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Age-related changes of cortical excitability in subjects with sleep-enhanced centrotemporal spikes: a somatosensory evoked potential study
Clinical Neurophysiology 111 (2000) 591±599 www.elsevier.com/locate/clinph
Age-related changes of cortical excitability in subjects with sleepenhanced centrotemporal spikes: a somatosensory evoked potential study Raffaele Ferri*, Stefano Del Gracco, Maurizio Elia, Sebastiano A. Musumeci Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging, Via Conte Ruggero 73, 94018 Troina, Italy Accepted 14 September 1999
Abstract Middle-latency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) have been reported in subjects with benign childhood epilepsy with centrotemporal spikes (BECT) and in normal children, which usually show signi®cant age-related changes. However, the mechanisms by which age modi®es the appearance of centrotemporal spikes and giant SEPs in these children, are not known. The characteristics of SEPs were studied in a group of 18 subjects (10 males and 8 females, aged 7.1±17.2 years) with sleepenhanced centrotemporal spikes, with or without BECT and the results were compared with those obtained from a group of age-matched normal controls. Giant SEPs were recorded in 6 subjects and, in 3 of these, EEG spikes evoked by hand tapping were obtained also. No subjects with giant SEPs were found in subjects older than 12 years, and an age-related decrease in amplitude of giant SEPs as this age approached was observed. Moreover, at repeated SEP recordings, a clear trend towards a more important reduction in amplitude of giant SEPs over the temporal and parietal than over the central regions was evident. The study of EEG spikes evoked by hand tapping showed a striking similarity between the averaged evoked spikes and the main negative component of giant SEPs. It was also possible to observe that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5±15 ms. Our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related modi®cations which can be interpreted in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Somatosensory evoked potentials; Benign childhood epilepsy with centrotemporal spikes; Tactile evoked spikes; Giant somatosensory evoked potentials; Central nervous system excitability; Epilepsy
1. Introduction The benign childhood epilepsy with centrotemporal spikes (BECT), also called rolandic spike epilepsy, is an idiopathic localization-related epilepsy with distinct sleepenhanced interictal EEG paroxysmal activity, age-related onset and benign course (Commission on Classi®cation and Terminology of the ILAE, 1989). BECT was ®rst described by Nayrac and Beaussart (1958) and is considered to be the most frequent form of epilepsy among children (Blom et al., 1972; Cavazzuti, 1980). Seizures can be very infrequent in this kind of epilepsy and exclusively nocturnal; an isolated event is observed in approximately 15% of patients whereas most subjects (approx. 62%), show only 2± 5 seizures (Bouma et al., 1997). * Corresponding author. Tel.: 139-0935-936111; fax: 139-0935653327. E-mail address: [email protected] (R. Ferri)
Centrotemporal (or rolandic) spikes are an autosomal dominant age-dependent genetic trait. They are found in 34% of siblings of patients with BECT but only 15% of these also develop seizures (Bray and Wiser, 1965; Heijbel et al., 1975). Moreover, 1±2% of children aged 5±12 years who are not affected by seizures, also show centrotemporal spikes in routine EEG recordings (Cavazzuti et al., 1980). For these reasons, it might be concluded that BECT represents a particular aspect of a wide-spectrum condition, the mildest form of which might only be characterized by the presence of centrotemporal spikes, without any other clinical sign. After the discovery of high-amplitude parietal spikes evoked by tactile stimulation (tapping) of the hand or foot in some nonepileptic subjects and BECT patients (De Marco and Negrin, 1973; De Marco and Tassinari, 1981), middlelatency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) were recorded in some of these
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subjects after stimulation of the median nerve (Tassinari et al., 1988; Plasmati et al., 1996). Similarly to centrotemporal spikes, also giant SEPs can be found in nonepileptic children (Micheloyannis et al., 1989). Middle-latency SEPs elicited by the stimulation of the median nerve originate from the sequential activation of different parietal and frontal generators (Desmedt and Bourguet, 1985; Desmedt et al., 1987; Allison et al., 1992; Urbano et al., 1997) and represent a useful tool for studying changes in cortical excitability over the same areas. The mechanisms by which age modi®es the appearance of centrotemporal spikes and giant SEPs, in these children are not known. In particular, there are no data regarding agerelated morphology and scalp topography changes of SEPs in subjects with centrotemporal spikes. Therefore it was decided to study the characteristics of these potentials in a group of young subjects with sleep-enhanced centrotemporal spikes, with or without BECT and to consider their age-related changes in amplitude and scalp distribution, with a view to determining the possible mechanisms involved.
