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Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy
Epilepsy Research 58 (2004) 43–52
Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy Fabio Placidi a,b,∗ , Mario Tombini a,b , Andrea Romigi a,b , Luigi Bianchi a,b , Francesca Izzi a , Francesca Sperli a , Donatella Mattia b , Angela Cervellino a , Maria Grazia Marciani a,b a
Neurofisiopatologia, Università di Roma Tor Vergata, V.le Oxford 81, Rome 00133, Italy b Fondazione Santa Lucia, IRCCS, Rome, Italy
Received 31 July 2003; received in revised form 1 December 2003; accepted 26 December 2003
Abstract Purpose: To evaluate the effects of topiramate (TPM) on interictal epileptiform abnormalities (IEA) and background activity by means of a computerized EEG analysis, in adult patients affected by focal epilepsy, with or without secondarily generalization, treated with TPM as adjunctive therapy or monotherapy. Methods: Twenty-four patients affected by symptomatic or cryptogenic focal epilepsy underwent long-term video-EEG recording before and after TPM addition (mean dose 175 ± 25 mg per day). Results: TPM addition induced a significant reduction of both partial and secondarily generalized tonic-clonic (SGTC) seizures; treatment responder patients (seizure reduction ≥ 50%) were 19 out of 24 patients (79.1%), of whom 5 were seizure-free. Quantitative analysis of IEA showed a significant decrease in the mean number of spikes/10 min during TPM therapy (4.2 ± 4.2 versus 2.2 ± 4.4; P < 0.003). The analysis of spatial distribution of interictal spikes showed that such reduction was more evident at the level of the epileptogenic area rather than on the spreading component. Statistical analysis revealed only a significant decrease of mean relative power of alpha band in the EEG spectral content, recorded at rest in a group of 18 out of 24 epileptic patients during TPM therapy. In addition, during TPM treatment we observed a significant reduction in alpha reactivity without any important changes of alpha indexes (peak frequency and median frequency). Conclusion: These findings suggest that TPM has a strong inhibitory effect on IEA, probably acting on the generating processes, and, if used at low dosage and gradually titrated, seems to have only mild interferences with EEG background activity. © 2004 Elsevier B.V. All rights reserved. Keywords: EEG; Topiramate; Focal epilepsy; Interictal epileptiform abnormalities (IEA); Background activity
1. Introduction
∗ Corresponding author. Tel.: +39-06-20902107; fax: +39-06-20902106. E-mail address: [email protected] (F. Placidi).
Topiramate (TPM) (2,3,4,5-bis-O-(1-methylethylidene)-beta-d-fructopyranose) is a novel antiepileptic drug (AED), effective in a wide variety of seizures types (Marson et al., 1997). Preclinical data and findings from clinical trials suggest that the broad spec-
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trum of TPM activity could be explained by its pharmacological mechanisms, that combine properties of AEDs regulating ion channels and of AEDs acting on neurotransmitters (Coulter et al., 1993, 1995; Sombati et al., 1995; White et al., 1995; Zhang et al., 2000; Shank et al., 1991). Data from animal models suggest that TPM may be effective against both partial and generalized seizures (White, 1997), and several clinical trials have demonstrated efficacy of TPM in the treatment of refractory partial-onset seizures, with or without secondarily generalization, and in refractory primary generalized tonic-clonic seizures (Faught, 1997; Ben-Menackem, 1997; Biton, 1997; Biton et al., 1999; Montouris et al., 2000). In the majority of studies TPM has been used adjunctively with existing treatments, but recently there are some evidences of the its efficacy also as monotherapy (Sachdeo et al., 1997; Rosenfeld et al., 1997; Gilliam et al., 2003). Nevertheless the studies on the effect of TPM on the EEG are few (Neufeld et al., 1999; Mecarelli et al., 2001). Particularly, in these papers TPM therapy has been reported to induce an increase in the delta and theta activities and a decrease in the fast frequency bands. The aim of our study was to evaluate by means of a computerized EEG analysis the effects of TPM on interictal epileptiform abnormalities (IEA) and background activity recorded in adult patients with focal epilepsy, treated with TPM as add-on or monotherapy; relationship between neurophysiological findings and drug clinical profile was also addressed.
2. Methods
tients were on single or multiple-drug therapy before starting TPM, three patients were newly diagnosed as having epilepsy and started taking TPM as monotherapy. In all patients, TPM was titrated from an initial dose of 25 mg/die, with weekly or biweekly dose increments of 25 mg/die to reach a mean effective maintenance dose (175 ± 25 mg/die). Exclusion criteria were: organic or psychiatric disorders, use of drugs interfering with the nervous system other than AEDs. It was required that seizures should be recognizable by the patients or their relatives and that seizure frequency was assessed by a seizure diary. Two patients dropped out after about 1 month because of the appearance of adverse effects consisting of anxiety and nervousness. Clinical features of the patients who completed the study protocol are summarized in Table 1. All patients underwent a long-term video-EEG monitoring session before and 4 months after the addition of TPM therapy. Neurological evaluation and blood chemical studies, including AED plasma levels, were monitored before each recording. The mean number of seizures during TPM treatment was compared with that during 3 months prior to the addition of TPM, or to starting therapy. Analysis was performed by means of a one-way ANOVA; a P value <0.05 was considered as significant. Changes of seizures frequency, observed during TPM treatment, were classified as: (a) improved (reduction ≥ 50%); (b) seizure free; (c) not significantly changed (reduction < 50%); (d) worsened (increased number of seizures); for instance, the reduction in seizure occurrence has been considered significant when ≥50%.
2.1. Patients 2.2. EEG procedures Twenty-six patients affected by focal epilepsy (6 males and 20 females; age range 17–61 years, mean age 40 ± 13 years) were studied after giving their informed consent. The study protocol was approved by Ethics Committee of the University of Rome “Tor Vergata”. On the basis of neuroimaging data (CT scan and/or MRI), clinical and EEG features, 10 patients were diagnosed as having symptomatic partial epilepsy and the remaining 16 as having cryptogenic partial epilepsy. Epilepsy onset was between 2 and 57 years (mean age 22 ± 17 years). Twenty-three pa-
The EEG recordings were performed through a 32-channel cable video-telemetry system. The EEG signal was transmitted from the patient’s room to the laboratory, where it was collected and simultaneously stored on hard disk and on magnetic tape. Recordings were carried out utilizing a common average reference and a time constant of 0.1 s. During recordings, scalp electrodes were placed according to the 10–20 International System. Specifically, montage consisted of 16 referential EEG channels, with the possibility of
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Table 1 Clinical features of patients Patient
Age (years)/Gender
Epilepsy onset (years)
Seizure type
Epilepsy aetiology
AEDs at entry
1 2 3 4 5 6 7 8 8 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
38/F 17/M 40/F 29/F 28/F 38/F 19/F 53/F 56/F 47/F 61/F 57/M 33/F 57/M 52/F 39/F 39/M 41/F 52/F 54/F 24/F 40/F 24/F 20/F
33 12 6 8 25 18 18 8 54 5 57 36 6 53 37 11 13 4 25 34 2 36 6 14
SPS, SG SPS, CPS SPS → SG SPS → SG SG CPS → SG CPS CPS → SG CPS → SG CPS, SG CPS CPS CPS CPS → SG CPS SPS, CPS, SG SPS, CPS CPS → SG CPS → SG CPS → SG CPS → SG SG CPS, SG CPS → SG
CFE SFE CFE CFE CFE CFE CFE SFE CFE CFE CFE SFE CFE CFE CFE CFE SFE SFE SFE SFE SFE CFE SFE CFE
GBP, PB CBZ CBZ, GBP, PB CBZ,LTG,CLB,LEV,PB – CBZ OXC GVG, PHT, PB – CBZ CBZ CBZ, PB PB – CBZ, GBP CBZ CBZ, PB CBZ,VPA, PB CBZ, GBP CBZ, PB CBZ,CLB,VPA CBZ VPA, GVG, CLB CBZ, LTG
CPS: complex partial seizures; seizures; SPS: simple partial seizures; seizures; SG: secondarily generalization; SFE: symptomatic focal epilepsy; CFE: cryptogenetic focal epilepsy. CBZ: carbamazepine; PB: phenobarbital; GBP: gabapentin; LTG: lamotrigine; GVG: vigabatrin; OXC: oxcarbazepine; PHT: phenitoine; VPA: valproic acid; CLB: clobazam; LEV: levetiracetam.
