Which is more deleterious to cognitive performance? Interictal epileptiform discharges vs anti-seizure medication.

Children with epilepsy commonly have comorbid neurocognitive impairments that severely affect their psychosocial well-being, education, and future career prospects. Although the provenance of these deficits is multifactorial, the effects of interictal epileptiform discharges (IEDs) and anti-seizure medications (ASMs) are thought to be particularly severe. Although certain ASMs can be leveraged to inhibit IED occurrence, it remains unclear whether epileptiform discharges or the medications themselves are most deleterious to cognition. To examine this question, 25 children undergoing invasive monitoring for refractory focal epilepsy performed one or more sessions of a cognitive flexibility task. Electrophysiological data were recorded to detect IEDs. Between repeated sessions, prescribed ASMs were either continued or titrated to <50% of the baseline dose. Hierarchical mixed-effects modeling assessed the relationship between task reaction time (RT), IED occurrence, ASM type, and dose while controlling for seizure frequency. Both presence (ß ± SE = 49.91 ± 16.55 ms, p = .003) and number of IEDs (ß ± SE = 49.84 ± 12.51 ms, p < .001) were associated with slowed task RT. Higher dose oxcarbazepine significantly reduced IED frequency (p = .009) and improved task performance (ß ± SE = -107.43 ± 39.54 ms, p = .007). These results emphasize the neurocognitive consequences of IEDs independent of seizure effects. Furthermore, we demonstrate that inhibition of IEDs following treatment with select ASMs is associated with improved neurocognitive function.

Interictal discharges delay target-directed eye movements and impair attentional set-shifting in children with epilepsy.

OBJECTIVE: The theory of transient cognitive impairment in epilepsy posits that lapses in attention result from ephemeral disruption of attentional circuitry by interictal events. Eye movements are intimately associated with human attention and can be monitored in real time using eye-tracking technologies. Here, we sought to characterize the associations between interictal epileptiform discharges (IEDs), gaze, and attentional behavior in children with epilepsy. METHODS: Eleven consecutive children undergoing invasive monitoring with stereotactic electrodes for localization-related epilepsy performed an attentional set-shifting task while tandem intracranial electroencephalographic signals and eye-tracking data were recorded. Using an established algorithm, IEDs were detected across all intracranial electrodes on a trial-by-trial basis. Hierarchical mixed-effects modeling was performed to delineate associations between trial reaction time (RT), eye movements, and IEDs. RESULTS: Hierarchical mixed-effects modeling revealed that both the presence of an IED (ß ± SE = 72.74 ± 24.21 ms, p = .003) and the frequency of epileptiform events (ß ± SE = 67.54 ± 17.30 ms, p < .001) were associated with prolonged RT on the attentional set-shifting task. IED occurrence at the time of stimulus presentation was associated with delays in gaze initiation toward the visual targets (p = .017). SIGNIFICANCE: The occurrence of epileptiform activity in close temporal association with stimulus presentation is associated with delays in target-directed gaze and prolonged response time, hallmarks of momentary lapses in attention. These findings provide novel insights into the mechanisms of transient impairments in children and support the use of visual tracking as a correlate of higher order attentional behavior.

Factors affecting interictal unilateral and bilateral discharges and ictal diffusion patterns of scalp electroencephalogram in temporal lobe epilepsy.