2. Subjects and methods 2.1. Subjects with sleep-enhanced centrotemporal spikes Eighteen subjects (10 males and 8 females; age range 7.1±17.2 years) with typical centrotemporal spikes recorded during sleep, from independent bilateral foci, were included in this study. Twelve of these subjects (6 males and 6 females) were affected by BECT and had shown few typical seizures in form of brief hemifacial
attacks and some generalized convulsions, often during sleep; none of them presented symptomatic rolandic epilepsy. Six were taking antiepileptic drug therapy with carbamazepine. The ages at SEP recording and clinical characteristics of subjects with centrotemporal spikes are shown in Table 1. 2.2. Control subjects Eleven normal subjects (7 males and 4 females) were used as a control group; mean age was 9.10 years (range 4.75±16.58 years). Sleep EEG was recorded during afternoon, covering at least one sleep cycle, in all these subjects in order to exclude the possibility of the presence of centrotemporal spikes. 2.3. SEP recording SEPs were recorded from 19 scalp electrodes (10±20 system) and the ear ipsilateral to the stimulated side was used as reference. An analysis time of 150 or 205 ms was used and 128 single responses were averaged, twice, for each median nerve, separately. Signals were bandpass ®ltered at 1±300 Hz and sampled in order to obtain 512 data points for each epoch. Stimuli were delivered by a Grass S10DSCM somatosensory stimulator with an interstimulus interval of 2000 ms, through silver±silver chloride electrodes applied at a distance of 3 cm from each other, over the median nerve at wrist, with the positive electrode placed distally. Stimuli were positive square waves of 0.1 ms of duration and with an intensity individually adjusted at about 10% over the motor threshold. A Neuro Scan system was utilized for data acquisition and analysis. In 3 subjects with centrotemporal spikes, spikes evoked
Table 1 Age at SEP recording and clinical characteristics of subjects with centrotemporal spikes Age, years
01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18
1st SEP
2nd SEP
3rd SEP
7.17 8.33 12.00 17.17 11.33 8.08 11.50 7.50 7.10 8.00 9.92 13.42 11.00 13.67 7.42 7.75 14.00 9.08
11.75 9.92
10.5
Seizures
Therapy
Neurological examination
Yes Yes Yes
Carbamazepine
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
Yes Yes 8.50 10.50
9.42
Yes Yes Yes
Carbamazepine Carbamazepine
Yes Yes Yes Yes
Carbamazepine Carbamazepine Carbamazepine
R. Ferri et al. / Clinical Neurophysiology 111 (2000) 591±599
by tapping of the hand were observed also, involving mostly the centrotemporal leads over the contralateral hemisphere and recorded using 19 scalp electrodes placed following the international 10±20 system. In this case, EEG was sampled and digitized by means of the same Neuro Scan system at a rate of 500 or 512 Hz. Each evoked spike was visually detected and marked; then, an average evoked spike signal was computed with a time window of 500 ms (250 ms preceding and 250 ms following the spike peak). 2.4. Data analysis The following SEP components were measured, in patients and controls, for peak latency and amplitude from the preceding peak of opposite polarity: N20 on the parietal channel contralateral to the stimulated side (P3 or P4), N30 on the frontal channel contralateral to the stimulated side (F3 or F4), and N60 on the central (C3 or C4), the parietal (P3 or P4,) and the temporal (T3 or T4) channels contralateral to the stimulated side. For the statistical analysis, for each subject belonging to the control group, the average value of SEPs obtained by right and left stimulation was calculated, in order to obtain a group average value. Differences in wave latency and amplitude between controls and subjects with centrotemporal spikes were evaluated by means of the analysis of variance. Finally, age-related changes in amplitude of the N60 component of SEPs were analyzed both in normal controls and subjects with centrotemporal spikes. 3. Results Six out of the 18 subjects with the typical centrotemporal spikes recorded during sleep were found to present SEPs with abnormally high amplitude to the stimulation of at
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least one median nerve (Fig. 1). The most prominent peak of this type of potential, which will be referred to here as giant, had a latency of approximately 60 ms and involved mostly the central-temporal-parietal areas contralateral to the stimulated side in 3 subjects, and the central region in the other 3. All of these 6 subjects were younger than 12 years of age. We considered these potentials as giant when the amplitude of the peak at around 60 ms was higher than N60 mean amplitude 12.5 standard deviations found in the group of normal controls. Also, in Fig. 1 it can be noted that the two subjects with the smallest main negative component at around 60 ms (traces on the bottom-left and on the top-right corners) show a scalp topography evoking the activity of a radial dipole; on the contrary, the remaining 4 subjects show a scalp topography of this component with a tangential orientation. Table 2 shows the statistical comparison between SEP parameters recorded in normal controls (group A) and in subjects with centrotemporal spikes subdivided into two subgroups, without (group B) and with `giant' SEPs (group C). As expected, signi®cant differences were found between subjects with giant SEPs and the other groups regarding the amplitude of N60. However, subjects with centrotemporal spikes and without giant SEPs also showed N20 latency signi®cantly longer and N30 amplitude signi®cantly higher than normal controls. Figs. 2 and 3 show the age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the parietal and the central areas, respectively. Also average (and mean 12.5 SD) of values found in the normal controls are shown. Moreover, in these ®gures it is possible to see that no subjects with giant SEPs were older than 12 years. In 5 subjects, 4 of whom had giant SEPs, repeated recordings of SEPs were obtained (3 recordings in one subject and two
Fig. 1. Giant SEPs recorded in 6 out of the 18 subjects with the typical centrotemporal spikes recorded during sleep. The maps represent the scalp distribution at peak of the main negative component at around 60 ms.
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Table 2 Statistical comparison between SEP parameters recorded in normal controls (group A) and in subjects with centrotemporal spikes subdivided into two subgroups, without (group B) and with `giant' SEPs (group C) Group A Mean (SD)
Group B Mean (SD)
Group C Mean (SD)
ANOVA P ,
Post-hoc comparison P , A/B
A/C
B/C
N.S.
±
±
±
0.035 N.S.
0.01 ±
N.S. a ±
N.S. ±
N.S. 0.012
± 0.012
± ±
± ±
Age, years
9.1 (3.57)
10.8 (3.30)
9.1 (1.70)
N20 lat. N20 amp.
16.8 (1.14) 2.9 (0.83)
18.6 (1.96) 2.8 (0.87)
17.5 (0.97) 3.6 (0.78)
N30 lat. N30 amp.
32.1 (2.50) 5.7 (2.37)
33.9 (3.20) 10.2 (4.87)
N60c lat. N60c amp.
57.5 (5.28) 6.6 (2.85)
62.5 (6.27) 9.0 (3.67)
60.6 (10.49) 42.6 (31.52)
N.S. 0.00007
± N.S.
± 0.00004
± 0.00007
N60p lat. N60p amp.
58.7 (5.91) 5.1 (2.03)
62.4 (8.04) 6.0 (2.85)
64.7 (6.71) 44.2 (37.51)
N.S. 0.0005
± N.S.
± 0.0005
± 0.0009
N60t lat. N60t amp.
62.1 (8.09) 5.1 (1.77)
62.0 (7.58) 5.9 (2.95)
68.8 (4.84) 45.9 (36.03)
N.S. 0.0009
± N.S.