different bipolar reconstructions; additional electrodes were utilized to monitor eyes movements, EMG activity and ECG signal and to better recognize artifacts. Interictal epileptiform abnormalities (IEA) were continuously analyzed and calculated by means of a specific computer program (Stellate Harmonie System 5.0) for automatic recognition of events like spikes and/or sharp waves. Seizures were recorded by an automatic recognition program or by means of a push-button activated by the patient himself or by an observer. The automatic recognition of IEA allowed the quantification of such events, providing data on temporal and spatial distribution for the entire duration of the monitoring. All detected paroxysmal events were visually evaluated and edited for false detections. The total number of IEA occurring in 10 minutes (IEA/10 min) recorded from all channels was considered in each patient before and after TPM therapy. Statistical analysis was performed by utilizing one-way ANOVA (a P value <0.05 was considered as significant).
A computerized study of the EEG background activity was performed for a period of 15–20 min, at the beginning of each long-term monitoring session in a group of 18 out of 24 epileptic patients before and after TPM therapy. The EEG was always recorded in a silent room at the same time of the day, constantly controlling the patient’s state of alertness by evaluation of EEG alpha rhythm. The recording sessions were performed in all patients in the following conditions: (1) at rest with eyes closed (EC) for 10 min; (2) during an attentive task consisting of blocking reaction (BR) induced by several episodes of eyes open lasting 8 to 9 s each. The off-line spectral analysis was performed by using the Fast Fourier Transform on 5–10 min of EEG signal, automatically segmented by software into 2.56 s epochs, after visual elimination of ictal and/or interictal abnormalities, movements artifacts, eye-blinking, muscle activity or drowsiness. These epochs were collected with a sampling rate of 200 Hz for each electrode and for each
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frequency band: delta [1–4] Hz; theta [4–8] Hz; alpha [8–12] Hz and beta [12–30] Hz. Relative power values were considered due to their lower inter-subject variability (Nuwer, 1988). According to Gasser et al. (1982), the relative power was normalized using the log [x/(1 − x)] where x is the untransformed relative power to approach normal distribution. Relative power data obtained from epileptic patients before TPM (EpiPre-TPM) were compared with those during TPM therapy (EpiPost-TPM) by means of a two-way ANOVA (repeated measure) with 2 within factors: (1) “therapy” with two levels (before and during); “band” with 4 levels (delta, theta, alpha, beta). In the case of significant effects of the “main factors” or significant interactions among main factors, statistical significance of single differences was assessed by means of post hoc LSD test. In addition, three alpha band indexes were also determined: peak frequency, median frequency, and re-
activity; in particular, the latter was evaluated by comparing the alpha mean relative power calculated during EC and BR in epileptic patients before and after TPM therapy.
3. Results 3.1. EEG interictal abnormalities before and after TPM therapy No patients presented clinical seizures during the video-EEG monitoring, except one (patient number 21 in Table 2) who experienced several complex partial seizures during EEG recording performed before starting TPM treatment. For EEG interictal activity, the mean number of spikes/10 min (relative to the whole population) detected during the recording session prior to TPM ther-
Table 2 Interictal epileptiform activity and seizures before and during TPM therapy Pre-TPM
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Post-TPM
Seizure frequency
IEA spatial distribution
IEA/10 min
IEA spatial distribution
IEA/10 min
A A A C B B A A A B A A B A A B A C C C C C C C
9.00 8.30 0.80 6.54 18.63 6.74 1.11 1.72 4.80 2.26 4.67 0.16 3.60 1.45 0.71 9.09 1.13 1.66 3.61 0.96 95∗ 2.80 4.74 0.81
A A A C B B B A B B A A B A A B A C C C C C C C
0.36 1.7 0.31 0.63 21.76 1.57 1.17 1.2 2.3 2.7 0.29 0.29 3.4 0.83 0.24 3.61 0.5 0.86 0.62 0.66 60.5 2.4 2.07 5.07
↓ ≥50% Seizure free ↓ ≥50% Seizure free ↓ ≥50% ↓ ≥50% ↓ ≥50% n.s.c. ↓ ≥50% ↓ ≥50% Seizure free ↓ ≥50% ↓ ≥50% Worsened ↓ ≥50% ↓ ≥50% Seizure free n.s.c. ↓ ≥50% n.s.c. ↓ ≥50% Seizure free ↓ ≥50% Worsened
A: unilateral-focal; B: bilateral with side predominance; C: bilateral-independent n.s.c.: no significant changes; IEA: interictal epileptiform abnormalities. ∗ Patient with clinical seizures during long-term EEG monitoring.
