Epilepsia, 49(Suppl. 1):19–25, 2008 doi: 10.1111/j.1528-1167.2008.01445.

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SUPPLEMENT - MANAGEMENT OF A FIRST SEIZURE

First seizure: EEG and neuroimaging following an epileptic seizure

Bernd Pohlmann-Eden and †Mark Newton

Bethel Epilepsy Center, Bielefeld, Germany; and †Comprehensive Epilepsy Program, Austin Health, Heidelberg, Australia

SUMMARY
An early EEG (within 48 h) and high-resolution magnetic resonance imaging (hr_MRI) are the methods of choice for an accurate diagnosis after a first seizure presentation. Together with a careful history and examination, they will allow definition of the epilepsy syndrome in two-thirds of patients and help assess the individual risk for seizure recurrence, which is determined by the specific syndrome and is highest with focal epileptiform activity on EEG. Despite the heterogeneity of first seizure studies, EEG and etiology are consistently found to be the best predictors for seizure recurrence and prognosis. The additional yield of sleep-

deprived EEG and sleep EEG is uncertain; yet MRI is essential for detecting brain tumors and other structural bases for new epilepsy. The rate occurrence of remote symptomatic seizures increases significantly with age and the most common etiology in the elderly with a first seizure is stroke; however, its exact relevance to epileptogenicity is yet to be defined. There is a striking lack of systematic studies using early EEG and hr_MRI in order to better characterize epileptogenic areas and elucidate the mechanisms of seizure provocation. KEY WORDS: First seizure, Diagnosis, EEG, Computerized tomography, Magnetic resonance imaging.

A first seizure is a very common condition and also a very frightening event, which raises urgent health and lifestyle issues and makes counseling rather complex. Particularly important is the question whether the seizure is a symptom of a transient encephalopathy or an underlying epileptogenic brain pathology as these conditions will determine the prognosis with regard to seizure recurrence. Numerous studies have been performed in the last 3 decades to identify predictors of seizure recurrence. Berg and Shinnar’s (1991) careful meta-analysis identified an abnormal EEG and an underlying documented cause as the most consistent findings. While the early studies based their etiological assessment and diagnosis of a symptomatic seizure or epilepsy mainly on clinical findings (seizure semiology, physical examination, history) aided sometimes by imaging with computerized tomography (CT) and EEG, there are now advanced EEG and neuroimaging procedures that not only confirm these data
Address correspondence to Bernd Pohlmann-Eden, M.D., Ph.D., Professor of Neurology and Public Health, Head and Chair, Bethel Epilepsy Center, Maraweg 21, D-33617 Bielefeld, Germany. E-mail: pohleden@gmx.net Blackwell Publishing, Inc. C International League Against Epilepsy

but also allow early determination of a possible underlying epilepsy syndrome (King et al., 1998; Jallon et al., 2001). This review will address the following: (1) What novel information can be derived from first seizure (FS) studies using functional and structural diagnostic procedures? (2) What are the potential interpretations and limitations of EEG and neuroimaging in current FS studies? (3) How much obligatory are EEG and neuroimaging to define an epilepsy syndrome? (4) What are the principal considerations for prognosis and the future challenges of FS research?

W HAT N OVEL I NFORMATION C AN BE D ERIVED FROM FS S TUDIES U SING F UNCTIONAL AND S TRUCTURAL D IAGNOSTIC P ROCEDURES ?
Seizure selection bias: An FS only comes to medical attention if the individual (or witness) becomes aware of it and feels threatened so to seek help. Thus, the entire discussion and evaluation of data is biased by the fact that most of the FS studies deal with patients after their first tonic-clonic seizure. Clinical experience and systematic investigations tell, however, that many of these patients 19