± 0.00025
± 0.0005
± ±
a
N.S., not signi®cant; lat., latency (in ms); amp., amplitude (in mV); N60c, N60 measured over the central areas (C3/C4); N60p, N60 measured over the parietal areas (P3/P4); N60t, N60 measured over the temporal areas (T3/T4).
recordings in the other 4; see Table 1); these subjects are represented by different symbols (one for each subject) connected by different line types. It is evident an age-related decrease in amplitude of giant SEPs as the above cited limit of 12 years approaches. Fig. 4 shows the morphologic and topographic changes of giant SEPs in one subject with increasing age from 8.33, to 9.92, to 10.58 years. A clear trend towards a greater reduc-
tion in amplitude of SEPs over the temporal and parietal than over the central regions is evident in this age range. Consequently, the topographic distribution of the main negative component of giant SEPs at around 60 ms shows a shift from the temporal and parietal areas to the central regions. Finally, Fig. 5 shows the results of the study of EEG spikes evoked by hand tapping in 3 subjects with centrotemporal spikes and giant SEPs. For each subject, 4 channels are shown (frontal, central, temporal and parietal) contralateral to the stimulated side; both superimposed (left) and averaged (right) epochs are reported with the topographic representation of the negative peak of the spike. A striking similarity was evident between the averaged evoked spikes and the main negative component of giant SEPs recorded in the same subjects both from the morphologic and topographic points of view. It is also possible to note that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5±15 ms. Moreover, this evoked spike is most prominent over the temporal and parietal areas in two subjects and over the central region in the other. 4. Discussion
Fig. 2. Age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the parietal areas. Also average and mean 12.5 SD of values found in the normal controls are shown. Points connected by lines indicate repeated recordings of the same subject; different symbols and line types indicate different subjects.
First of all, the results of our study seem to indicate that the 3 main signs considered, i.e. seizures, sleep-enhanced centrotemporal spikes, and giant SEPs (with or without EEG spikes evoked by hand tapping), can occur in a relatively independent way in these subjects. Probably, the most
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Fig. 3. Age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the central areas. Also average and mean 12.5 SD of values found in the normal controls are shown. Points connected by lines indicate repeated recordings of the same subject; different symbols and line types indicate different subjects.
common sign is the presence of centrotemporal spikes which might be the simplest expression of a genetic entity with a wide clinical variability. De Marco (1980) already reported some children in whom, after the discovery of spikes evoked by tactile stimulation of their feet or hands, a spontaneous focus of spikes during sleep or waking and a later convulsive status could be observed. In our experience, we observed that some children with sleep-enhanced centrotemporal spikes might present some seizures at a later stage. In our group there was no strict correlation between the presence of giant SEPs (or evoked spikes) and seizures; thus, these characteristics should also be considered as independent to some extent. We cannot exclude that even if developmental factors are very important in this clinical condition, and might cause dif®culties in the interpretation of data collected in groups of children with different ages, genetic variability might also be at the basis of the clinical and neurophysiological diversity found. However, the exact genetic condition at the basis of the BECT or the centrotemporal spike trait is not known and is certainly different from that of benign neonatal familial convulsions (Neubauer et al., 1997). On the contrary, linkage analysis ®rst failed to demonstrate a possible linkage of BECT with the fragile X syndrome (Rees et al., 1993) but, subsequently, a molecular genetic study suggested a possible impact of the fragile X gene mutations on brain maturation and epileptogenesis at least in some subjects with BECT (Kluger et al., 1996). More recently, evidence of linkage between BECT and chromosome 15q14 has been found (Neubauer et al., 1998). Our study shows a clear developmental maturation of giant SEPs which tend to decrease in amplitude and to assume different morphological characteristics with age. We have not yet observed subjects older than 12 years with this type
of abnormal SEPs. This phenomenon is parallel to that of the disappearance of seizures observed in most of patients with BECT after this age (Bouma et al., 1997). For this reason, we believe that when present giant SEPs might represent a good tool for quantitatively monitoring the neurophysiological course of this condition and its age-related changes. We also detected signi®cant changes in the topography of giant SEPs in subjects in whom repeated recordings were available (see Fig. 4). In particular, in the ®rst recording giant SEPs showed a characteristic topographic pattern with the main abnormal negativity involving mostly the temporal and parietal areas contralateral to the stimulated side. However, also on the homologous central areas an abnormally high component was detected (Table 2) with a latency slightly shorter than that of the main negative wave on the parietal and temporal regions, respectively. This phenomenon was clearly evident also in the averaged spikes evoked by hand tapping. For this reason, we agree with the idea already expressed by other authors (Manganotti et al., 1998a,b) that giant SEPs are evoked spikes and share common cortical sensorimotor generators with the latter. In subsequent recordings, in the same subjects, giant SEPs tended to show a peculiar behavior with a striking reduction in amplitude more evident on the temporal and parietal regions than on the central areas; over this region we observed a longer persistence of the abnormally high negative peak. As already pointed out in Section 1, the main negative component of giant SEPs showed a scalp topography evoking the activity of a radial dipole, in two subjects; on the contrary, the remaining 4 subjects showed a scalp topography of this component with a tangential orientation. Most likely, the different topographic distribution of giant SEPs shown in Fig. 1, in different patients, re¯ects the different maturational state of each individual patient.
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Fig. 4. Morphologic and topographic changes of giant SEPs recorded in one subject at 8.33, 9.92, and 10.58 years of age. The maps represent the scalp distribution at peak of the main negative component at around 60 ms.
The signi®cantly but less impressive increase in the frontal N30 component found in our subjects with centrotemporal spikes without giant SEPs (Table 2), as compared with normal controls, might be interpreted as a minor sign of disturbed excitability/inhibition at the level of the frontal areas in these subjects. However, the subtle but signi®cant increase in N20 latency found in the same subjects should be correlated with their slightly older age, as compared with the control group (Table 2); this might have been accompanied by a slightly but signi®cantly taller stature.