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apy was significantly higher than that obtained during TPM treatment (4.1 ± 4.2 versus 2.4 ± 4.4; P < 0.01). It should be noted that the patient number 21 was excluded from the analysis, considering the appearance of ictal spiking activity. In particular, on the basis of the spatial extent of the scalp EEG pattern of the interictal spikes, the IEA recorded from all patients could be grouped as: (1) unilateral-focal (11 patients, 45.8%); (2) bilateral with side predominance (5 patients, 20.8%); (3) bilateral-independent; (8 patients, 33.3%). In the first group after 4 months of TPM treatment, even if we often observed a significant decrease in interictal spike frequency, no clear changes in IEA spatial distribution were detected in the majority of patients (Fig. 1). Among the second group of patients TPM addition did not modify the tendency of IEA to spread, also in those patients who showed a clear reduction in the spiking activity. Finally, in the last group the recordings performed before TPM therapy revealed two bilateral independent epileptogenic areas; during TPM a significant decrease in IEA was more evident at level of the epileptogenic area more active, leading the better expression of the other one (Fig. 2). 3.2. EEG background activity changes after TPM therapy The EEG spectral data of background activity, recorded at rest in the group of 18 epileptic patients before TPM therapy were compared with those obtained from the same patients after TPM (Fig. 3). ANOVA study revealed a significant decrease in the alpha mean relative power (38.57 ± 11.53 versus 34.86±15.68; P < 0.05) and a trend towards an increment in the theta mean relative power (29.49 ± 12.79 versus 31.74 ± 14.87, P = 0.08) in the EEG spectral content of epileptic patients during TPM therapy. No clear changes of delta (16.1 ± 6.05 versus 17.31 ± 8.61, n.s.) and beta (15.82 ± 9.83 ± 9.83 versus 16.07 ± 8.35 ± 8.35; n.s.) mean relative power were also detected after TPM. In addition, we found during TPM therapy a reduction in alpha reactivity. In fact, statistical analysis relative to EC situation revealed a significant decrease in the alpha mean relative power during BR in epileptic patients before TPM therapy (38.5 versus 29.6; P <
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0.05); this was not observed in epileptic patients after the chronic administration of TPM (34.8% versus 26.8%; n.s.). Finally, analysis of other alpha indexes (peak frequency and median frequency) relative to EpiPre-TPM patients compared with those of EpiPost-TPM patients showed no significant changes (median frequency: 9.14 9.14 ± 0.61 ± 0.61 versus 9.33 ± 0.69, n.s.; peak; peak frequency: 8.83 ± 0.84 versus 8.95 ± 1.14, n.s.). 3.3. TPM effect on seizure type and frequency All patients (n = 24) presented simple and/or complex partial seizures; 16 patients had secondarily generalized tonic clonic (SGTC) seizures. Treatment responder patients (showing a reduction in both partial and generalized seizures ≥50%) were 19 out of 24 patients (79.1%), of whom five were seizure-free. In three patients (12.5%) we did not observe significant changes and two patients (8.3%) showed a worsening in seizure frequency. An improvement of partial seizure frequency was evident in the majority of the patients and 71.4% of them (15/21) showed an amelioration of 50% or more. TPM seemed to have a strong inhibition effect on SGTC seizures, since 12 out of 16 patients (75%) did not have this type of seizures at the end of the 4-month follow-up. Therefore in our study, TPM addition allowed a significant reduction in all types of seizures (46.1±70 versus 10.1 ± 25.6; P < 0.002), and it seemed to have a good control for both partial (41.6 ± 69 versus 10 ± 25; P < 0.005) and SGTC seizures (4.4 ± 7.2 versus 0.2 ± 0.7; P < 0.01). Moreover we analyzed the relationship between interictal spiking rate and seizures. As indicated in Table 2, 15 patients showed a relevant decrease in the interictal spiking rate, six patients no changes, and the remaining three revealed an increase in IEA. Although, no correlation was found between changes of the spiking activity rate (calculated as [(IEApre − IEApost )/IEApre ] and seizure frequency [(seizurespre − seizurespost )/seizurespre ]; (P = 0.11; Spearman rank order correlations)), among the group of patients with a relevant reduction in IEA (n = 15), 13 patients displayed a remarkable decrease in the seizure frequency up to a seizure-free condition.
48 F. Placidi et al. / Epilepsy Research 58 (2004) 43–52 Fig. 1. Effect of TPM on patients with unilateral-focal interictal epileptiform abnormalities (IEA). In the EEG recording performed in the baseline condition (A) spikes localized in the right, fronto-temporal regions are evident. After 4 months TPM addition (B) the automatic detection of IEA revealed a significant reduction in the interictal epileptiform activity up to a nearly normal EEG condition pattern of EEG.
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Fig. 2. Effect of TPM on bilateral-independent interictal epileptiform abnormalities (IEA). (A) The baseline recording session shows interictal EEG abnormalities localized over the right centro-temporo-parietal regions. (B) In the recording performed after TPM addition we observed a clear reduction of interictal spikes relative to epileptogenic area more active (right), allowing the expression or the predominance of the other one localized on the contralateral fronto-temporal regions, poorly evident in the first recording.
Fig. 3. EEG background activity in control subjects and epileptic patients before (EpiPre-TPM) and during TPM therapy (EpiPost-TPM).
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4. Discussion In our study we reported the effects of TPM on both paroxysmal abnormalities and EEG background activity recorded from patient with focal epilepsy. First, TPM addition to previously treatment or as monotherapy induced a marked decrease in total number of the IEA, without interfering with spatial distribution of the interictal abnormalities. Second, EEG background activity was not significantly modified by the addition of the drug, with the except of the reduction of alpha mean relative power and alpha reactivity. Consistent with these EEG findings, the evaluation of the effect of TPM on clinical seizure pattern showed a good control of both partial and SGTC seizures. Several double-blind placebo-controlled studies have demonstrated the effectiveness of TPM in adults and children with partial-onset seizures, with or without secondary generalization (Faught et al., 1996; Privitera et al., 1996, Sharief et al., 1996, Tassinari et al., 1996; Ben-Menachem et al., 1996, Elterman et al., 1999). In these randomized controlled trials TPM was administrated at variable target doses (400–1000 mg/day) and showed that 40–50% of the epileptic patients experienced at least 50% reduction in seizure frequency. In particular TPM revealed a strong inhibition effect on SGTC seizures (Ramsay and DeToledo, 1997). TPM may also have activity in seizures associated with Lennox-Gastaut syndrome (Sachdeo et al., 1997), and in primary generalized tonic-clonic seizures (Biton et al., 1999). Moreover there are some evidences of its efficacy as monotherapy (Sachdeo et al., 1997; Rosenfeld et al., 1997; Gilliam et al., 2003). Our study confirms clinical efficacy of TPM on the control of partial seizures with or without secondarily generalization. Seizures were reduced ≥50% in 79.1% of TPM-treated patients, and five patients were seizure free during 4 months of treatment. A significant reduction in both partial and, especially, SGTC seizures was observed (P < 0.002). These results are certainly better than previous reports on the clinical efficacy of TPM. Indeed, in the aforementioned studies epileptic patients with partial and/or generalized seizures resistant to the other antiepileptic drugs were enrolled and TMP treatment was performed with rather TPM high doses. In our study, the sample of patients was more heterogeneous in the clinical characteristics, only few
