the last 48 h. All patients agreed to the study after a signed informed consent. 2.2. Measures The motor functional status in ALS patients was assessed using both the ALS Functional Rating Scale (ALSFRS) [39] and the Manual Muscle Testing (MMT) [40]. The sensory functional status was assessed by a standard clinical neurological method to explore touch, pinprick, cold/heat and vibration sense. Tactile sense was assessed by a piece of cotton wool, pinprick by blunted needles, thermal sense by hot/cold tubes and vibration sense by 128 Hz tuning fork. Quantitative sensory testing was not performed, since it was much time consuming for our patients with limited compliance. Moreover, the duration of LEP analysis was very long as well. Quality, location and intensity of pain were assessed in all patients. Patients were asked to define the type of pain, as muscular cramps, musculoskeletal pain (artralgic pain related to immobility or to motion) and neuropathic pain (burning or lancinating sensation or intermittent shooting pain). According to established clinical criteria, we defined central neuropathic pain a pain without a distribution in the territory of a route or nerve [41]. Pain intensity was recorded by Visual Analog scale (VAS) with numerical rating ranging from 0 (no pain) to 10 (pain as bad as it could be) [42]. Depression was evaluated using the Beck Depression Inventory (BDI) scale [43]. Demographic and clinical features of ALS patients are shown in Table 1. 2.3. Neurophysiological study All patients were submitted to standardized electromyography and electroneurography, according to El Escorial guidelines [38]. SEPs were also recorded, in line with the recent recommendations [44], in 18 out of 24 patients, stimulating both the median and tibial nerve. They were compared with those recorded in a group of 30 healthy age and sex matched controls. In 12 patients abnormal prolonged N13–N20 and N22– P39 times were found, concurring with an amplitude reduction of cortical N20 in 5 patients and abnormal P39 duration in three patients. 2.3.1. CO2 laser stimulation and LEP recording Each subject was seated in a comfortable chair, positioned in a quiet room with a temperature of 21–23 °C, in an awake and relaxed Table 1 Clinical and demographic features in ALS patients. ALS patients
n.24
Sex ratio (M/F) Age at observation (mean ± SD) El Escorial criteria diagnosis Site of onset Disease duration (mean ± SD) ALSFRS (mean ± SD) MMT (mean ± SD) BDI (mean ± SD)
11/13 66.6 ± 9.22 years n. 12 definite, n. 8 probable, n. 4 possible n. 19 spinal, n. 5 bulbar 24.8 ± 17.54 months 29.37 ± 6.8 8.7 ± 1.13 8.4 ± 6.6
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state. Subjects and experimenters wore protective goggles during data acquisition. The pain stimulus was a laser pulse (wavelength 10.6 µm) generated by a CO2 laser (Neurolas; Electronic Engineering, Florence, Italy; www.elengroup.com). The beam diameter was 2.5 mm and the stimulus duration was 25 ms. All laser stimuli were adjusted at an intensity of 7.5 W, with an inter-stimulus interval of 10 s, preceded by a verbal warning. We placed four electrodes at Cz, T3, T4 and Fz positions, with the reference electrode at the nasion; the T3 and T4 electrodes were referred off-line to Fz, in order to detect the N1 component [45]. Another electrode was placed above the right eye to record the electroculogram. Signals were amplified, filtered (0.5– 80 Hz) and stored on a biopotential analyzer (MICROMED System Plus, Italy). Four series of 20 laser pulses each were applied to both right and left hands in a random order, with an inter-series interval of at least 5 min. Patients and healthy controls were asked to pay attention to the stimuli and to count them. At the end of each stimulation series, all subjects were requested to rate the pain induced by the laser stimuli, using a 0–100 visual analog pain scale (laser-VAS), in which 0 indicated no pain (white) and 100 (red) indicated the most severe pain imaginable. 