The differential maturation of regional giant SEPs, together with the time lag observed between the giant negative component of SEPs recorded over the parietal and temporal regions, seems to indicate that a complex mechanism is active in the generation of this type of evoked potentials which might be dif®cult to explain by means of a single or very limited number of equivalent dipoles, as it has been already attempted (Minami et al., 1996; Rubboli et al., 1996; Manganotti et al., 1998b). It should be mentioned, at this point, that despite the fact that in the past some authors have tried to explain early components of SEPs by means of few generators located around the central sulcus (Allison et al., 1989a,b), a different view was also proposed stressing the activation of multiple early SEP generators within the pre- and postrolandic areas (Desmedt and Cheron, 1980, 1981; Kimura and Yamada, 1982; LuÈders et al., 1983; MauguieÁre et al., 1983; Desmedt et al., 1987; Tsuji et al., 1988; Hashimoto et al., 1990; Urbano et al., 1997). The multiple generator hypothesis received supportive evidence by the demonstration of dissociation of pre- and postcentral effects following focal damage (MauguieÁre and Desmedt, 1991; Sonoo et al., 1991; Furlong et al., 1993; GuÈtling et al., 1993). Our data support the idea that different dipoles might be most active at different maturational stages, maybe as an effect of development of brain physiology and/or anatomy, an early one with a tangential orientation which is replaced later by another with a radial orientation, giving rise to a scalp topographic distribution similar to that of the normal N60 component of SEPs (see Fig. 4). Only few studies have been carried out in order to explain the generators of late SEP components such as N60, the normal component observed at the same latency of the abnormal giant negative peak reported in this study. Allison et al. (1992) reported that N60 seems to be generated mostly by the parietal area 1; in the monkey, late cortical SEP components seem to re¯ect the composite of activity distributed across multiple cortical laminae and the interaction of overlapping excitatory an inhibitory events (Peterson et al., 1995). Our results seem to indicate that the early giant negative component of SEPs recorded in subjects with centrotemporal spikes is different from the normal N60 because of its topography and developmental behavior; however, these two different components might share some common generator mechanisms with abnormal excitatory/inhibitory features in the case of giant SEPs. Finally, as stated above, we have also observed a differential developmental effect on SEPs recorded from different areas in our subjects with centrotemporal spikes, with a reduction in amplitude of giant SEPs occurring over the temporal and parietal regions ®rst, followed by a decrease in amplitude over the central areas. This phenomenon parallels the disappearance of seizures in BECT (Bouma et al., 1997) and, even if observed at a different age, carries some resemblance with the already well known posteroanterior migration of epileptic foci in childhood (Gibbs and Gibbs,
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Fig. 5. EEG spikes evoked by hand tapping in 3 subjects with centrotemporal spikes and giant SEPs. For each subject, 4 channels are shown (frontal, central, temporal, and parietal) contralateral to the stimulated side; both superimposed (top) and averaged (bottom) epochs are reported with the topographic representation of the negative peak of the spike. The maps represent, for each subject, the scalp distribution at peak of the evoked spike (SPIKE) and of the main negative SEP component at around 60 ms (SEP).
1954). Similarly, also spectral EEG band power shows maturational changes from posterior to anterior regions (Gasser et al., 1988). In conclusion, our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related changes which can be interpreted
in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present. Acknowledgements We would like to thank Mrs. Neusa da Guia, Mrs.
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GuÈtling E, Gonser A, Regard M, Glinz W, Landis T. Dissociation of frontal and parietal components of somatosensory evoked potentials in severe head injury. Electroenceph clin Neurophysiol 1993;88:369±376. Hashimoto S, Segawa Y, Kawamura J, Harada Y, Yamamoto T, Suenaga T, Shigematu K, Iwami O, Nakamura M. Volume conduction of the parietal N20 potential to the prerolandic frontal area. Brain 1990;113:1501± 1509. Heijbel J, Blom S, Rasmuson M. Benign epilepsy of childhood with centrotemporal EEG foci: a genetic study. Epilepsia 1975;16:285±293. Kimura J, Yamada T. Short-latency somatosensory evoked potentials following median nerve stimulation. Ann N Y Acad Sci 1982;388: 689±694. Kluger G, BoÈhm I, Laub MC, Waldenmaier C. Epilepsy and fragile X gene mutations. Pediatr Neurol 1996;15:358±360. LuÈders H, Lesser RP, Hahn J, Dinner DS, Klem G. Cortical somatosensory evoked potentials in response to hand stimulation. J Neurosurg 1983;58:885±894. Manganotti P, Miniussi C, Santorum E, Tinazzi M, Bonato C, Marzi CA, Fiaschi A, Dalla Bernardina B, Zanette G. In¯uence of somtosensory input on paroxysmal activity in benign rolandic epilepsy with `extreme somatosensory evoked potentials'. Brain 1998a;121:647±658. Manganotti P, Miniussi C, Santorum E, Tinazzi M, Bonato C, Polo A, Marzi CA, Fiaschi A, Dalla Bernardina B, Zanette G. Scalp topography and source analysis of interictal spontaneous spikes and evoked spikes by digital stimulation in benign rolandic epilepsy. Electroenceph clin Neurophysiol 1998b;107:18±26. MauguieÁre F, Desmedt JE. Focal capsular lesions can selectively deafferent the prerolandic or the parietal cortex: somatosensory evoked potentials evidence. Ann Neurol 1991;30:71±75. MauguieÁre F, Desmedt JE, Courjon J. Astereognosis and dissociated loss of frontal or parietal components of somatosensory evoked potentials in hemispheric lesions. Brain 1983;106:271±311. Micheloyannis J, Samara C, Liakakos T. Giant somatosensory evoked potentials in children without myoclonic epilepsy. Acta Neurol Scand 1989;79:146±149. Minami T, Gondo K, Yamamoto T, Yanai S, Tasaki K, Ueda K. Magnetoencephalographic analysis of rolandic discharges in benign childhood epilepsy. Ann Neurol 1996;39:326±334. Nayrac P, Beaussart M. Les pointe-ondes preÂrolandiques: expression EEG treÂs particulieÁre. Etude eÂlectroclinique de 21 cas. Rev Neurol (Paris) 1958;99:201±206. Neubauer BA, Moises HW, LaÈssker U, Waltz S, Diebold U, Stephani U. Benign childhood epilepsy with centrotemporal spikes and electroencephalography trait are not linked to EBN1 and EBN2 of benign neonatal familial convulsions. Epilepsia 1997;38:782±787. Neubauer BA, Fiedler B, Himmelein B, KaÈmpfer F, LaÈssker U, Schwabe G, Spanier I, Tams D, Bretscher C, Moldenhauer K, Kurlemann G, Weise S, Tedroff K, Eeg-Olofsson O, Wadelius C, Stephani U. Centrotemporal spikes in families with rolandic epilepsy. Linkage to chromosome 15q14. Neurology 1998;51:1608±1612. Peterson NN, Schroeder CE, Arezzo JC. Neural generators of early somatosensory evoked potentials in the awake monkey. Electroenceph clin Neurophysiol 1995;96:248±260. Plasmati R, Borghi AM, Lucchi D, Rubboli G, Tassinari CA. Somatosensory evoked potentials in patients with benign epilepsy with rolandic spikes. Epilepsia 1996;37(Suppl. 