of them could be considered pharmacoresistant and, finally TPM was administered with doses ranging from 100 to 300 mg per day. In contrast to the number of clinical trials, very few data are available about the effect of the TPM on EEG. In particular no author studied the effect of TPM on EEG paroxysmal abnormalities, and previous reports of the EEG changes induced by TPM have shown an increase in the delta and theta activities and a reduction in the fast frequency bands (Neufeld et al., 1999; Mecarelli et al., 2001). We observed a significant reduction in the rate of occurrence of interictal events (P < 0.003). There was no statistical correlation between the rate of spiking activity reduction and seizure frequency; nevertheless the majority of patients who showed a significant reduction in IEA presented a remarkable improvement of seizures. This finding is consistent with previous clinical and experimental evidence of a dissociation between the EEG spiking rate and the occurrence of seizures with focal origin (Gotman, 1984, 1991; Gotman and Marciani, 1985). The analysis of spatial distribution of IEA performed before and during TPM therapy revealed that the reduction of interictal spikes was more evident at the level of the epileptogenic area rather than on the spreading component. In fact, the majority of patients did not show any change in the spike distribution. In addition, some patients with bilateral-independent IEAs showed after TPM treatment a modulation in the topographic expression of epileptiform discharges characterized by the prevalence of the epileptogenic area less active prior to TPM therapy. Several experimental findings demonstrated the capability of TPM to inhibit the generation of epileptiform discharges and to reduce seizure spreading (DeLorenzo et al., 2000; White et al., 1996; Nakamura et al., 1994; Pina-Garza and McLean, 1996). Overall, our findings lead us to hypothesize that TPM in our patients might have a prevalent inhibitory effect on the genesis of interictal and ictal abnormalities. Analysis of the EEG background activity showed that add-on treatment with TPM induced in our sample of epileptic patients a significant reduction in the alpha mean relative power and alpha reactivity with no changes in the other alpha band indexes (i.e. peak frequency and median frequency). In addition, we ob-
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served only a trend towards an increment in the theta band activity in epileptic patients before and during TPM treatment. These data appear partially discordant with previous reports (Neufeld et al., 1999; Mecarelli et al., 2001), where TPM treatment was also associated with a slow band activities increase. A possible explanation for this discordance may be that in our study the TPM titration was slower and we reached a lower mean effective maintenance dose; in addition, a part of our case series was in TPM mono-or bi-therapy. For this reason, we hypothesize that if TPM is introduced gradually using lower maintenance doses, as it is possible in monotherapy, adverse sedative and cognitive reactions could be significantly reduced. In conclusion, we found that the marked clinical effect of TPM against partial and secondarily generalized seizures was paralleled by a strong inhibitory effect of this drug on IEA, probably acting on the generating processes. Finally TPM, if used at low dosage and gradually titrated seems to have only mild interferences with EEG background activity. References Ben-Menackem, E., 1997. Clinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: the European experience. Epilepsia 38 (Suppl. 1), S28–S30. Biton, V., 1997. Preliminary open-label experience with topiramate in primary generalized seizures. Epilepsia 38 (Suppl. 1), S42– S44. Biton, V., Montouris, G.D., Ritter, F., 1999. A randomized placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 52, 1330–1337. Coulter, D.A., Sombati, S., DeLorenzo, R.J., 1993. Selective effects of topiramate on sustained repetitive firing and spontaneous bursting in cultured hippocampal neurons. Epilepsia 34 (Suppl. 2), 123. Coulter, D.A., Sombati, S., DeLorenzo, R.J., 1995. Topiramate effects on excitatory amino acid-mediated responses in cultured hippocampal neurons: selective blockade of kainate currents. Epilepsia 36 (Suppl. 3), S40. DeLorenzo, R.J., Sombati, S., Coulter, D.A., 2000. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia 41 (Suppl. 1), S40–S44. Faught, E., 1997. Efficacy of topiramate as adjunctive therapy in refractory partial seizures: United States trial experience. Epilepsia 38 (Suppl. 1), S24–S27. Gasser, T., Bacher, P., Mocks, J., 1982. Transformation towards the normal distribution of broad spectral parameters of
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the EEG. Electroencephalogr. Clin. Neurophysiol. 53, 119– 124. Gilliam, F.G., Reife, R., Wu, S.-C., 2003. A dose-comparison trial of TPM as monotherapy in recently diagnosed partial epilepsy. Neurology 60, 196–201. Gotman, J., 1984. Relationships between triggered seizures, spontaneous seizures and interictal spiking in the kindling model of epilepsy. Exp. Neurol. 84, 259–264. Gotman, J., 1991. Relationships between interictal spiking and seizures: human and experimental evidence. Can J. Neurol. Sci. 18 (4), 537–576. Gotman, J., Marciani, M.G., 1985. Electroencephalografic spiking activity drug levels and seizure occurrence in epileptic patients. Ann. Neurol. 17, 597–603. Marson, A.G., Kadir, Z.A., Hutton, J.L., Chadwick, D.W., 1997. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 38, 859–880. Mecarelli, O., Piacenti, A., Pulitano, P., Vicenzini, E., Rizzo, C., Rinalduzzi, S., de Feo, M.R., Accornero, N., 2001. Clinical and electroencephalographic effects of topiramate in patients with epilepsy and healthy volunteers. Clin. Neuropharmacol. 24 (5), 284–289. Montouris, G.D., Biton, V., Rosenfeld, W.E., 2000. Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group. Epilepsia 41 (Suppl. 1), S77–S81. Nakamura, J., Tamura, S., Kanda, T., 1994. Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice. Eur. J. Pharmacol. 254, 83–89. Neufeld, M.Y., Kogan, E., Chistik, V., Korczyn, A.D., 1999. Comparison of the effects of Vigabatrin, Lamotrigine, and Topiramate on quantitative EEGs in patients with epilepsy. Clin. Neuropharmacol. 22 (2), 80–86. Nuwer, M.R., 1988. Quantitative EEG: I. Techniques and problems of frequency analysis and topographic mapping. J. Clin. Neurophysiol. 5, 1–43. Pina-Garza, J.E., McLean, M.J., 1996. Different effects of topiramate and phenitoine on mouse seizures and responses of cultured neurons to excitatory amino acids. Epilepsia 37 (Suppl. 5), 26. Ramsay, R.E., DeToledo, J., 1997. Tonic-clonic seizure: a systemic review of antiepileptic drug efficacy and safety. Clin. Ther. 19, 433–446. Rosenfeld, W.E., Sachdeo, R.C., Faught, R.E., Privitera, M., 1997. Long-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: retrospective survey of open-label treatment. Epilepsia 38 (Suppl. 1), S34–S36. Sachdeo, R.C., Reife, R.A., Lim, P., Pledger, G., 1997. Topiramate monotherapy for partial onset seizures. Epilepsia 38 (3), 294– 300. Shank, R.P., Vaught, J.L., Raffa, R.B., Maryanoff, B.E., 1991. Investigation of the mechanism of topiramate’s anticonvulsant activity. Epilepsia 32, 7–8. Sombati, S., Coulter, D.A., DeLorenzo, R.J., 1995. Effects of topiramate on sustained repetitive firing and low Mg 2+-induced seizure discharges in cultured hippocampal neurons. Epilepsia 36 (Suppl. 4), 38.
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White, H.S., 1997. Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia 38 (Suppl. 1), S9–S17. White, H.S., Brown, D., Skeen, G.A., Wolf, H.H., Twyman, R.E., 1995. The anticonvulsant topiramate displays a unique ability to potentiate GABA-evoked chloride currents. Epilepsia 36 (Suppl. 3), S39–S40.
White, H.S., Woodhead, J., Wolf, H.H., 1996. Effect of topiramate (TPM) on pentylenetetrazole (PTZ) seizure threshold. Epilepsia 37 (Suppl. 5), 26. Zhang, X.-L., Velumian, A.A., Jones, O.T., Carlen, P.L., 2000. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41 (Suppl. 1), S77–S81.