2.3.2. LEP analysis An investigator blind to the clinical condition analyzed the LEPs for 1 s, with a 100 ms pre-stimulus time, at a sampling rate of 512 Hz. All runs that contained transient activities that exceeded 65 μV at each recording channel were excluded from the average by an automatic artefact rejection algorithm. In addition, further artefacts were visually inspected and an average of at least 15 artefact-free responses was obtained off-line. For each stimulation site, an average across the two series of stimuli was obtained for the right and left hands. LEPs were identified based on their latency and distribution, and three responses were labelled according to Valeriani et al. [45]. The N2a (namely N2) and P2 components were analyzed at the vertex (Cz), and the N1 component was analyzed at T3–Fz for right-hand stimulation and T4–Fz for lefthand stimulation. Absolute latencies of the scalp potentials were measured at the highest peak of each response component, and the amplitude of each wave was measured from the baseline. We examined the amplitude of the N1 wave and N2–P2 complex. The mean values of laser-VAS and LEP latencies and amplitudes were computed across the two sides for patients and normal subjects. The asymmetry of LEP amplitudes and latencies was computed considering the absolute interside difference in patients and controls. LEPs were considered abnormal when the values of latencies and amplitudes differed for over 2 SD from the mean normal values. 3. Statistical analysis The Student's t test for unpaired data was used to compare LEP features, laser-VAS values and asymmetry indexes between patients and controls, between patients referring and not referring pain, and patients with and without SEP abnormalities. The one-way ANOVA test with Bonferroni correction was applied to compare LEPs and laser-VAS across ALS patients with different types of pain. The Pearson χ2 square and Fisher exact test were employed to evaluate the correspondence between SEP and LEP abnormalities. The Spearman correlation was employed to test the correlations between LEPs, pain
Table 2 Pain features in ALS patients. Presence of pain
n.18 patients (75%)
Mean pain severity (mean ± SD) Muscular cramps Musculoskeletal pain Central neuropathic pain
4.4 ± 1.91 n.2 (11%) n.13 (72%) n.3 (16.6%)
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Table 3 Laser evoked potentials and laser-VAS in ALS patients and controls.
ALS patients n. 24 Control subjects n. 23
ALS patients n. 24 Control subjects n. 23
Latencies
N1(ms)
N2(ms)
P2 (ms)
VAS(0–100)
Mean ± SD Asymmetry Mean ± SD Asymmetry
199.6 ± 22.5⁎⁎ 31.9 ± 31.6 160.4 ± 21.3 29.7 ± 17.4
257.6 ± 32.4⁎⁎ 30 ± 27.6 221.8 ± 28.45 25.4 ± 21
379.9 ± 58⁎⁎ 33.9 ± 23.7 303.8 ± 21.2 21.9 ± 22.3
44 ± 26.7 10.8 ± 9.2 37.6 ± 22.2 12.4 ± 10
Amplitudes
N1 (uV)
N2–P2 (uV)
Mean ± SD Asymmetry Mean ± SD Asymmetry
7.3 ± 6⁎ 5 ± 3.6⁎ 4.1 ± 1.3 1.9 ± 1.6
15.4 ± 9.8 5.9 ± 4.6 11.4 ± 6.8 3.7 ± 3.5
For latency, amplitude and laser-VAS, the average values across right and left sides are considered. Results of the unpaired Student's t test are reported: ⁎p < 0.05; ⁎⁎p < 0.001.
intensity and demographic and clinical features. All the analyses were performed using SPSS version 8. 4. Results 4.1. Pain features in ALS On clinical examination, all ALS patients did not refer subjective negative signs of sensory impairment, as thermal and touch hypoesthesia or vibration and sense position hypoesthesia. Six patients did not refer any kind of pain, 13 patients reported musculoskeletal pain, two had muscular cramps and three referred symptoms of central neuropathic pain. The mean intensity of pain was 4.44 (1.91 SD) (Table 2) and the pain was most frequently located in patients' legs (65%) and arms (43%). Patients with and without pain did not differ for demographic and clinical features, including neurological status and disease duration. Intensity of pain did not correlate with age at observation, ALSFRS, BDI and disease duration. Nevertheless, patients with longer disease duration had a significantly more intense pain (Student's t test, p = 0.019). A significant negative correlation was found with MMT (rs = −0.443; p = 0.03).