5):88. Rees M, Diebold U, Parker K, Doose H, Gardiner RM, Whitehouse WP. Benign childhood epilepsy with centrotemporal spikes and the focal wave trait is not linked to the fragile X region. Neuropediatrics 1993;24:211±213. Rubboli G, Plasmati R, Parmeggiani L, Meletti S, Gardella E, Borghi AM, Tassinari CA. Source modelling of spontaneous and `hand tapping' evoked spikes in epilepsy with extreme somatosensory evoked potentials. Epilepsia 1996;37(Suppl. 5):55. Sonoo M, Shimpo T, Takeda K, Genba K, Nakano I, Mannen T. SEPs in two patients with localized lesions of the postcentral gyrus. Electroenceph clin Neurophysiol 1991;80:536±546.
R. Ferri et al. / Clinical Neurophysiology 111 (2000) 591±599 Tassinari CA, De Marco P, Plasmati R, Pantieri R, Blanco M, Michelucci R. Extreme somatosensory evoked potentials (ESEPs) elicited by tapping of hands or feet in children: a somatosensory cerebral evoked potentials study. Neurophysiol Clin 1988;18:123±128. Tsuji S, Murai Y, Hashimoto M. Frontal distribution of early cortical
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Age-related changes of cortical excitability in subjects with sleepenhanced centrotemporal spikes: a somatosensory evoked potential study Raffaele Ferri*, Stefano Del Gracco, Maurizio Elia, Sebastiano A. Musumeci Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging, Via Conte Ruggero 73, 94018 Troina, Italy Accepted 14 September 1999
Abstract Middle-latency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) have been reported in subjects with benign childhood epilepsy with centrotemporal spikes (BECT) and in normal children, which usually show signi®cant age-related changes. However, the mechanisms by which age modi®es the appearance of centrotemporal spikes and giant SEPs in these children, are not known. The characteristics of SEPs were studied in a group of 18 subjects (10 males and 8 females, aged 7.1±17.2 years) with sleepenhanced centrotemporal spikes, with or without BECT and the results were compared with those obtained from a group of age-matched normal controls. Giant SEPs were recorded in 6 subjects and, in 3 of these, EEG spikes evoked by hand tapping were obtained also. No subjects with giant SEPs were found in subjects older than 12 years, and an age-related decrease in amplitude of giant SEPs as this age approached was observed. Moreover, at repeated SEP recordings, a clear trend towards a more important reduction in amplitude of giant SEPs over the temporal and parietal than over the central regions was evident. The study of EEG spikes evoked by hand tapping showed a striking similarity between the averaged evoked spikes and the main negative component of giant SEPs. It was also possible to observe that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5±15 ms. Our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related modi®cations which can be interpreted in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Somatosensory evoked potentials; Benign childhood epilepsy with centrotemporal spikes; Tactile evoked spikes; Giant somatosensory evoked potentials; Central nervous system excitability; Epilepsy
1. Introduction The benign childhood epilepsy with centrotemporal spikes (BECT), also called rolandic spike epilepsy, is an idiopathic localization-related epilepsy with distinct sleepenhanced interictal EEG paroxysmal activity, age-related onset and benign course (Commission on Classi®cation and Terminology of the ILAE, 1989). BECT was ®rst described by Nayrac and Beaussart (1958) and is considered to be the most frequent form of epilepsy among children (Blom et al., 1972; Cavazzuti, 1980). Seizures can be very infrequent in this kind of epilepsy and exclusively nocturnal; an isolated event is observed in approximately 15% of patients whereas most subjects (approx. 62%), show only 2± 5 seizures (Bouma et al., 1997). * Corresponding author. Tel.: 139-0935-936111; fax: 139-0935653327. E-mail address: [email protected] (R. Ferri)
Centrotemporal (or rolandic) spikes are an autosomal dominant age-dependent genetic trait. They are found in 34% of siblings of patients with BECT but only 15% of these also develop seizures (Bray and Wiser, 1965; Heijbel et al., 1975). Moreover, 1±2% of children aged 5±12 years who are not affected by seizures, also show centrotemporal spikes in routine EEG recordings (Cavazzuti et al., 1980). For these reasons, it might be concluded that BECT represents a particular aspect of a wide-spectrum condition, the mildest form of which might only be characterized by the presence of centrotemporal spikes, without any other clinical sign. After the discovery of high-amplitude parietal spikes evoked by tactile stimulation (tapping) of the hand or foot in some nonepileptic subjects and BECT patients (De Marco and Negrin, 1973; De Marco and Tassinari, 1981), middlelatency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) were recorded in some of these
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subjects after stimulation of the median nerve (Tassinari et al., 1988; Plasmati et al., 1996). Similarly to centrotemporal spikes, also giant SEPs can be found in nonepileptic children (Micheloyannis et al., 1989). Middle-latency SEPs elicited by the stimulation of the median nerve originate from the sequential activation of different parietal and frontal generators (Desmedt and Bourguet, 1985; Desmedt et al., 1987; Allison et al., 1992; Urbano et al., 1997) and represent a useful tool for studying changes in cortical excitability over the same areas. The mechanisms by which age modi®es the appearance of centrotemporal spikes and giant SEPs, in these children are not known. In particular, there are no data regarding agerelated morphology and scalp topography changes of SEPs in subjects with centrotemporal spikes. Therefore it was decided to study the characteristics of these potentials in a group of young subjects with sleep-enhanced centrotemporal spikes, with or without BECT and to consider their age-related changes in amplitude and scalp distribution, with a view to determining the possible mechanisms involved.