Topiramate: effect on EEG interictal abnormalities and background activity in patients affected by focal epilepsy Fabio Placidi a,b,∗ , Mario Tombini a,b , Andrea Romigi a,b , Luigi Bianchi a,b , Francesca Izzi a , Francesca Sperli a , Donatella Mattia b , Angela Cervellino a , Maria Grazia Marciani a,b a
Neurofisiopatologia, Università di Roma Tor Vergata, V.le Oxford 81, Rome 00133, Italy b Fondazione Santa Lucia, IRCCS, Rome, Italy
Received 31 July 2003; received in revised form 1 December 2003; accepted 26 December 2003
Abstract Purpose: To evaluate the effects of topiramate (TPM) on interictal epileptiform abnormalities (IEA) and background activity by means of a computerized EEG analysis, in adult patients affected by focal epilepsy, with or without secondarily generalization, treated with TPM as adjunctive therapy or monotherapy. Methods: Twenty-four patients affected by symptomatic or cryptogenic focal epilepsy underwent long-term video-EEG recording before and after TPM addition (mean dose 175 ± 25 mg per day). Results: TPM addition induced a significant reduction of both partial and secondarily generalized tonic-clonic (SGTC) seizures; treatment responder patients (seizure reduction ≥ 50%) were 19 out of 24 patients (79.1%), of whom 5 were seizure-free. Quantitative analysis of IEA showed a significant decrease in the mean number of spikes/10 min during TPM therapy (4.2 ± 4.2 versus 2.2 ± 4.4; P < 0.003). The analysis of spatial distribution of interictal spikes showed that such reduction was more evident at the level of the epileptogenic area rather than on the spreading component. Statistical analysis revealed only a significant decrease of mean relative power of alpha band in the EEG spectral content, recorded at rest in a group of 18 out of 24 epileptic patients during TPM therapy. In addition, during TPM treatment we observed a significant reduction in alpha reactivity without any important changes of alpha indexes (peak frequency and median frequency). Conclusion: These findings suggest that TPM has a strong inhibitory effect on IEA, probably acting on the generating processes, and, if used at low dosage and gradually titrated, seems to have only mild interferences with EEG background activity. © 2004 Elsevier B.V. All rights reserved. Keywords: EEG; Topiramate; Focal epilepsy; Interictal epileptiform abnormalities (IEA); Background activity
1. Introduction
∗ Corresponding author. Tel.: +39-06-20902107; fax: +39-06-20902106. E-mail address: [email protected] (F. Placidi).
Topiramate (TPM) (2,3,4,5-bis-O-(1-methylethylidene)-beta-d-fructopyranose) is a novel antiepileptic drug (AED), effective in a wide variety of seizures types (Marson et al., 1997). Preclinical data and findings from clinical trials suggest that the broad spec-
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trum of TPM activity could be explained by its pharmacological mechanisms, that combine properties of AEDs regulating ion channels and of AEDs acting on neurotransmitters (Coulter et al., 1993, 1995; Sombati et al., 1995; White et al., 1995; Zhang et al., 2000; Shank et al., 1991). Data from animal models suggest that TPM may be effective against both partial and generalized seizures (White, 1997), and several clinical trials have demonstrated efficacy of TPM in the treatment of refractory partial-onset seizures, with or without secondarily generalization, and in refractory primary generalized tonic-clonic seizures (Faught, 1997; Ben-Menackem, 1997; Biton, 1997; Biton et al., 1999; Montouris et al., 2000). In the majority of studies TPM has been used adjunctively with existing treatments, but recently there are some evidences of the its efficacy also as monotherapy (Sachdeo et al., 1997; Rosenfeld et al., 1997; Gilliam et al., 2003). Nevertheless the studies on the effect of TPM on the EEG are few (Neufeld et al., 1999; Mecarelli et al., 2001). Particularly, in these papers TPM therapy has been reported to induce an increase in the delta and theta activities and a decrease in the fast frequency bands. The aim of our study was to evaluate by means of a computerized EEG analysis the effects of TPM on interictal epileptiform abnormalities (IEA) and background activity recorded in adult patients with focal epilepsy, treated with TPM as add-on or monotherapy; relationship between neurophysiological findings and drug clinical profile was also addressed.
2. Methods
tients were on single or multiple-drug therapy before starting TPM, three patients were newly diagnosed as having epilepsy and started taking TPM as monotherapy. In all patients, TPM was titrated from an initial dose of 25 mg/die, with weekly or biweekly dose increments of 25 mg/die to reach a mean effective maintenance dose (175 ± 25 mg/die). Exclusion criteria were: organic or psychiatric disorders, use of drugs interfering with the nervous system other than AEDs. It was required that seizures should be recognizable by the patients or their relatives and that seizure frequency was assessed by a seizure diary. Two patients dropped out after about 1 month because of the appearance of adverse effects consisting of anxiety and nervousness. Clinical features of the patients who completed the study protocol are summarized in Table 1. All patients underwent a long-term video-EEG monitoring session before and 4 months after the addition of TPM therapy. Neurological evaluation and blood chemical studies, including AED plasma levels, were monitored before each recording. The mean number of seizures during TPM treatment was compared with that during 3 months prior to the addition of TPM, or to starting therapy. Analysis was performed by means of a one-way ANOVA; a P value <0.05 was considered as significant. Changes of seizures frequency, observed during TPM treatment, were classified as: (a) improved (reduction ≥ 50%); (b) seizure free; (c) not significantly changed (reduction < 50%); (d) worsened (increased number of seizures); for instance, the reduction in seizure occurrence has been considered significant when ≥50%.
2.1. Patients 2.2. EEG procedures Twenty-six patients affected by focal epilepsy (6 males and 20 females; age range 17–61 years, mean age 40 ± 13 years) were studied after giving their informed consent. The study protocol was approved by Ethics Committee of the University of Rome “Tor Vergata”. On the basis of neuroimaging data (CT scan and/or MRI), clinical and EEG features, 10 patients were diagnosed as having symptomatic partial epilepsy and the remaining 16 as having cryptogenic partial epilepsy. Epilepsy onset was between 2 and 57 years (mean age 22 ± 17 years). Twenty-three pa-
The EEG recordings were performed through a 32-channel cable video-telemetry system. The EEG signal was transmitted from the patient’s room to the laboratory, where it was collected and simultaneously stored on hard disk and on magnetic tape. Recordings were carried out utilizing a common average reference and a time constant of 0.1 s. During recordings, scalp electrodes were placed according to the 10–20 International System. Specifically, montage consisted of 16 referential EEG channels, with the possibility of
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Table 1 Clinical features of patients Patient
Age (years)/Gender
Epilepsy onset (years)
Seizure type
Epilepsy aetiology
AEDs at entry
1 2 3 4 5 6 7 8 8 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
38/F 17/M 40/F 29/F 28/F 38/F 19/F 53/F 56/F 47/F 61/F 57/M 33/F 57/M 52/F 39/F 39/M 41/F 52/F 54/F 24/F 40/F 24/F 20/F
33 12 6 8 25 18 18 8 54 5 57 36 6 53 37 11 13 4 25 34 2 36 6 14
SPS, SG SPS, CPS SPS → SG SPS → SG SG CPS → SG CPS CPS → SG CPS → SG CPS, SG CPS CPS CPS CPS → SG CPS SPS, CPS, SG SPS, CPS CPS → SG CPS → SG CPS → SG CPS → SG SG CPS, SG CPS → SG
CFE SFE CFE CFE CFE CFE CFE SFE CFE CFE CFE SFE CFE CFE CFE CFE SFE SFE SFE SFE SFE CFE SFE CFE
GBP, PB CBZ CBZ, GBP, PB CBZ,LTG,CLB,LEV,PB – CBZ OXC GVG, PHT, PB – CBZ CBZ CBZ, PB PB – CBZ, GBP CBZ CBZ, PB CBZ,VPA, PB CBZ, GBP CBZ, PB CBZ,CLB,VPA CBZ VPA, GVG, CLB CBZ, LTG
CPS: complex partial seizures; seizures; SPS: simple partial seizures; seizures; SG: secondarily generalization; SFE: symptomatic focal epilepsy; CFE: cryptogenetic focal epilepsy. CBZ: carbamazepine; PB: phenobarbital; GBP: gabapentin; LTG: lamotrigine; GVG: vigabatrin; OXC: oxcarbazepine; PHT: phenitoine; VPA: valproic acid; CLB: clobazam; LEV: levetiracetam.