4.2. LEPs ALS patients showed a significant increase in latency of all LEPs compared with healthy controls. In addition, the N1 amplitude was significantly higher in ALS, and the N2–P2 amplitude showed a similar, though not significant, trend (Table 3, Figs. 1, 2). In 19 patients (79%) the N1, N2 and P2 latencies exceeded for more than 2 SD the normal range, and among these, 8 patients had also an increase of N1 amplitude, and 7 patients of N2–P2 amplitude. The laser-VAS values were similar between patients and controls. The asymmetry indexes did not differ between groups, either for latencies or for amplitudes (Table 3). The LEPs and the laser-VAS values did not differ between patients who complained or did not complain of the pain, although there was a trend towards an increase of latencies and amplitudes of LEP waves in patients with pain (Fig. 3). Moreover, no differences were found between LEPs and laser-VAS values in patients referring various kinds of pain, as well as in patients with and without SEP abnormalities. There was no correspondence between LEP and SEP abnormalities (χ2 test 2.21, Fisher exact test 0.26, n.s.) (Fig. 4). LEP latencies and amplitudes did not correlate with age at observation, disease duration, pain intensity, ALSFRS and MMT.
Fig. 1. An example of LEPs by the right-hand stimulation in a representative ALS patient, a 65-year-old male (on the right) and in a 62-year-old healthy male (on the left). A latency increase of the main waves is visible in ALS patient, who also shows an increase of N1 and N2–P2 amplitude. Each trace is the average of 15 artefact-free tracks.
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Fig. 3. Mean values ± SD of LEP latencies and amplitudes in ALS patients complaining and not complaining of pain. The increase of LEP amplitudes and latencies in patients with painful symptoms was not significant at the Student's t test.
Fig. 2. Mean values ± SD of LEP latencies and amplitudes in ALS patients and controls. Results of Student's t test for unpaired data are shown: *p < 0.05 **p < 0.01.
5. Discussion Interest in pain in neuromuscular diseases, particularly ALS, has been on the increase in recent years. Pain in ALS could arise from different causes including mechanisms related to muscular cramps or musculoskeletal problems, as confirmed in our patients, who exhibited in large majority pain of musculoskeletal origin. Consistent with the previous results, we found that intensity of pain was significantly higher in patients with longer disease duration [8]. In addition, the negative correlation between pain intensity and muscular strength suggests that pain may be an – indirect – symptom of the disease, largely caused by motor and postural deficits. Nevertheless, an abnormal LEP pattern was found in our ALS series. All cortical components showed a significant latency increase in ALS patients compared to controls, suggesting a conduction slowing due to an impairment of nociceptive pathways. This finding concurs with most of the studies on SEPs, showing a prolonged central conduction time [12,17,19–21], though our LEP method did not allow us to discriminate a peripheral from a central delay. In ALS degeneration of subcortical structures, including the thalamus, has been reported [9], and this may subtend the delay in the afferent input to the nociceptive cortex; on the other hand no study has described peripheral involvement of nociceptive afferents. In our patients, there was no correspondence between LEP and SEP abnormalities, nor LEP latencies were more prolonged in patients with SEP central delay, suggesting a specific involvement of nociceptive pathways in most of the patients.
Another data emerging from our results, was the amplitude increase of N1 wave, with a similar trend for the N2–P2 complex. The LEP amplitude abnormalities were less represented in our series than the LEP latency increase. Nevertheless, this result concurs with recent findings about SEPs, which were found to be increased in amplitude in the moderate weakness ALS group, and reduced in the severe weakness group [21]. Those authors interpreted their data in light of sensory cortical compensation for motor disturbances. Considering that the N1 component is supposed to be generated from the SII cortex, mainly devoted to the discriminative aspects of the pain [45], the hypothesis of an increase of cortical sensory performances in order to compensate for the motor
Fig. 4. Distribution of patients with SEP and LEP abnormalities. Results of Pearson χ2 test: n.s.