2. Subjects and methods 2.1. Subjects with sleep-enhanced centrotemporal spikes Eighteen subjects (10 males and 8 females; age range 7.1±17.2 years) with typical centrotemporal spikes recorded during sleep, from independent bilateral foci, were included in this study. Twelve of these subjects (6 males and 6 females) were affected by BECT and had shown few typical seizures in form of brief hemifacial
attacks and some generalized convulsions, often during sleep; none of them presented symptomatic rolandic epilepsy. Six were taking antiepileptic drug therapy with carbamazepine. The ages at SEP recording and clinical characteristics of subjects with centrotemporal spikes are shown in Table 1. 2.2. Control subjects Eleven normal subjects (7 males and 4 females) were used as a control group; mean age was 9.10 years (range 4.75±16.58 years). Sleep EEG was recorded during afternoon, covering at least one sleep cycle, in all these subjects in order to exclude the possibility of the presence of centrotemporal spikes. 2.3. SEP recording SEPs were recorded from 19 scalp electrodes (10±20 system) and the ear ipsilateral to the stimulated side was used as reference. An analysis time of 150 or 205 ms was used and 128 single responses were averaged, twice, for each median nerve, separately. Signals were bandpass ®ltered at 1±300 Hz and sampled in order to obtain 512 data points for each epoch. Stimuli were delivered by a Grass S10DSCM somatosensory stimulator with an interstimulus interval of 2000 ms, through silver±silver chloride electrodes applied at a distance of 3 cm from each other, over the median nerve at wrist, with the positive electrode placed distally. Stimuli were positive square waves of 0.1 ms of duration and with an intensity individually adjusted at about 10% over the motor threshold. A Neuro Scan system was utilized for data acquisition and analysis. In 3 subjects with centrotemporal spikes, spikes evoked
Table 1 Age at SEP recording and clinical characteristics of subjects with centrotemporal spikes Age, years
01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18
1st SEP
2nd SEP
3rd SEP
7.17 8.33 12.00 17.17 11.33 8.08 11.50 7.50 7.10 8.00 9.92 13.42 11.00 13.67 7.42 7.75 14.00 9.08
11.75 9.92
10.5
Seizures
Therapy
Neurological examination
Yes Yes Yes
Carbamazepine
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
Yes Yes 8.50 10.50
9.42
Yes Yes Yes
Carbamazepine Carbamazepine
Yes Yes Yes Yes
Carbamazepine Carbamazepine Carbamazepine
R. Ferri et al. / Clinical Neurophysiology 111 (2000) 591±599
by tapping of the hand were observed also, involving mostly the centrotemporal leads over the contralateral hemisphere and recorded using 19 scalp electrodes placed following the international 10±20 system. In this case, EEG was sampled and digitized by means of the same Neuro Scan system at a rate of 500 or 512 Hz. Each evoked spike was visually detected and marked; then, an average evoked spike signal was computed with a time window of 500 ms (250 ms preceding and 250 ms following the spike peak). 2.4. Data analysis The following SEP components were measured, in patients and controls, for peak latency and amplitude from the preceding peak of opposite polarity: N20 on the parietal channel contralateral to the stimulated side (P3 or P4), N30 on the frontal channel contralateral to the stimulated side (F3 or F4), and N60 on the central (C3 or C4), the parietal (P3 or P4,) and the temporal (T3 or T4) channels contralateral to the stimulated side. For the statistical analysis, for each subject belonging to the control group, the average value of SEPs obtained by right and left stimulation was calculated, in order to obtain a group average value. Differences in wave latency and amplitude between controls and subjects with centrotemporal spikes were evaluated by means of the analysis of variance. Finally, age-related changes in amplitude of the N60 component of SEPs were analyzed both in normal controls and subjects with centrotemporal spikes. 3. Results Six out of the 18 subjects with the typical centrotemporal spikes recorded during sleep were found to present SEPs with abnormally high amplitude to the stimulation of at
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least one median nerve (Fig. 1). The most prominent peak of this type of potential, which will be referred to here as giant, had a latency of approximately 60 ms and involved mostly the central-temporal-parietal areas contralateral to the stimulated side in 3 subjects, and the central region in the other 3. All of these 6 subjects were younger than 12 years of age. We considered these potentials as giant when the amplitude of the peak at around 60 ms was higher than N60 mean amplitude 12.5 standard deviations found in the group of normal controls. Also, in Fig. 1 it can be noted that the two subjects with the smallest main negative component at around 60 ms (traces on the bottom-left and on the top-right corners) show a scalp topography evoking the activity of a radial dipole; on the contrary, the remaining 4 subjects show a scalp topography of this component with a tangential orientation. Table 2 shows the statistical comparison between SEP parameters recorded in normal controls (group A) and in subjects with centrotemporal spikes subdivided into two subgroups, without (group B) and with `giant' SEPs (group C). As expected, signi®cant differences were found between subjects with giant SEPs and the other groups regarding the amplitude of N60. However, subjects with centrotemporal spikes and without giant SEPs also showed N20 latency signi®cantly longer and N30 amplitude signi®cantly higher than normal controls. Figs. 2 and 3 show the age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the parietal and the central areas, respectively. Also average (and mean 12.5 SD) of values found in the normal controls are shown. Moreover, in these ®gures it is possible to see that no subjects with giant SEPs were older than 12 years. In 5 subjects, 4 of whom had giant SEPs, repeated recordings of SEPs were obtained (3 recordings in one subject and two
Fig. 1. Giant SEPs recorded in 6 out of the 18 subjects with the typical centrotemporal spikes recorded during sleep. The maps represent the scalp distribution at peak of the main negative component at around 60 ms.