20 B. Pohlmann-Eden and M. Newton already had previous minor epilepsy symptoms. Awareness of the event or aftermath is crucial for presentation and events during sleep will pass unnoticed. Thus, the “first seizure” is a concept (or sometimes the tip of an iceberg) rather than a clearly defined event. We have no clear idea of the individual considerations making a brain epileptic or of the complex interplay between genetic, structural, biochemical, and functional factors. We do not know if an accumulation of provoking factors over time will lower the seizure threshold. Nor do we know why a significant provoking factor only sometimes leads to a seizure in one individual, but not in another. This raises the question of what exactly is provocation. Is every seizure somehow provoked? According to the International League Against Epilepsy (ILAE) definition, a seizure or repeated seizures occurring in close temporal association with an acute systemic, metabolic, or toxic cerebral insult are considered to be “provoked,” as compared to seizures occurring in relation to a well-demonstrated antecedent condition, substantially increasing the risk for epileptic seizures, which are considered to be “unprovoked” (Commission on Epidemiology and Prognosis and International League Against Epilepsy, 1993). Hauser & Beghi (2007) review these widely accepted definitions in this volume, which have operationally helped to organize and understand study findings. However, they leave us with the question if “provoked” and “unprovoked” are distinct points rather than transitional states within a spectrum of provoking and inhibiting factors. According to the most recent ILAE definition, epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In that sense, the definition of epilepsy requires the occurrence of at least one epileptic seizure (Fisher et al., 2005). We certainly want to get subtle information with regard to this enduring predisposition, by collecting detailed information of the functional state and structural condition of the brain close to the time of the FS and in clearly defined homogenous study groups. Unfortunately, we are currently far from this ideal situation. Data have therefore to be interpreted with all caution and qualification. There are surprisingly few data on the significance and prognosis of EEG recordings in the early course of epilepsy for long-term prognosis. A community-based study almost 20 years ago identified three variables highly predictive of achieving 5-year seizure-freedom: (1) no earlylife damage, (2) never having had a generalized tonic– clonic seizure, and (3) no generalized epileptiform activity (Shafer et al., 1988). However, several studies have addressed the role of EEG for early prognosis in patients presenting with an FS. This will be the focus of this brief review, which is not intended to be exhaustive, addressing only the most relevant findings in well-controlled clinical trials and acknowledging the heterogeneous nature of the study populations. The importance of these studies for practical counseling was recently emphasized (PohlmannEden et al., 2006). The value of the EEG lies in (1) suggesting the presence of focal lesions (with localized slow waves), (2) allowing individual prediction of SR, and (3) indicating a specific epilepsy syndrome (e.g., 3-Hz spikewave pattern). In a prospective FS study in 157 adult patients presenting mostly with generalized tonic clonic seizures, standard EEG was more sensitive in detecting abnormalities compared to the clinical and neuroradiological data (Schreiner & Pohlmann-Eden, 2003); the neurological status was absolutely normal in 10 out of 20 patients (50%) with cerebral neoplasms, while the EEG was abnormal in 91.7%. In patients with underlying cerebrovascular disease, the EEG showed abnormalities in 88.6% when only one-third had obvious focal clinical findings. According to the careful meta-analysis of 16 FS studies in children and adults by Berg and Shinnar in 1996, in all reports except one (Hopkins et al., 1988), the presence of any EEG abnormality was associated with a significantly higher risk for seizure recurrence. To appropriately interpret these data, however, it is necessary to carefully look at the study population, design, and methodology, yet this information is often lacking or incomplete (see Table 1). Till the mid nineties, the available studies (Cleland et al., 1981; Elwes et al., 1985; Annegers et al., 1986; Hopkins et al., 1988; Hauser et al., 1990) provided very little information on the study populations. Since 1995 very few additional studies have been performed using MRI in a high percentage (Forsgren et al., 1996; King et al., 1998; Pohlmann-Eden & Schreiner 1998a; Lindsten et al., 2001; Schreiner & Pohlmann-Eden, 2003), and only one specifically aimed at identifying the underlying epilepsy syndrome by means of clinical, EEG, and neuroimaging data (King et al., 1998). The importance of the study design was emphasized in Berg and Shinnar’s meta-analysis, explaining the wide range of reported seizure recurrence rates (from 30% to 80% within 3–4 years). The most relevant sources of heterogeneity are the selection of patients (age, site of

EEG F INDINGS IN C URRENT FS S TUDIES : P OTENTIAL I NTERPRETATIONS AND L IMITATIONS
Whether an EEG should be obtained routinely in patients after an FS is still under debate. There are pragmatic implications (Fountain & Freeman, 2006) and some authors would not treat after an FS, even if the EEG is abnormal. Yet EEG remains an essential tool for understanding the underlying process and providing the best counseling.
Epilepsia, 49(Suppl. 1):19–25, 2008 doi: 10.1111/j.1528-1167.2008.01445.x