different bipolar reconstructions; additional electrodes were utilized to monitor eyes movements, EMG activity and ECG signal and to better recognize artifacts. Interictal epileptiform abnormalities (IEA) were continuously analyzed and calculated by means of a specific computer program (Stellate Harmonie System 5.0) for automatic recognition of events like spikes and/or sharp waves. Seizures were recorded by an automatic recognition program or by means of a push-button activated by the patient himself or by an observer. The automatic recognition of IEA allowed the quantification of such events, providing data on temporal and spatial distribution for the entire duration of the monitoring. All detected paroxysmal events were visually evaluated and edited for false detections. The total number of IEA occurring in 10 minutes (IEA/10 min) recorded from all channels was considered in each patient before and after TPM therapy. Statistical analysis was performed by utilizing one-way ANOVA (a P value <0.05 was considered as significant).
A computerized study of the EEG background activity was performed for a period of 15–20 min, at the beginning of each long-term monitoring session in a group of 18 out of 24 epileptic patients before and after TPM therapy. The EEG was always recorded in a silent room at the same time of the day, constantly controlling the patient’s state of alertness by evaluation of EEG alpha rhythm. The recording sessions were performed in all patients in the following conditions: (1) at rest with eyes closed (EC) for 10 min; (2) during an attentive task consisting of blocking reaction (BR) induced by several episodes of eyes open lasting 8 to 9 s each. The off-line spectral analysis was performed by using the Fast Fourier Transform on 5–10 min of EEG signal, automatically segmented by software into 2.56 s epochs, after visual elimination of ictal and/or interictal abnormalities, movements artifacts, eye-blinking, muscle activity or drowsiness. These epochs were collected with a sampling rate of 200 Hz for each electrode and for each
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frequency band: delta [1–4] Hz; theta [4–8] Hz; alpha [8–12] Hz and beta [12–30] Hz. Relative power values were considered due to their lower inter-subject variability (Nuwer, 1988). According to Gasser et al. (1982), the relative power was normalized using the log [x/(1 − x)] where x is the untransformed relative power to approach normal distribution. Relative power data obtained from epileptic patients before TPM (EpiPre-TPM) were compared with those during TPM therapy (EpiPost-TPM) by means of a two-way ANOVA (repeated measure) with 2 within factors: (1) “therapy” with two levels (before and during); “band” with 4 levels (delta, theta, alpha, beta). In the case of significant effects of the “main factors” or significant interactions among main factors, statistical significance of single differences was assessed by means of post hoc LSD test. In addition, three alpha band indexes were also determined: peak frequency, median frequency, and re-
activity; in particular, the latter was evaluated by comparing the alpha mean relative power calculated during EC and BR in epileptic patients before and after TPM therapy.
3. Results 3.1. EEG interictal abnormalities before and after TPM therapy No patients presented clinical seizures during the video-EEG monitoring, except one (patient number 21 in Table 2) who experienced several complex partial seizures during EEG recording performed before starting TPM treatment. For EEG interictal activity, the mean number of spikes/10 min (relative to the whole population) detected during the recording session prior to TPM ther-
Table 2 Interictal epileptiform activity and seizures before and during TPM therapy Pre-TPM
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Post-TPM
Seizure frequency
IEA spatial distribution
IEA/10 min
IEA spatial distribution
IEA/10 min
A A A C B B A A A B A A B A A B A C C C C C C C
9.00 8.30 0.80 6.54 18.63 6.74 1.11 1.72 4.80 2.26 4.67 0.16 3.60 1.45 0.71 9.09 1.13 1.66 3.61 0.96 95∗ 2.80 4.74 0.81
A A A C B B B A B B A A B A A B A C C C C C C C
0.36 1.7 0.31 0.63 21.76 1.57 1.17 1.2 2.3 2.7 0.29 0.29 3.4 0.83 0.24 3.61 0.5 0.86 0.62 0.66 60.5 2.4 2.07 5.07
↓ ≥50% Seizure free ↓ ≥50% Seizure free ↓ ≥50% ↓ ≥50% ↓ ≥50% n.s.c. ↓ ≥50% ↓ ≥50% Seizure free ↓ ≥50% ↓ ≥50% Worsened ↓ ≥50% ↓ ≥50% Seizure free n.s.c. ↓ ≥50% n.s.c. ↓ ≥50% Seizure free ↓ ≥50% Worsened
A: unilateral-focal; B: bilateral with side predominance; C: bilateral-independent n.s.c.: no significant changes; IEA: interictal epileptiform abnormalities. ∗ Patient with clinical seizures during long-term EEG monitoring.