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Table 2 Statistical comparison between SEP parameters recorded in normal controls (group A) and in subjects with centrotemporal spikes subdivided into two subgroups, without (group B) and with `giant' SEPs (group C) Group A Mean (SD)
Group B Mean (SD)
Group C Mean (SD)
ANOVA P ,
Post-hoc comparison P , A/B
A/C
B/C
N.S.
±
±
±
0.035 N.S.
0.01 ±
N.S. a ±
N.S. ±
N.S. 0.012
± 0.012
± ±
± ±
Age, years
9.1 (3.57)
10.8 (3.30)
9.1 (1.70)
N20 lat. N20 amp.
16.8 (1.14) 2.9 (0.83)
18.6 (1.96) 2.8 (0.87)
17.5 (0.97) 3.6 (0.78)
N30 lat. N30 amp.
32.1 (2.50) 5.7 (2.37)
33.9 (3.20) 10.2 (4.87)
N60c lat. N60c amp.
57.5 (5.28) 6.6 (2.85)
62.5 (6.27) 9.0 (3.67)
60.6 (10.49) 42.6 (31.52)
N.S. 0.00007
± N.S.
± 0.00004
± 0.00007
N60p lat. N60p amp.
58.7 (5.91) 5.1 (2.03)
62.4 (8.04) 6.0 (2.85)
64.7 (6.71) 44.2 (37.51)
N.S. 0.0005
± N.S.
± 0.0005
± 0.0009
N60t lat. N60t amp.
62.1 (8.09) 5.1 (1.77)
62.0 (7.58) 5.9 (2.95)
68.8 (4.84) 45.9 (36.03)
N.S. 0.0009
± N.S.
± 0.00025
± 0.0005
± ±
a
N.S., not signi®cant; lat., latency (in ms); amp., amplitude (in mV); N60c, N60 measured over the central areas (C3/C4); N60p, N60 measured over the parietal areas (P3/P4); N60t, N60 measured over the temporal areas (T3/T4).
recordings in the other 4; see Table 1); these subjects are represented by different symbols (one for each subject) connected by different line types. It is evident an age-related decrease in amplitude of giant SEPs as the above cited limit of 12 years approaches. Fig. 4 shows the morphologic and topographic changes of giant SEPs in one subject with increasing age from 8.33, to 9.92, to 10.58 years. A clear trend towards a greater reduc-
tion in amplitude of SEPs over the temporal and parietal than over the central regions is evident in this age range. Consequently, the topographic distribution of the main negative component of giant SEPs at around 60 ms shows a shift from the temporal and parietal areas to the central regions. Finally, Fig. 5 shows the results of the study of EEG spikes evoked by hand tapping in 3 subjects with centrotemporal spikes and giant SEPs. For each subject, 4 channels are shown (frontal, central, temporal and parietal) contralateral to the stimulated side; both superimposed (left) and averaged (right) epochs are reported with the topographic representation of the negative peak of the spike. A striking similarity was evident between the averaged evoked spikes and the main negative component of giant SEPs recorded in the same subjects both from the morphologic and topographic points of view. It is also possible to note that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5±15 ms. Moreover, this evoked spike is most prominent over the temporal and parietal areas in two subjects and over the central region in the other. 4. Discussion
Fig. 2. Age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the parietal areas. Also average and mean 12.5 SD of values found in the normal controls are shown. Points connected by lines indicate repeated recordings of the same subject; different symbols and line types indicate different subjects.
First of all, the results of our study seem to indicate that the 3 main signs considered, i.e. seizures, sleep-enhanced centrotemporal spikes, and giant SEPs (with or without EEG spikes evoked by hand tapping), can occur in a relatively independent way in these subjects. Probably, the most
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Fig. 3. Age-related changes of SEP amplitudes (N60) found in the whole group of subjects with centrotemporal spikes, measured over the central areas. Also average and mean 12.5 SD of values found in the normal controls are shown. Points connected by lines indicate repeated recordings of the same subject; different symbols and line types indicate different subjects.