BACKGROUND: The interictal discharges of temporal lobe epilepsy (TLE) can be unilateral or bilateral. In addition, the ictal electroencephalogram (EEG) showed the discharges also tend to spread to the contralateral brain in TLE. OBJECTIVE: The factors influencing unilateral and bilateral interictal discharges in TLE as well as ictal diffusion patterns in scalp EEG during onset of seizure were evaluated in the present study. MATERIALS AND METHODS: This was a retrospective analysis of 129 patients with TLE. Cases were classified into unilateral and bilateral discharge groups based on interictal discharge patterns in the EEG. Differences between the two groups in age, gender, disease duration, seizure frequency, magnetic resonance imaging (MRI) findings, origin of TLE, antiepileptic drug (AED) administration, and ictal diffusion patterns during seizures were statistically analyzed. In addition, the differences in ictal diffusion patterns between left and right TLE were statistically analyzed. RESULTS: Statistically significant differences were not observed in gender, disease duration, seizure frequency, MRI findings, administration of AEDs, and ictal diffusion patterns between interictal unilateral and bilateral discharge groups but with statistically significant differences in age and side of origin of the TLE. In addition, whether the EEG-recorded diffusion pattern was confined to the same hemisphere or spread to both hemispheres was investigated and shown statistically significant differences between the left and right temporal lobes. CONCLUSIONS: Age and side of origin of TLE affects the TLE interictal discharge patterns. Older patients are more prone to bilateral discharges. Bilateral discharges are more common in right TLE, and the onset of EEG more likely to bilateral diffusion in right TLE.

Pre-Operative Interictal Discharge Patterns and Magnetic Resonance Imaging Findings Affect Prognosis of Temporal Lobe Epilepsy Surgery.

OBJECTIVE: This study investigated whether pre-operative interictal discharge patterns detected by electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings affect the surgical prognosis in temporal lobe epilepsy (TLE) patients. METHODS: A retrospective analysis of 115 cases of patients with refractory TLE was carried out from October 2010 to 2014 based on the classification of pre-operative interictal discharge patterns in EEG and MRI findings. The patients were followed up for 4 years after surgery. The ILAE method was used to assess differences in seizure-free rate among different types of interictal discharge pattern as well as in MRI findings. RESULTS: A total of 115 cases were classified according to interictal discharge patterns in EEG, including normal cases, unilateral anterior discharge, unilateral multi-region discharge, and bilateral discharge. MRI findings were classified into negative results and positive results. Unilateral anterior and bilateral discharges showed statistically significant differences in post-operative seizure-free rates (p< 0.001). MRI-positive cases showed good overall post-operative outcome, irrespective of interictal discharge pattern in the EEG, whereas MRI-negative cases showed good overall prognosis if the interictal discharge pattern in EEG occurred in the unilateral anterior region. CONCLUSION: If the pre-operative interictal discharge pattern in EEG is confined to the unilateral anterior region, prognosis is good. If there are abnormalities in MRI findings, post-operative prognosis is good, regardless of pre-operative interictal discharge patterns in EEG. Surgical intervention is highly recommended for TLE patients with normal MRI findings and interictal discharge confined to the unilateral anterior region.

On the contribution of KCC2 and carbonic anhydrase to two types of in vitro interictal discharge.

GABAA receptor-mediated inhibition--which is due to Cl(-) and HCO3 (-) currents controlled by KCC2 and carbonic anhydrase activity, respectively--contributes to short- and long-lasting interictal events recorded from the CA3 region of hippocampus during application of 4-aminopyridine (4AP, 50 µM). Here, we employed field potential recordings in an in vitro brain slice preparation to establish the effects induced by the KCC2 blockers VU0240551 (10 µM) or bumetanide (50 µM) and by the carbonic anhydrase inhibitor acetazolamide (10 µM) on the two types of interictal events. We found that blocking KCC2 activity decreased the amplitude of the short-lasting events. In addition, this pharmacological procedure increased the interval of occurrence of the long-lasting events and reduced their amplitude. Blocking carbonic anhydrase activity with acetazolamide reduced the interval of occurrence and the duration of the short-lasting events while increasing their amplitude; acetazolamide also reduced the duration and amplitude of the long-lasting events. Finally, blocking either KCC2 or carbonic anhydrase activity increased the interval of occurrence of pharmacologically isolated synchronous GABAergic events and decreased their duration and amplitude. These data substantiate further the role of GABAA receptor-mediated signaling in driving neuronal populations toward hypersynchronous states presumably by increasing extracellular [K(+)].