21 EEG and Neuroimaging after a First Seizure Table 1.
Authors Blom et al., 1978 Cleland et al., 1981 Camfield et al., 1985 Elwes et al., 1985 Annegers et al., 1986 Hopkins et al., 1988 Hart et al., 1990 Hauser et al., 1990 van Donselaar et al., 1992 FIR.S.T. 1993 Bora et al., 1995 Forsgren et al., 1996 King et al., 1998 Ramos Lizana et al., 2000 Neufeld et al., 2000 Jallon et al., 2001 Hui et al., 2001 Lindsten et al., 2001 Schreiner & Pohlmann-Eden, 2003a
a

Age groups, study design and study population, ancillary methods in first seizure studies
n 74 70 168 133 424 408 564 208 157 397 147 563 300 217 91 926 132 107 166 Age groups Children Adults Children All age groups All age groups Adults Adults Adults Adults Adults Adults Adults All age groups Children Adults All age groups All age groups Adults Adults Study design Prospective Retrospective Retrospective Retrospective and prospective Retrospective Prospective Retrospective and prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Retrospective Prospective Retrospective Prospective Prospective Setting Hospital Hospital Hospital Hospital Outpatients Hospital Outpatients Hospital Hospital Hospital Hospital Population-based Hospital Hospital Hospital Practice hospital Hospital Population-based Hospital EEG-classes 3 classes NA 4 classes NA 4 classes 4 classes NA 5 classes 3 classes 2 classes 4 classes NA 3 classes 5 classes NA 3 classes NA 4 classes Early EEG (<48 h) No No No No No No No No No No No No YES No No No No YES CT NA NA NA NA NA NA NA NA NA NA NA 80% NA 69% 58% 64% 98% 94% MRI NA NA NA NA NA NA NA NA NA NA NA 58% 89% Few cases 7% NA 45% 60%

CT, computerized tomography; MRI, magnetic resonance imaging; NA, not available. The classification of the EEG findings varied across studies (most frequently classified as normal, diffuse slowing, focal slowing, focal epileptiform, or generalized epileptiform).

recruitment, exclusion criteria, definition of “provoked” seizure, inclusion of patients with uncertain seizures) the time point of study entry, and the retrospective versus prospective design. According to Berg & Shinnar (1991), the seizure recurrence was 40% in prospective and 52% in retrospective studies that employed first seizure methods and 67% in non-FS studies (i.e., new-onset epilepsy). With regard to the EEG methodology, the time point of the EEG (tpEEG) recording seems to be of paramount significance. The average time from FS to the first EEG was 3 years in a community-based study as compared to 1 month if the diagnosis of epilepsy was already established (Shafer et al., 1988). This surprising observation may reflect the above-mentioned and still current controversy about the pragmatic (decision-influencing) value of an EEG after an FS (Fountain & Freeman, 2006). In the study by King et al. (1998), an EEG performed within 24 h after an FS detected epileptiform abnormalities in 51%, compared with only 34% of the patients with a later EEG. The only two other studies with EEG recordings within 48 h reported EEG abnormalities in up to 70% (Neufeld et al., 2000; Schreiner & Pohlmann-Eden, 2003). In the remaining studies (with no information available but perhaps later tpEEG; Table 1), the EEG abnormality rates were significantly lower, between 9% and 51%. Most of the studies included hyperventilation and photic stimulation in their routine EEG recordings, but did not de-