common sign is the presence of centrotemporal spikes which might be the simplest expression of a genetic entity with a wide clinical variability. De Marco (1980) already reported some children in whom, after the discovery of spikes evoked by tactile stimulation of their feet or hands, a spontaneous focus of spikes during sleep or waking and a later convulsive status could be observed. In our experience, we observed that some children with sleep-enhanced centrotemporal spikes might present some seizures at a later stage. In our group there was no strict correlation between the presence of giant SEPs (or evoked spikes) and seizures; thus, these characteristics should also be considered as independent to some extent. We cannot exclude that even if developmental factors are very important in this clinical condition, and might cause dif®culties in the interpretation of data collected in groups of children with different ages, genetic variability might also be at the basis of the clinical and neurophysiological diversity found. However, the exact genetic condition at the basis of the BECT or the centrotemporal spike trait is not known and is certainly different from that of benign neonatal familial convulsions (Neubauer et al., 1997). On the contrary, linkage analysis ®rst failed to demonstrate a possible linkage of BECT with the fragile X syndrome (Rees et al., 1993) but, subsequently, a molecular genetic study suggested a possible impact of the fragile X gene mutations on brain maturation and epileptogenesis at least in some subjects with BECT (Kluger et al., 1996). More recently, evidence of linkage between BECT and chromosome 15q14 has been found (Neubauer et al., 1998). Our study shows a clear developmental maturation of giant SEPs which tend to decrease in amplitude and to assume different morphological characteristics with age. We have not yet observed subjects older than 12 years with this type
of abnormal SEPs. This phenomenon is parallel to that of the disappearance of seizures observed in most of patients with BECT after this age (Bouma et al., 1997). For this reason, we believe that when present giant SEPs might represent a good tool for quantitatively monitoring the neurophysiological course of this condition and its age-related changes. We also detected signi®cant changes in the topography of giant SEPs in subjects in whom repeated recordings were available (see Fig. 4). In particular, in the ®rst recording giant SEPs showed a characteristic topographic pattern with the main abnormal negativity involving mostly the temporal and parietal areas contralateral to the stimulated side. However, also on the homologous central areas an abnormally high component was detected (Table 2) with a latency slightly shorter than that of the main negative wave on the parietal and temporal regions, respectively. This phenomenon was clearly evident also in the averaged spikes evoked by hand tapping. For this reason, we agree with the idea already expressed by other authors (Manganotti et al., 1998a,b) that giant SEPs are evoked spikes and share common cortical sensorimotor generators with the latter. In subsequent recordings, in the same subjects, giant SEPs tended to show a peculiar behavior with a striking reduction in amplitude more evident on the temporal and parietal regions than on the central areas; over this region we observed a longer persistence of the abnormally high negative peak. As already pointed out in Section 1, the main negative component of giant SEPs showed a scalp topography evoking the activity of a radial dipole, in two subjects; on the contrary, the remaining 4 subjects showed a scalp topography of this component with a tangential orientation. Most likely, the different topographic distribution of giant SEPs shown in Fig. 1, in different patients, re¯ects the different maturational state of each individual patient.
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Fig. 4. Morphologic and topographic changes of giant SEPs recorded in one subject at 8.33, 9.92, and 10.58 years of age. The maps represent the scalp distribution at peak of the main negative component at around 60 ms.
The signi®cantly but less impressive increase in the frontal N30 component found in our subjects with centrotemporal spikes without giant SEPs (Table 2), as compared with normal controls, might be interpreted as a minor sign of disturbed excitability/inhibition at the level of the frontal areas in these subjects. However, the subtle but signi®cant increase in N20 latency found in the same subjects should be correlated with their slightly older age, as compared with the control group (Table 2); this might have been accompanied by a slightly but signi®cantly taller stature.
The differential maturation of regional giant SEPs, together with the time lag observed between the giant negative component of SEPs recorded over the parietal and temporal regions, seems to indicate that a complex mechanism is active in the generation of this type of evoked potentials which might be dif®cult to explain by means of a single or very limited number of equivalent dipoles, as it has been already attempted (Minami et al., 1996; Rubboli et al., 1996; Manganotti et al., 1998b). It should be mentioned, at this point, that despite the fact that in the past some authors have tried to explain early components of SEPs by means of few generators located around the central sulcus (Allison et al., 1989a,b), a different view was also proposed stressing the activation of multiple early SEP generators within the pre- and postrolandic areas (Desmedt and Cheron, 1980, 1981; Kimura and Yamada, 1982; LuÈders et al., 1983; MauguieÁre et al., 1983; Desmedt et al., 1987; Tsuji et al., 1988; Hashimoto et al., 1990; Urbano et al., 1997). The multiple generator hypothesis received supportive evidence by the demonstration of dissociation of pre- and postcentral effects following focal damage (MauguieÁre and Desmedt, 1991; Sonoo et al., 1991; Furlong et al., 1993; GuÈtling et al., 1993). Our data support the idea that different dipoles might be most active at different maturational stages, maybe as an effect of development of brain physiology and/or anatomy, an early one with a tangential orientation which is replaced later by another with a radial orientation, giving rise to a scalp topographic distribution similar to that of the normal N60 component of SEPs (see Fig. 4). Only few studies have been carried out in order to explain the generators of late SEP components such as N60, the normal component observed at the same latency of the abnormal giant negative peak reported in this study. Allison et al. (1992) reported that N60 seems to be generated mostly by the parietal area 1; in the monkey, late cortical SEP components seem to re¯ect the composite of activity distributed across multiple cortical laminae and the interaction of overlapping excitatory an inhibitory events (Peterson et al., 1995). Our results seem to indicate that the early giant negative component of SEPs recorded in subjects with centrotemporal spikes is different from the normal N60 because of its topography and developmental behavior; however, these two different components might share some common generator mechanisms with abnormal excitatory/inhibitory features in the case of giant SEPs. Finally, as stated above, we have also observed a differential developmental effect on SEPs recorded from different areas in our subjects with centrotemporal spikes, with a reduction in amplitude of giant SEPs occurring over the temporal and parietal regions ®rst, followed by a decrease in amplitude over the central areas. This phenomenon parallels the disappearance of seizures in BECT (Bouma et al., 1997) and, even if observed at a different age, carries some resemblance with the already well known posteroanterior migration of epileptic foci in childhood (Gibbs and Gibbs,
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Fig. 5. EEG spikes evoked by hand tapping in 3 subjects with centrotemporal spikes and giant SEPs. For each subject, 4 channels are shown (frontal, central, temporal, and parietal) contralateral to the stimulated side; both superimposed (top) and averaged (bottom) epochs are reported with the topographic representation of the negative peak of the spike. The maps represent, for each subject, the scalp distribution at peak of the evoked spike (SPIKE) and of the main negative SEP component at around 60 ms (SEP).
1954). Similarly, also spectral EEG band power shows maturational changes from posterior to anterior regions (Gasser et al., 1988). In conclusion, our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related changes which can be interpreted
in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present. Acknowledgements We would like to thank Mrs. Neusa da Guia, Mrs.
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