Interictal discharge traveling waves recorded from stereoelectroencephalography electrodes.

OBJECTIVE: Interictal epileptiform discharges (IEDs) are intermittent high-amplitude electrical signals that occur between seizures. They have been shown to propagate through the brain as traveling waves when recorded with epicortical grid-type electrodes and small penetrating microelectrode arrays. However, little work has been done to translate experimental IED analyses to more clinically relevant platforms such as stereoelectroencephalography (SEEG). In this pilot study, the authors aimed to define a computational method to identify and characterize IEDs recorded from clinical SEEG electrodes and leverage the directionality of IED traveling waves to localize the seizure onset zone (SOZ). METHODS: Continuous SEEG recordings from 15 patients with medically refractory epilepsy were collected, and IEDs were detected by identifying overlapping peaks of a minimum prominence. IED pathways of propagation were defined and compared to the SOZ location determined by a clinical neurologist based on the ictal recordings. For further analysis of the IED pathways of propagation, IED detections were divided into triplets, defined as a set of 3 consecutive contacts within the same IED detection. Univariate and multivariate linear regression models were employed to associate IED characteristics with colocalization to the SOZ. RESULTS: A median (range) of 22.6 (4.4-183.9) IEDs were detected per hour from 15 patients over a mean of 23.2 hours of recording. Depending on the definition of the SOZ, a median (range) of 20.8% (0.0%-54.5%) to 62.1% (19.2%-99.4%) of IEDs per patient traversed the SOZ. IEDs passing through the SOZ followed discrete pathways that had little overlap with those of the IEDs passing outside the SOZ. Contact triplets that occurred more than once were significantly more likely to be detected in an IED passing through the SOZ (p < 0.001). Per our multivariate model, patients with a greater proportion of IED traveling waves had a significantly greater proportion of IEDs that localized to the SOZ (ß = 0.64, 95% CI 0.01-1.27, p = 0.045). CONCLUSIONS: By using computational methods, IEDs can be meaningfully detected from clinical-grade SEEG recordings of patients with epilepsy. In some patients, a high proportion of IEDs are traveling waves according to multiple metrics that colocalize to the SOZ, offering hope that IED detection, with further refinement, could serve as an alternative method for SOZ localization.

Interictal Discharge Pattern in Preschool-Aged Children With Tuberous Sclerosis Complex Before and After Resective Epilepsy Surgery.

Objective: To analyze the interictal discharge (IID) patterns on pre-operative scalp electroencephalogram (EEG) and compare the changes in IID patterns after removal of epileptogenic tubers in preschool children with tuberous sclerosis complex (TSC)-related epilepsy. Methods: Thirty-five preschool children who underwent resective surgery for TSC-related epilepsy were enrolled retrospectively, and their EEG data collected before surgery to 3 years after surgery were analyzed. Results: Twenty-three (65.7%) patients were seizure-free post-operatively at 1-year follow-up, and 37-40% of post-operative patients rendered non-IID on scalp EEGs, and patients with focal IIDs or generalized IID patterns on pre-operative EEG presented a high percentage of normal post-operative scalp EEGs. IID patterns on pre-operative scalp EEGs did not influence the outcomes of post-operative seizure controls, while patients with non-IID and focal IID on post-operative EEGs were likely to achieve post-operative seizure freedom. Patients with new focal IIDs presented a significantly lower percentage of seizure freedom than those without new focal IIDs on post-operative EEGs at 3-year follow-up. Conclusion: Over 1/3 children with TSC presented normal scalp EEGs after resective epileptsy surgery. Patients with post-operative seizure freedom were more likely to have non-IIDs on post-operative EEGs. New focal IIDs were negative factors for seizure freedom at the 3-year follow-up.

Relative Source Power: A novel method for localizing epileptiform EEG discharges.