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deficit might be coherent with our results. Sensory input can facilitate motor cortex (MI) [46–48], and we also suppose that the same type of facilitation occurs through painful stimuli. The LEP amplitude enhancement may be a consequence of motor cortex hypofunction, as suggested by the studies showing that the activation of nociceptive cortex is modulated by the state of cortical motor excitation. Voluntary movement and motor cortex excitation inhibit LEPs and laser pain perception in healthy subjects [29–31]. Another possible explanation for LEP amplitude increase in ALS is a diffuse decrease of intra-cortical inhibition, with neuro-excitotoxic changes in the motor and non-motor cortex, as indicated by previous SEP results [21]. To support this hypothesis, a decrease of 5-HT and 5 hydroxyindolacetic acid was found in cerebrospinal fluid, plasma as well as in post-mortem spinal cord of ALS patients [49]. Furthermore, histopathological and PET studies showed a loss of inhibitory GABAergic interneurons in motor, extra-motor cortex and spinal cord of ALS patients [23–25]. In this context it is also interesting to note that a decrease of GABA was found in the spinal cord of a mouse model of ALS over expressing the mutated G93A-SOD1 [50]. Therefore, all these data might suggest a loss of function in the central and peripheral inhibitory pain pathways, both in descending serotonergic dorsolateral funiculus, and in GABA-releasing interneurons. In fibromyalgia the finding of a generalized amplitude increase of LEPs, even if reported in few conditions, suggested a greater activation of the CNS under nociceptive stimulation [51], concurring with a phenomenon of “hyperattention” to laser pain [52]. According to Garcia-Larrea et al. [53], normal or enhanced LEPs to stimulation of a painful territory suggest the integrity of pain pathways, and do not support a neuropathic pathophysiology. We can suppose that ALS may represent a peculiar condition where LEPs enhancement may be subtended by a dysfunction of structures involved in pain processing. In fact, in our ALS series, the N1 amplitude increase contrasts with latency prolongation. Similarly, Hamada et al. showed an increase of amplitude and a N20 conduction delay and explained this delay as a phenomenon correlated to a prolongation of sensory cortex production processes [21]. In our study, this hypothesis does not seem appropriate for the whole group of ALS patients, since the LEP latency prolongation did not constantly match with LEP amplitude increase. It is likely that the facilitation of the nociceptive cortex, induced by motor cortex hypofunction and determining LEP amplitude enhancement, may co-exist with initial degeneration of subcortical structures, including the thalamus [9], with a subsequent delay in the afferent input to the nociceptive cortex. In conclusion the present LEP findings may be a result of concurrent phenomena, which consist of an initial degeneration of subcortical structures and a hyper-activation of the cortical nociceptive zones mainly devoted to the discriminative aspects of pain, induced by motor cortex dysfunction and loss of intra-cortical inhibition. LEP findings did not correlate with disease duration, severity and pain intensity. Therefore, nociceptive pathway dysfunction does not seem to be associated with or causative of the pain in ALS and the changes in nociceptive pathways do not seem to influence the clinical outcome of ALS patients, whose painful symptoms are confirmed to be mainly an “indirect” feature, prevalently of muscular–skeletal origin. Nevertheless, there was a trend towards an increase of LEP abnormalities in patients reporting pain symptoms, when compared to patients with no pain. Further evidence in ALS animal models and longitudinal observation in larger number of ASL patients may be useful to clarify if the pain may be enhanced by mechanisms which are intrinsic to the disease and/or linked with functional and degenerative changes of nociceptive pathways. References [1] Gibson SJ, Voukelatos X, Ames D, Flicker L, Helme RD. An examination of pain perception and cerebral event-related potentials following carbon dioxide laser stimulation in patients with Alzheimer's disease and age-matched control volunteers. Pain Res Manag 2001;6:126–32. [2] Benedetti F, Arduino C, Vighetti S, Asteggiano G, Tarenzi L, Rainero I. Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration. Pain 2004;111:22–9.
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