fine the exact methodology for a correct interpretation of potential value and findings of these activations. The additional yield of sleep-deprived and sleep EEG is still uncertain. Most patients underwent sleep-deprived EEG, if they had no epileptiform abnormalities on their first routine EEG (King et al., 1998; Schreiner & Pohlmann-Eden, 2003). Most of the studies (Table 1) distinguished and stratified 3 to 5 classes of EEG findings (normal, diffuse abnormal [slowing], focal slowing, focal epileptiform, generalized epileptiform). The rate of any abnormality ranged from 41% to 80% in nonselected and from 9% to 63% in selected populations, and were predictive of seizure recurrence in all but two studies (Hopkins et al., 1988; Bora et al., 1995). Schreiner and Pohlmann-Eden reported only 10% normal EEGs in their FS patients with seizure recurrence compared to 38% who remained seizure-free. The reported yield of epileptiform activity in routine EEG ranged from 12% to 27% (Hopkins et al., 1988; van Donselaar et al., 1992; Neufeld et al., 2000; Schreiner & Pohlmann-Eden, 2003) and increased to 23–50% if sleep recordings could be obtained (van Donselaar et al., 1992; King et al., 1998; Schreiner & Pohlmann-Eden, 2003). The proportion with epileptiform activity on the first EEG was found to be significantly greater in children compared to patients older than 16 years both in a prospective series (59% versus 39%, King et al., 1998) and in
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22 B. Pohlmann-Eden and M. Newton a retrospective investigation (Neufeld et al., 2000). In a Dutch prospective study of children, the seizure recurrence rate was 71% when an epileptiform EEG was present (Stroink et al., 1998), while the overall recurrence rate was 54%. In King et al.’s 300 patients, additional sleep deprived EEG showed epileptiform activity in another 55 patients (35%). The much lower additional yield of epileptiform activity in the series of Schreiner and Pohlmann-Eden (9 out of 166; 8 with generalized epileptiform activity) could be explained by a longer time interval between first routine EEG and the sleep deprived study. The high predictive value of generalized epileptiform activity for seizure recurrence was only reported in selected patient populations most likely representing idiopathic epilepsy (Hauser et al., 1990; van Donselaar et al., 1992). However, in van Donselaar’s cohort the risk for seizure recurrence was up to 83% as compared to patients with nonepileptiform abnormalities (41%) and normal EEGs (12%). Focal epileptiform activity especially when associated with focal slowing carried a significantly higher risk for seizure recurrence in an FS patient population containing a substantial proportion of cases with cerebrovascular disease: focal epileptiform activity was found in 26.5% of the seizure recurrence group as compared to 13.0% of the seizure-free patients. These data are also in agreement with few previous reports in which information was provided on recurrence risk as a function of etiology and EEG; the risk was lowest in the idiopathic group and highest in the remote symptomatic group with abnormal EEG (Camfield et al., 1985, Annegers et al., 1986). In conclusion, an early abnormal EEG, especially when showing focal epileptiform activity, seems to be an excellent predictor for seizure recurrence. The yield of subsequent sleep-deprived EEG and sleep EEG remains uncertain; however, the few data available support the view that they provide valuable additional information with regard to syndrome classification and seizure recurrence rates. Until 1995, etiology and subsequent classification as either remote symptomatic or cryptogenic according to the ILAE criteria was mainly based on clinical data and CT. However, in those studies there was a striking lack of detailed information on the CT methodology (e.g., slice thickness, use of contrast media) and even on the exact number of patients undergoing CT (classified as “not available” = “NA” in Table 1). Often CT (and MRI) was only performed in patients with abnormal clinical findings. Not too surprisingly, the number of pathological findings increases significantly with MRI, which is more sensitive than CT in detecting subtle lesions. The abnormality rate is also dependent on the study population; a higher rate of acquired brain pathologies will be expected in older patients. In a retrospective Hong Kong study (Hui et al., 2001) using CT in 64% of their 132 adult patients, very few (6.8%, 9 out of 85) showed abnormalities such as cerebral atrophy, arachnoid cysts, and cerebrovascular disease. It is speculative whether these findings had any causal relationship to the FS event. In the population-based study by Forsgren et al. (1996) done almost 5 years earlier, 563 patients presenting with an “unprovoked seizure” received CT (80%) and/or MRI (54%) investigations. In this study, the rate of imaging findings was much higher: stroke was the most common etiology, detected in 30% (increasing to 45% at age >60 years). Tumors were detected in 11%, and changes consistent with Alzheimer’s dementia in 7%. Unfortunately, the additional yield of MRI above CT is not documented in this study. A Swedish prospective study examining remission rates of newly diagnosed unprovoked epileptic seizures, CT (performed in 99%) and MRI (41%) revealed a remote symptomatic etiology in 61% of cases (Lindsten et al., 2001). However, data on the spectrum of radiological abnormalities are scant, with only a high percentage of brain tumors mentioned (5 meningiomas and 4 gliomas). The superiority of MRI in the detection of tumors is stressed by the Australian study (King et al., 1998) and confirmed by Pohlmann-Eden & Schreiner (1998a). MRI was done in the majority of King et al’s 300 patients (89%), showing epileptogenic lesions in 38 patients, 17 being tumors. CT with contrast, however, missed 8 tumors out of 17 (45%), including four astrocytomas—all surgical remediable lesions. In our series without MRI, we would have missed 3 out of 20 patients with brain tumor diagnosis (12% of all 166 FS patients) all of them with no focal clinical signs (Pohlmann-Eden & Schreiner, 1998a). When children were included in the analysis of the Australian study (mean age 31.2 years, median 25.6 year), MRI detected 22 more subtle epileptogenic lesions (disorders of cortical development, trauma, hippocampal sclerosis and atrophy, cavernous angioma) and most of these did not show on CT. In a prospective observational study in children presenting with their first unprovoked seizure,