OBJECTIVE: To validate relative source power (RSP) imaging of extratemporal interictal epileptiform discharges (IEDs). METHODS: The accuracy of RSP was validated in a cohort of patients with extratemporal focal epilepsy and a confined epileptogenic lesion (<19 cm3) using distance to the lesion, concordance with resected area and postoperative outcome. Performance was compared with three conventional methods: voltage maps, equivalent current dipole and a distributed source model. RESULTS: Thirty-three of 41 consecutive patients (80%) had IED averages suitable for analysis. While the peak negativity in voltage maps localized above the epileptogenic lesion only in 18 cases, RSP-maps matched in 29 cases (88%, p < 0.0026). Source localization showed a median distance of 9.8 mm from the lesion. Source-regions with 20 mm radius included 98% of all source-to-lesion distances. In the 21 surgical cases, outcome showed a sensitivity of 82.35% and specificity of 50% without significant differences between the three source imaging methods. CONCLUSIONS: RSP-maps provide a rapid, intuitive and more accurate source estimation than voltage maps. At sublobar level, RSP localizes with an accuracy similar to conventional methods and results of previous studies. SIGNIFICANCE: The definition of a source region with 20 mm radius helps in guiding further exploration in extratemporal focal epilepsy.

Towards fast and reliable simultaneous EEG-fMRI analysis of epilepsy with automatic spike detection.

OBJECTIVE: The process of manually marking up epileptic spikes for simultaneous electroencephalogram (EEG) and resting state functional MRI (rsfMRI) analysis in epilepsy studies is a tedious and subjective task for a human expert. The aim of this study was to evaluate whether automatic EEG spike detection can facilitate EEG-rsfMRI analysis, and to assess its potential as a clinical tool in epilepsy. METHODS: We implemented a fast algorithm for detection of uniform interictal epileptiform discharges (IEDs) in one-hour scalp EEG recordings of 19 refractory focal epilepsy datasets (from 16 patients) who underwent a simultaneous EEG-rsfMRI recording. Our method was based on matched filtering of an IED template (derived from human markup) used to automatically detect other 'similar' EEG events. We compared simultaneous EEG-rsfMRI results between automatic IED detection and standard analysis with human EEG markup only. RESULTS: In contrast to human markup, automatic IED detection takes a much shorter time to detect IEDs and export an output text file containing spike timings. In 13/19 focal epilepsy datasets, statistical EEG-rsfMRI maps based on automatic spike detection method were comparable with human markup, and in 6/19 focal epilepsy cases automatic spike detection revealed additional brain regions not seen with human EEG markup. Additional events detected by our automated method independently revealed similar patterns of activation to a human markup. Overall, automatic IED detection provides greater statistical power in EEG-rsfMRI analysis compared to human markup in a short timeframe. CONCLUSIONS: Automatic spike detection is a simple and fast method that can reproduce comparable and, in some cases, even superior results compared to the common practice of manual EEG markup in EEG-rsfMRI analysis of epilepsy. SIGNIFICANCE: Our study shows that IED detection algorithms can be effectively used in epilepsy clinical settings. This work further helps in translating EEG-rsfMRI research into a fast, reliable and easy-to-use clinical tool for epileptologists.

Predictors of seizure outcome following resective surgery for drug-resistant epilepsy associated with focal gliosis.

