Clinical Neurophysiology

Transcription

1 Clinical Neurophysiology 122 (2011) Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: Localization of pediatric seizure semiology Martina Vendrame a, Marcin Zarowski a,b, Andreas V. Alexopoulos c,d, Elaine Wyllie d, Sanjeev V. Kothare a, Tobias Loddenkemper a, a Epilepsy and Clinical Neurophysiology, Children s Hospital Boston, Boston, MA, United States b Polysomnography and Sleep Research Unit, Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland c Epilepsy Center, Cleveland Clinic, Cleveland, OH, United States d Pediatric Neurology Center, Cleveland Clinic, Cleveland, OH, United States article info highlights Article history: Accepted 2 March 2011 Available online 6 April 2011 Keywords: Epilepsy surgery Epileptogenic zone Ictal zone Seizure semiology Electroencephalography EEG monitoring On examination of seizure semiology and EEG localization we did not find a one-to-one relationship. Different seizure semiologies relate to specific brain regions, but this relationship is not exclusive. Our findings support the recent separation of seizure semiology and epilepsy localization by the ILAE. abstract Objective: The aim of this study was to evaluate the relationship between semiology of seizures in children and adolescents to the corresponding EEG localization. Methods: Charts of 225 consecutive pediatric epilepsy patients undergoing Video-EEG monitoring (VEM) over 2 years were reviewed. Seizure semiology recorded during VEM was classified according to ILAE seizure semiology terminology and EEG localization, and analyzed based on onset as defined by the EEG data (generalized, frontal, temporal, parietal, occipital or multilobar). Results: A total of 1008 seizures were analyzed in 225 children (mean age 8.5 years, range 0 20), with 50% boys. Auras and seizures with automatisms arose predominantly from the temporal lobes (p < 0.001). Tonic, clonic and tonic-clonic seizures had most commonly generalized onset (p < 0.001). Hypomotor seizures were most frequently seen from the frontal lobes (p < 0.001). Hypermotor seizures had most commonly temporal lobe or multiple lobe onset (p < and p < 0.05 respectively). Atonic, myoclonic seizures and epileptic spasms had almost exclusively a generalized onset (p < 0.001). Conclusions: Different seizure semiologies relate to specific brain regions, with overlap between focal and generalized semiological seizure types, as identified electrographically. Significance: Semiology of seizures can provide important information for epilepsy localization, and should not be overlooked, especially in patients undergoing pre-surgical evaluation. Separation of clinical seizure description and EEG findings may be useful, in particular when only incomplete information is available. i.e. during the first office visit. Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. 1. Introduction The main goal of resective epilepsy surgery is the complete resection of the epileptogenic zone, i.e. the area of cortex that is indispensable for the generation of epileptic seizures (Rosenow and Luders, 2001). The pre-surgical work-up aims at the estimation of the epileptogenic zone, and consists of a multi-step evaluation of Corresponding author. Address: Epilepsy and Clinical Neurophysiology, Children s Hospital Boston, 300 Longwood Ave., Fegan 9, Boston, MA 02115, United States. Tel.: ; fax: address: Tobias.loddenkemper@childrens.harvard.edu (T. Loddenkemper). clinical data, including seizure semiology, electrographic (EEG) recordings, neuroimaging, functional imaging and other neurophysiological tools, and neuropsychological testing. It is well accepted that the availability and use of information on seizure semiology during the pre-surgical workup improves lateralization and localization of the epileptogenic zone (Loddenkemper and Kotagal, 2005). Data on semiology is gathered historically (i.e. from the patient s description, and observer reports of seizures if available), and by further analysis during video-eeg recordings. The relevance of clinical localizing signs and seizure semiology has also been recognized by the ILAE. A descriptive terminology of ictal semiology has been introduced to better describe and recognize semiological features, which may be of localizing or lateraliz /$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi: /j.clinph