N EUROIMAGING F INDINGS IN C URRENT FS S TUDIES : P OTENTIAL I NTERPRETATIONS AND L IMITATIONS
Compared to the EEG studies, information on structural findings in FS patients is much poorer and only recently it has become of interest for the availability of MRI. It cannot be emphasized enough that these “subclinical structural” findings have to be interpreted with all caution in regard to their potential epileptogenicity. They might be coincidental and have always to be considered in the light of the epileptogenic mechanisms, encompassing all clinical, functional, and structural information.
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23 EEG and Neuroimaging after a First Seizure 45 (21%) out of 218 imaging studies (159 underwent CT, 59 had MRI) revealed abnormalities, most of them showing focal ischemic lesions (16 out of 45) or cerebral dysgenesis (11 out of 45) (Shinnar et al., 2001). Clinically significant neuroimaging abnormalities occurred in only 8% of a large, retrospective review of children presenting with emergent new-onset afebrile seizures; however, this percentage increased up to 26%, if the subgroup of children who met risk factors such as focal seizures or predisposing conditions were analyzed (Sharma et al., 2003). The German study which included a significantly older study population (mean age 47.8 years, only adults), showed a high percentage of cerebrovascular lesions (26% of their 166 patients), followed by brain tumors (12%), traumatic scars (5%), and other lesions (4%). Neuroimaging of an FS in the elderly has become a very important topic. There is no doubt that cerebrovascular disease is the most frequent underlying pathology associated with both single seizures and new-onset epilepsy in the elderly, accounting for almost one-third of these patients, despite the fact that many studies are flawed by fundamental design problems (e.g., grouping together different subtypes of stroke, no distinction between single seizures and epilepsy). However, in these cases the causal relationship is not always clear (Pohlmann-Eden et al., 1996). While it has been repeatedly emphasized that cortical involvement is a strong predictor for SR in poststroke seizures, our own rigorous analysis of the topography of stroke lesions in FS patients clearly favored the concept that a disturbed interaction (and/or lesion) of both cortical and subcortical functions may increase the risk of SR: 67.8% had a combined cortical-subcortical lesion, 19.9% a subcortical lesion, and 12.3% a cortical lesion (Pohlmann-Eden et al., 1996). There is some evidence that patients with the PCI sign (“preserved cortical islands”) and undercut cortex may also be at particular risk for seizure recurrence after stroke (Pohlmann-Eden et al., 2001). However, this has yet to be demonstrated by a prospective trial. Subcortical vascular encephalopathy was also found to be associated with an increased risk for seizures (Schreiner et al., 1995). The potential relevance of occult cerebrovascular disease in FS in the elderly was recently emphasized by an epidemiological study. According to the large U.K. General Practice Research Database, 4,709 patients older than 60 years presenting with their FS “of unknown etiology” were at significantly higher risk to develop stroke compared to 4,709 randomly selected controls without seizures (Cleary et al., 2004). However, as cerebrovascular lesions are very frequent, their actual “epileptogenicity” has to be carefully assessed in each individual. We agree with the conclusion of the Australian group that the final diagnostic yield of MRI in FS cases is not yet known as there are too few data reported so far. MRI is therefore the method of choice for neuroimaging in the FS of unknown etiology, with very few exceptions such as children with 3 s/ spike-wave on EEG and no focal clinical or EEG findings (Pohlmann-Eden et al., 2006). The role of MRI in adults presenting with electroclinical features of IGE is not yet clear, although it is unlikely to be of value. CT should be only performed when MRI is either not available or contraindicated.