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apy was significantly higher than that obtained during TPM treatment (4.1 ± 4.2 versus 2.4 ± 4.4; P < 0.01). It should be noted that the patient number 21 was excluded from the analysis, considering the appearance of ictal spiking activity. In particular, on the basis of the spatial extent of the scalp EEG pattern of the interictal spikes, the IEA recorded from all patients could be grouped as: (1) unilateral-focal (11 patients, 45.8%); (2) bilateral with side predominance (5 patients, 20.8%); (3) bilateral-independent; (8 patients, 33.3%). In the first group after 4 months of TPM treatment, even if we often observed a significant decrease in interictal spike frequency, no clear changes in IEA spatial distribution were detected in the majority of patients (Fig. 1). Among the second group of patients TPM addition did not modify the tendency of IEA to spread, also in those patients who showed a clear reduction in the spiking activity. Finally, in the last group the recordings performed before TPM therapy revealed two bilateral independent epileptogenic areas; during TPM a significant decrease in IEA was more evident at level of the epileptogenic area more active, leading the better expression of the other one (Fig. 2). 3.2. EEG background activity changes after TPM therapy The EEG spectral data of background activity, recorded at rest in the group of 18 epileptic patients before TPM therapy were compared with those obtained from the same patients after TPM (Fig. 3). ANOVA study revealed a significant decrease in the alpha mean relative power (38.57 ± 11.53 versus 34.86±15.68; P < 0.05) and a trend towards an increment in the theta mean relative power (29.49 ± 12.79 versus 31.74 ± 14.87, P = 0.08) in the EEG spectral content of epileptic patients during TPM therapy. No clear changes of delta (16.1 ± 6.05 versus 17.31 ± 8.61, n.s.) and beta (15.82 ± 9.83 ± 9.83 versus 16.07 ± 8.35 ± 8.35; n.s.) mean relative power were also detected after TPM. In addition, we found during TPM therapy a reduction in alpha reactivity. In fact, statistical analysis relative to EC situation revealed a significant decrease in the alpha mean relative power during BR in epileptic patients before TPM therapy (38.5 versus 29.6; P <
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0.05); this was not observed in epileptic patients after the chronic administration of TPM (34.8% versus 26.8%; n.s.). Finally, analysis of other alpha indexes (peak frequency and median frequency) relative to EpiPre-TPM patients compared with those of EpiPost-TPM patients showed no significant changes (median frequency: 9.14 9.14 ± 0.61 ± 0.61 versus 9.33 ± 0.69, n.s.; peak; peak frequency: 8.83 ± 0.84 versus 8.95 ± 1.14, n.s.). 3.3. TPM effect on seizure type and frequency All patients (n = 24) presented simple and/or complex partial seizures; 16 patients had secondarily generalized tonic clonic (SGTC) seizures. Treatment responder patients (showing a reduction in both partial and generalized seizures ≥50%) were 19 out of 24 patients (79.1%), of whom five were seizure-free. In three patients (12.5%) we did not observe significant changes and two patients (8.3%) showed a worsening in seizure frequency. An improvement of partial seizure frequency was evident in the majority of the patients and 71.4% of them (15/21) showed an amelioration of 50% or more. TPM seemed to have a strong inhibition effect on SGTC seizures, since 12 out of 16 patients (75%) did not have this type of seizures at the end of the 4-month follow-up. Therefore in our study, TPM addition allowed a significant reduction in all types of seizures (46.1±70 versus 10.1 ± 25.6; P < 0.002), and it seemed to have a good control for both partial (41.6 ± 69 versus 10 ± 25; P < 0.005) and SGTC seizures (4.4 ± 7.2 versus 0.2 ± 0.7; P < 0.01). Moreover we analyzed the relationship between interictal spiking rate and seizures. As indicated in Table 2, 15 patients showed a relevant decrease in the interictal spiking rate, six patients no changes, and the remaining three revealed an increase in IEA. Although, no correlation was found between changes of the spiking activity rate (calculated as [(IEApre − IEApost )/IEApre ] and seizure frequency [(seizurespre − seizurespost )/seizurespre ]; (P = 0.11; Spearman rank order correlations)), among the group of patients with a relevant reduction in IEA (n = 15), 13 patients displayed a remarkable decrease in the seizure frequency up to a seizure-free condition.
48 F. Placidi et al. / Epilepsy Research 58 (2004) 43–52 Fig. 1. Effect of TPM on patients with unilateral-focal interictal epileptiform abnormalities (IEA). In the EEG recording performed in the baseline condition (A) spikes localized in the right, fronto-temporal regions are evident. After 4 months TPM addition (B) the automatic detection of IEA revealed a significant reduction in the interictal epileptiform activity up to a nearly normal EEG condition pattern of EEG.
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Fig. 2. Effect of TPM on bilateral-independent interictal epileptiform abnormalities (IEA). (A) The baseline recording session shows interictal EEG abnormalities localized over the right centro-temporo-parietal regions. (B) In the recording performed after TPM addition we observed a clear reduction of interictal spikes relative to epileptogenic area more active (right), allowing the expression or the predominance of the other one localized on the contralateral fronto-temporal regions, poorly evident in the first recording.
Fig. 3. EEG background activity in control subjects and epileptic patients before (EpiPre-TPM) and during TPM therapy (EpiPost-TPM).
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4. Discussion In our study we reported the effects of TPM on both paroxysmal abnormalities and EEG background activity recorded from patient with focal epilepsy. First, TPM addition to previously treatment or as monotherapy induced a marked decrease in total number of the IEA, without interfering with spatial distribution of the interictal abnormalities. Second, EEG background activity was not significantly modified by the addition of the drug, with the except of the reduction of alpha mean relative power and alpha reactivity. Consistent with these EEG findings, the evaluation of the effect of TPM on clinical seizure pattern showed a good control of both partial and SGTC seizures. Several double-blind placebo-controlled studies have demonstrated the effectiveness of TPM in adults and children with partial-onset seizures, with or without secondary generalization (Faught et al., 1996; Privitera et al., 1996, Sharief et al., 1996, Tassinari et al., 1996; Ben-Menachem et al., 1996, Elterman et al., 1999). In these randomized controlled trials TPM was administrated at variable target doses (400–1000 mg/day) and showed that 40–50% of the epileptic patients experienced at least 50% reduction in seizure frequency. In particular TPM revealed a strong inhibition effect on SGTC seizures (Ramsay and DeToledo, 1997). TPM may also have activity in seizures associated with Lennox-Gastaut syndrome (Sachdeo et al., 1997), and in primary generalized tonic-clonic seizures (Biton et al., 1999). Moreover there are some evidences of its efficacy as monotherapy (Sachdeo et al., 1997; Rosenfeld et al., 1997; Gilliam et al., 2003). Our study confirms clinical efficacy of TPM on the control of partial seizures with or without secondarily generalization. Seizures were reduced ≥50% in 79.1% of TPM-treated patients, and five patients were seizure free during 4 months of treatment. A significant reduction in both partial and, especially, SGTC seizures was observed (P < 0.002). These results are certainly better than previous reports on the clinical efficacy of TPM. Indeed, in the aforementioned studies epileptic patients with partial and/or generalized seizures resistant to the other antiepileptic drugs were enrolled and TMP treatment was performed with rather TPM high doses. In our study, the sample of patients was more heterogeneous in the clinical characteristics, only few