OBJECTIVEThe authors studied the clinical characteristics and postoperative outcomes of drug-resistant epilepsy associated with focal gliosis.METHODSFrom their epilepsy surgery database, the authors selected the patients with drug-resistant epilepsy and MRI-defined focal gliosis who underwent focal resective surgery. All patients underwent standard presurgical evaluation. Intracranial electroencephalography (EEG) was performed in patients with discordant presurgical data, ill-defined lesions, and lesions close to eloquent regions. Completeness of resection was defined on the basis of extraoperative and intraoperative electrocorticography studies. Favorable postoperative outcome was defined as Engel class I outcome during the last 2 years of follow-up.RESULTSSixty-six patients fulfilled inclusion criteria. An initial precipitating injury was present in 38 (57.6%) patients, mainly in the form of perinatal injury (n = 10), trauma (n = 10), and meningoencephalitis (n = 8). Gliosis involved a single lobe in 38 (57.6%) patients and 2 adjacent lobes in 14 (21.2%) patients; the remaining 14 (21.2%) patients had multilobar gliosis. In patients with unilobar or bilobar gliosis, the posterior region of the head was involved in 34 (65%) patients and the frontal lobes in 12 (23%) patients. During a median follow-up of 4 years (range 2-9 years), 41 (62.1%) patients had favorable outcome. On multivariate analysis, the presence of a well-defined aura (p = 0.019), electrocorticographically defined completeness of resection (p = 0.024), and normal postoperative EEG findings at 1 year (p = 0.003) were predictive of favorable postoperative seizure outcome.CONCLUSIONSFocal gliosis is a common etiology for drug-resistant extratemporal epilepsy in developing countries and is most often located in the posterior region of the head. The majority of these patients have perinatal injuries or neurological infections as initial precipitating injuries. Patients with focal gliosis have good postoperative seizure outcomes after well-planned resective surgery.

Epileptic interictal discharges are more frequent during NREM slow wave downstates.

Epileptiform activity in various but not all epilepsy and recording types and cerebral areas is more frequent in NREM sleep, and especially during sleep periods with high-amplitude EEG slow waves. Slow waves synchronize high-frequency oscillations: physiological activity from the theta through the gamma band usually appears during scalp-positive upstates while epileptiform activity occurs at transitory phases and the scalp-negative downstate. It has been proposed that interictal discharges (IIDs) are facilitated by the high degree of neuronal firing synchrony during slow wave transitory and downstates. This would suggest that their occurrence increases as a function of slow wave synchronization, indicated by greater amplitude, steeper slopes and higher EEG signal synchronization. We investigated the occurrence of IIDs during NREM sleep slow waves in epileptic patients undergoing presurgical electrophysiological monitoring. Intracranially registered IIDs preferentially occurred during the scalp-negative downstates of frontal scalp slow waves in all subjects. IID occurrence was more frequent during larger slow waves in the pooled sample and a subset of subjects. However, slow wave slope steepness and EEG signal synchronization between two frontal scalp channels was not significantly associated with IID occurrence. Our results indicate that IIDs indeed do not occur at the same slow wave phase as physiological rhythms, but contrary to previous hypotheses their occurrence is not strongly affected by EEG synchronization.

Synaptic Conductances during Interictal Discharges in Pyramidal Neurons of Rat Entorhinal Cortex.

In epilepsy, the balance of excitation and inhibition underlying the basis of neural network activity shifts, resulting in neuronal network hyperexcitability and recurrent seizure-associated discharges. Mechanisms involved in ictal and interictal events are not fully understood, in particular, because of controversial data regarding the dynamics of excitatory and inhibitory synaptic conductances. In the present study, we estimated AMPAR-, NMDAR-, and GABAA R-mediated conductances during two distinct types of interictal discharge (IID) in pyramidal neurons of rat entorhinal cortex in cortico-hippocampal slices. Repetitively emerging seizure-like events and IIDs were recorded in high extracellular potassium, 4-aminopyridine, and reduced magnesium-containing solution. An original procedure for estimating synaptic conductance during IIDs was based on the differences among the current-voltage characteristics of the synaptic components. The synaptic conductance dynamics obtained revealed that the first type of IID is determined by activity of GABAA R channels with depolarized reversal potential. The second type of IID is determined by the interplay between excitation and inhibition, with early AMPAR and prolonged depolarized GABAA R and NMDAR-mediated components. The study then validated the contribution of these components to IIDs by intracellular pharmacological isolation. These data provide new insights into the mechanisms of seizures generation, development, and cessation.