EEG AND N EUROIMAGING AS O BLIGATORY D IAGNOSTIC P ROCEDURES TO D EFINE THE E PILEPSY S YNDROME
Two studies specifically addressed the question to what extent EEG and neuroimaging (together with clinical data) were able to identify an epilepsy syndrome already at the stage of a probable FS or new-onset epilepsy (King et al., 1998; Jallon et al., 2001). In the French CAROLE study (Jallon et al., 2001), all but 17 patients had EEG, 57.9% had CT, and 6.5% had MRI, although half of the patients who presented with the “first” unprovoked seizure actually met epidemiological criteria for epilepsy (926 out of 1,942 patients). There were substantial differences in the distribution of epilepsy syndromes in the FS group compared with the newly diagnosed epilepsy group. IGE with absence and myoclonic seizures were not represented in the FS group (except those presenting as status epilepticus with ongoing behavioral and motor disturbances), as they did not come to attention with their very first symptoms. A specific epilepsy syndrome could be assigned to nearly half the FS patients: 8.6% idiopathic localization-related, 16.1% symptomatic localization-related, 10% cryptogenic localization-related, 16% idiopathic generalized, 1.4% symptomatic generalized, and 0.2% undetermined (2 out of 926 patients). The remaining 441 cases were classified as “isolated seizures.” A most rigorous approach to determine an epilepsy syndrome in an FS presentation (including also new-onset epilepsy) was adopted by King et al. (1998) using MRI in up to 90% of their patients and early EEG plus sleepdeprived EEG, if routine EEG was normal. The authors were able to classify localization-related or generalized syndromes in only 47% of cases with clinical information versus 77% of those with EEG findings, and 81% of those with MRI. Their findings emphasize the outstanding role of EEG for syndrome classification and the comparably low additional impact of MRI at this time point. These results confirm the previous pre-MRI studies in which EEG and clinical data allowed syndrome classification in the majority of their cases. In summary, we strongly suggest that both early EEG and MRI should be part of a systematic comprehensive
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24 B. Pohlmann-Eden and M. Newton diagnostic approach in FS patients including all appropriate clinical information.
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P RINCIPAL C ONSIDERATIONS AND F UTURE C HALLENGES
In general, current studies have no rigorous design and basically confirm the results of the old studies with EEG and etiology as the most significant risk factors. To understand the ephemeral hyperexcitability state of the brain after an FS and its epileptogenic potential, more sophisticated data, prospectively acquired, are needed in both functional and structural domains in well defined populations. The additional yield of an early EEG recording is already a clear directive for future research. It is speculative that a prolonged EEG recording with standardized inclusion of both sleep and sleep-deprivation (short-term EEG monitoring) could provide more insight into the ictogenic and epileptogenic processes. It could be anticipated that MRI with its increasing sensitivity will contribute to a much larger extent to the understanding of epileptogenic structural changes, and the potential of functional MRI in this context has yet to be explored. A methodological paradigm shift and new perspectives on the “FS scenario” might bring new understanding to both isolated and early epilepsy seizures. For example, there are very few data on EEG-monitored functional brain disturbances in patients considered to be at risk for an FS. We ourselves started a pilot project and prospectively investigated 30 “seizure-free” consecutive stroke patients with standardized early EEG-monitoring: almost one-third presented with subclinical epileptiform activity such as period lateralized epileptiform activity, spikes, sharp waves, most of them within the very first hours after the stroke, and significantly more were observed in combined cortical-subcortical extended lesions (Pohlmann-Eden et al., 1998b); this was confirmed in an extended series by Strittmatter et al. (2002), in which 6 of 26 poststroke patients developed clinical and subclinical seizures, some of them simultaneously in topographically distant areas. We speculate that future FS studies will carry a high potential for a better understanding of both ictogeneses and epileptogenesis and the pathophysiological circumstances of “provocation.”
Disclosure of Conflicts of Interest: The authors have declared no conflicts of interest.

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Epilepsia, 49(Suppl. 1):19–25, 2008 doi: 10.1111/j.1528-1167.2008.01445.x