of them could be considered pharmacoresistant and, finally TPM was administered with doses ranging from 100 to 300 mg per day. In contrast to the number of clinical trials, very few data are available about the effect of the TPM on EEG. In particular no author studied the effect of TPM on EEG paroxysmal abnormalities, and previous reports of the EEG changes induced by TPM have shown an increase in the delta and theta activities and a reduction in the fast frequency bands (Neufeld et al., 1999; Mecarelli et al., 2001). We observed a significant reduction in the rate of occurrence of interictal events (P < 0.003). There was no statistical correlation between the rate of spiking activity reduction and seizure frequency; nevertheless the majority of patients who showed a significant reduction in IEA presented a remarkable improvement of seizures. This finding is consistent with previous clinical and experimental evidence of a dissociation between the EEG spiking rate and the occurrence of seizures with focal origin (Gotman, 1984, 1991; Gotman and Marciani, 1985). The analysis of spatial distribution of IEA performed before and during TPM therapy revealed that the reduction of interictal spikes was more evident at the level of the epileptogenic area rather than on the spreading component. In fact, the majority of patients did not show any change in the spike distribution. In addition, some patients with bilateral-independent IEAs showed after TPM treatment a modulation in the topographic expression of epileptiform discharges characterized by the prevalence of the epileptogenic area less active prior to TPM therapy. Several experimental findings demonstrated the capability of TPM to inhibit the generation of epileptiform discharges and to reduce seizure spreading (DeLorenzo et al., 2000; White et al., 1996; Nakamura et al., 1994; Pina-Garza and McLean, 1996). Overall, our findings lead us to hypothesize that TPM in our patients might have a prevalent inhibitory effect on the genesis of interictal and ictal abnormalities. Analysis of the EEG background activity showed that add-on treatment with TPM induced in our sample of epileptic patients a significant reduction in the alpha mean relative power and alpha reactivity with no changes in the other alpha band indexes (i.e. peak frequency and median frequency). In addition, we ob-
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served only a trend towards an increment in the theta band activity in epileptic patients before and during TPM treatment. These data appear partially discordant with previous reports (Neufeld et al., 1999; Mecarelli et al., 2001), where TPM treatment was also associated with a slow band activities increase. A possible explanation for this discordance may be that in our study the TPM titration was slower and we reached a lower mean effective maintenance dose; in addition, a part of our case series was in TPM mono-or bi-therapy. For this reason, we hypothesize that if TPM is introduced gradually using lower maintenance doses, as it is possible in monotherapy, adverse sedative and cognitive reactions could be significantly reduced. In conclusion, we found that the marked clinical effect of TPM against partial and secondarily generalized seizures was paralleled by a strong inhibitory effect of this drug on IEA, probably acting on the generating processes. Finally TPM, if used at low dosage and gradually titrated seems to have only mild interferences with EEG background activity. References Ben-Menackem, E., 1997. Clinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: the European experience. Epilepsia 38 (Suppl. 1), S28–S30. Biton, V., 1997. Preliminary open-label experience with topiramate in primary generalized seizures. Epilepsia 38 (Suppl. 1), S42– S44. Biton, V., Montouris, G.D., Ritter, F., 1999. A randomized placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology 52, 1330–1337. Coulter, D.A., Sombati, S., DeLorenzo, R.J., 1993. Selective effects of topiramate on sustained repetitive firing and spontaneous bursting in cultured hippocampal neurons. Epilepsia 34 (Suppl. 2), 123. Coulter, D.A., Sombati, S., DeLorenzo, R.J., 1995. Topiramate effects on excitatory amino acid-mediated responses in cultured hippocampal neurons: selective blockade of kainate currents. Epilepsia 36 (Suppl. 3), S40. DeLorenzo, R.J., Sombati, S., Coulter, D.A., 2000. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia 41 (Suppl. 1), S40–S44. Faught, E., 1997. Efficacy of topiramate as adjunctive therapy in refractory partial seizures: United States trial experience. Epilepsia 38 (Suppl. 1), S24–S27. Gasser, T., Bacher, P., Mocks, J., 1982. Transformation towards the normal distribution of broad spectral parameters of
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the EEG. Electroencephalogr. Clin. Neurophysiol. 53, 119– 124. Gilliam, F.G., Reife, R., Wu, S.-C., 2003. A dose-comparison trial of TPM as monotherapy in recently diagnosed partial epilepsy. Neurology 60, 196–201. Gotman, J., 1984. Relationships between triggered seizures, spontaneous seizures and interictal spiking in the kindling model of epilepsy. Exp. Neurol. 84, 259–264. Gotman, J., 1991. Relationships between interictal spiking and seizures: human and experimental evidence. Can J. Neurol. Sci. 18 (4), 537–576. Gotman, J., Marciani, M.G., 1985. Electroencephalografic spiking activity drug levels and seizure occurrence in epileptic patients. Ann. Neurol. 17, 597–603. Marson, A.G., Kadir, Z.A., Hutton, J.L., Chadwick, D.W., 1997. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 38, 859–880. Mecarelli, O., Piacenti, A., Pulitano, P., Vicenzini, E., Rizzo, C., Rinalduzzi, S., de Feo, M.R., Accornero, N., 2001. Clinical and electroencephalographic effects of topiramate in patients with epilepsy and healthy volunteers. Clin. Neuropharmacol. 24 (5), 284–289. Montouris, G.D., Biton, V., Rosenfeld, W.E., 2000. Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group. Epilepsia 41 (Suppl. 1), S77–S81. Nakamura, J., Tamura, S., Kanda, T., 1994. Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice. Eur. J. Pharmacol. 254, 83–89. Neufeld, M.Y., Kogan, E., Chistik, V., Korczyn, A.D., 1999. Comparison of the effects of Vigabatrin, Lamotrigine, and Topiramate on quantitative EEGs in patients with epilepsy. Clin. Neuropharmacol. 22 (2), 80–86. Nuwer, M.R., 1988. Quantitative EEG: I. Techniques and problems of frequency analysis and topographic mapping. J. Clin. Neurophysiol. 5, 1–43. Pina-Garza, J.E., McLean, M.J., 1996. Different effects of topiramate and phenitoine on mouse seizures and responses of cultured neurons to excitatory amino acids. Epilepsia 37 (Suppl. 5), 26. Ramsay, R.E., DeToledo, J., 1997. Tonic-clonic seizure: a systemic review of antiepileptic drug efficacy and safety. Clin. Ther. 19, 433–446. Rosenfeld, W.E., Sachdeo, R.C., Faught, R.E., Privitera, M., 1997. Long-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: retrospective survey of open-label treatment. Epilepsia 38 (Suppl. 1), S34–S36. Sachdeo, R.C., Reife, R.A., Lim, P., Pledger, G., 1997. Topiramate monotherapy for partial onset seizures. Epilepsia 38 (3), 294– 300. Shank, R.P., Vaught, J.L., Raffa, R.B., Maryanoff, B.E., 1991. Investigation of the mechanism of topiramate’s anticonvulsant activity. Epilepsia 32, 7–8. Sombati, S., Coulter, D.A., DeLorenzo, R.J., 1995. Effects of topiramate on sustained repetitive firing and low Mg 2+-induced seizure discharges in cultured hippocampal neurons. Epilepsia 36 (Suppl. 4), 38.
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F. Placidi et al. / Epilepsy Research 58 (2004) 43–52
White, H.S., 1997. Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia 38 (Suppl. 1), S9–S17. White, H.S., Brown, D., Skeen, G.A., Wolf, H.H., Twyman, R.E., 1995. The anticonvulsant topiramate displays a unique ability to potentiate GABA-evoked chloride currents. Epilepsia 36 (Suppl. 3), S39–S40.
White, H.S., Woodhead, J., Wolf, H.H., 1996. Effect of topiramate (TPM) on pentylenetetrazole (PTZ) seizure threshold. Epilepsia 37 (Suppl. 5), 26. Zhang, X.-L., Velumian, A.A., Jones, O.T., Carlen, P.L., 2000. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 41 (Suppl. 1), S77–S81.