Minimum norm estimates in MEG can delineate the onset of interictal epileptic discharges: A comparison with ECoG findings.

The analysis of epileptic discharges in magnetoencephalography with minimum norm estimates (MNE) is expected to provide more precise localization of epileptic discharges compared with electroencephalographic estimations. However, the clinical feasibility of MNE remains unclear. In this study, we aimed to elucidate the onset and propagation patterns of interictal spikes using MNE. Seven patients with intractable epilepsy whose epileptogenicity was assumed to exist in the convexity of the cerebral cortex were studied. For MNE and electrocorticography (ECoG), we characterized the propagation patterns of interictal epileptic discharges according to the area in which they originated and where they extended; we then examined whether the propagation patterns observed in MNE were identified by ECoG. We also examined the relationship between the positions of spikes estimated by the equivalent current dipole (ECD) method and MNE. Among the seven patients, nine propagation patterns of epileptic discharges were observed by MNE, all of which were also identified by ECoG. In seven patterns, the epileptic activity propagated around the initial portion. However, in two patterns, the center of activities moved according to propagation with maintained activity of the initial portion. The locations of spikes identified by the ECD method were within the areas estimated by MNE when the epileptic activity propagated. However, the ECD method failed to detect onset activities identified by MNE in three of nine patterns. Thus, MNE is more useful as a means of presurgical evaluation for epilepsy than the ECD method because it can delineate the onset of epileptic activities as shown in ECoG.

The Effects of Lamotrigine on Epileptiform Discharges Induced by Mg2+ -free Medium and 4-aminopyridine in Hippocampal Slices of Immature Rats / 대한소아신경학회지

PURPOSE: In order to elucidate the actual mechanism and the optimal concentration of Lamotrigine(LTG) that suppresses epileptiform discharges, we observed epileptiform discharges from hippocampal slices of immature rat in 4-aminopyridine(4-AP) added Mg2+ - free medium of artificial cerebrospinal fluid(aCSF) with various LTG concentrations. METHODS: We divided 19-23 day-old Sprague-Dawley rats into 4 groups; control group(n=12) and 3 LTG groups depending on the concentrations of LTG such as 400 (n=9), 800(n=7), and 1,000(n=8) microM. The rats were anesthetized and their brains were taken, soaked in aCSF(NaCl 125 mM, KCl 2.5 mM, NaH2PO4 2 mM, MgSO4 1.25 mM NaHCO3 25 mM, CaCl2 2 mM, Glucose 10 mM, pH 7.3-7.4). And then the brains were cut into 400 microm hippocampal slices by a vibratome. The slices of control group were soaked in 200 microM 4-AP added Mg2+ -free medium of aCSF for 1 hour, and then extracellular recordings were performed in hippocampal CA1 pyramidal region. The slices of LTG groups were soaked in the solution containing 400, 800, and 1,000 microM LTG, then extracellular recordings were performed. RESULTS: Interictal discharges were observed in all the control and the LTG groups. The latency to the first interictal discharges after 4-AP addition was 52.7+/-26.9 sec in control group, but was 225.0+/-28.2 sec in 800 microM and 322.1+/-116.4 sec in 1,000 microM group of LTG(P<0.05). The duration of interictal discharges was 64.6+/-35.6 sec in control group, but was the shortest in 800 microM group of LTG at 39.3+/-12.6 sec. Ictal discharges were observed in all of control and 400 microM group, but the frequency was decreased as the concentration of LTG increases, 57.1% in 800 microM, 12.5% in 1,000 microM group. The latency to ictal discharge after 4-AP addition was 142.1+/-52.6 sec in control group, but increased as the concentration of LTG increases, 304.4+/-84.5 sec in 400 microM group and 689.8+/-213.1 sec in 800 microM group(P<0.05). The duration of ictal discharges was 1,534.7/-339.3 sec in control group, but decreased as the concentration of LTG increases, it was 126.5+/-76.1 sec in 800 microM group(P <0.05) and 42 sec in 1,000 microM group. CONCLUSION: The antiepileptic effects of LTG were most significant when the concentration, inhibiting epileptiform discharges induced by 4-AP and Mg2+ -free medium in hippocampal slices of immature rats, was 800 microM or higher. Although the basic pharmacologic mechanism of LTG is the inhibition of sodium channel, it may also work on potassium channel at higher concentrations.

The Effects of Topiramate on Epileptiform Discharges Induced by Mg(2+)- Free Medium and 4-Aminopyridine in Hippocampal Slices of Immature Rats / 대한소아신경학회지

PURPOSE: Topiramate(TPM), one of the newest antiepileptic drugs, has been prescribed not only to refractory partial seizures but to generalized tonic-clonic seizures. However, its action mechanisms are not well understood and the optimal dose of antiepileptic efficacy in animal seizure models is not determined yet. In order to elucidate the action mechanisms and the optimal concentration of TPM that suppresses epileptic discharges, we observed ictal and interictal discharges from immature rat hippocampal slices in Mg(2+)-free, and 4-aminopyridine(AP) added artificial CSF with various TPM concentrations. METHODS: We divided Sprague-Dawley rats of 19 to 23 days old into 5 groups; namely, a control group(n=12) and 4 TPM groups according to the concentration of TPM, 6 (n=11), 20(n=7), 60(n=10), and 200(n=14) micrometer. The rats were anesthetized and their brains were taken, and soaked in artificial CSF(NaCl 125 mM; KCl 2.5 mM; NaH2PO4 2 mM; MgSO4 1.25 mM; NaHCO3 25 mM; CaCl2 2 mM, Glucose 10 mM, and pH 7.3-7.4). Then the brains were cut into 400 micrometer hippocampal slices by a vibratome. The slices of the control group were soaked in 200 micrometer 4-AP added Mg(2+)-free medium for 1 hour, and then extracellular recordings were performed in the hippocampal CA1 pyramidal region. The slices of TPM groups were soaked in solutions containing 6, 20, 60, 200 micrometer TPM, and then extracellular recordings were performed. RESULTS: Interictal discharges were observed in the control group and 6, 20 micrometer groups but the frequency decreased as the concentration of TPM increased:90% in 60 micrometer group, and 35.7% in 200 micrometer group. And the amplitude of TPM groups was much smaller than that of the control group. The latency to the first interictal discharge after 4-AP addition was 52.7+/-7.5 sec in the control group, 290.2+/-78 sec in 60 micrometer group, and 568+/-113.1 sec in 200 micrometer group. Duration of the interictal discharge was 64.6+/-10.3 sec in the control group, but was prolonged to 141+/-38.1 sec in 60 micrometer group(P<0.05). Ictal discharges were observed in all of the control and 6 micrometer groups, but the frequency decreased as the concentration of TPM increased:55.6% in 60 micrometer, and 28.6% in 200 micrometer groups. The amplitude of the TPM groups was much smaller than that of the control group. The latency to ictal discharges after 4-AP addition was 141+/-15.2 sec in the control group, but increased as the concentration of TPM increased:431.8+/-57.4 sec in 60 micrometer, and 627.8+/-143.5 sec in 200 micrometer group(P<0.05). The duration of ictal discharges was 1,534.7+/-97.9 sec in the control group, but decreased as the concentration of TPM increased, the shortest in 60 micrometer group, 155.2+/-65.5 sec(P<0.05). Status epilepticus was seen in 58.3% of the control and 27.2% of 6 microM groups. CONCLUSION: TPM suppresses the frequency, latency, and duration of epileptiform discharges induced by Mg(2+)-free, and 4-AP added artificial CSF in immature rat hippocampal slices, starting from 20 micrometer and reaching the maximal effect at over 60 micrometereter. This finding is presumably due to TPM enhancing of GABA receptor currents and/or K+ channel conductance in response to TPM.