2 M. Vendrame et al. / Clinical Neurophysiology 122 (2011) ing significance (Berg et al., 2010; Blume et al., 2001). Similarly, proposals for classification of epilepsy have also included such considerations (Berg et al., 2010; Loddenkemper et al., 2005; Kellinghaus et al., 2004; Engel 2001; Luders et al., 1998). The available information on the localizing significance of different semiological features has mostly relied on selected case series and retrospective analysis of surgical data. To our knowledge, no systematic analysis of the corresponding EEG data in seizures of different semiology has been reported. The aim of this study was to evaluate the relationship between semiology of seizures in children and adolescents to the corresponding EEG localization. 2. Methods 2.1. Patient selection We undertook a retrospective review of charts of 380 consecutive patients undergoing Video EEG monitoring (VEM) at our pediatric epilepsy monitoring unit. We excluded 155 patients due to one or more non-epileptic events recorded during VEM (regardless of the presence of epileptic events) (79), missing data (26), no recorded seizures (8), and age >21 years (42). A total of 225 patients were thus included Continuous video-eeg monitoring Patients underwent VEM for a period of time ranging from 1 day up to 9 days. During the admission, antiepileptic drugs (AEDs) were tapered as needed, in a patient-specific pattern, taking into account seizure frequency and severity as well as prior history of status epilepticus. All scalp-eeg recordings were performed using the international system of electrode placement, with additional placement of anterior temporal electrodes. Video recordings were obtained by digital closed-circuit video cameras and continuously monitored during day-time and night-time by EEG technologists. The EEG and video data were interpreted by at least two clinical epileptologists/clinical neurophysiologists Seizure semiology analysis The semiology of all archived seizures was classified according to the ILAE seizure semiology terminology (Blume et al., 2001; Luders et al., 1993). In addition, the term hypomotor seizures was included in our classification. When the seizure evolved into other clinical seizure types, the first semiological seizure phase (onset) was used for analysis. Subclinical EEG seizures were not included in the analysis. All seizure videos were analyzed by two independent clinical epileptologists/clinical neurophysiologists, who were blinded to the patient s clinical history. Assignment to different seizure semiologies was completed by consensus with a third neurophysiologist in rare cases of disagreement. Data on circadian occurrence of seizure patterns has been submitted in a separate manuscript, but relationship of seizure semiology to EEG localization data has not been submitted for publication elsewhere EEG analysis For the purposes of the present study, two independent clinical epileptologists/clinical neurophysiologists undertook a second analysis of all EEG data. Both EEG reviewers were blinded to the clinical history and seizure video. Data analysis was based on lobar localization (i.e. frontal, temporal, parietal, occipital, generalized), as determined by the ictal EEG recording. When seizures involved two or more lobes at onset, or when the localization of onset was not clear (including when record was obscured by significant myogenic/movement artifact), these were classified under a separate combined category (i.e. multilobar). When there was no concordance between the two EEG reviewers on EEG seizure onset, data were reviewed by a third reviewer (less than 5% of seizures) whose decision was decisive Statistical analysis Statistical analysis was performed with binomial testing using SPSS 16.0 for Macintosh computers (SPSS Inc, Chicago, IL). 3. Results 3.1. Demographics and clinical characteristics of patients A total of 1008 seizures were analyzed in 225 children. The mean age was 8.5 years ± 5.7 (range 0 20 years), with 50% boys. The mean VEM duration was 4 days ± 1.88 (range 1 9 days). The mean number of AEDs per patient was 1.99 ± 0.97 (range 1 5). Details of seizures and epilepsies of the 225 patients are presented in Table 1. In most cases, the etiology of epilepsy was unknown (132 of 225 cases, 59%). The most common seizure localization onset was generalized, seen in 374 of 1008 seizures (37%), in 67 of the 225 patients (30%) Semiology and EEG localization of seizure onset Distribution of EEG seizure onset per different lobes and semiology is presented in Table 2. Auras and seizures with automatisms [or seizures characterized by (oromanual) automatisms] arose predominantly from the temporal lobes (60/152 and 44/82 respectively, both p < 0.001). Tonic and clonic seizures had most commonly generalized onset (84/201 and 35/91 respectively, both p < 0.001), and tonic-clonic seizures had always generalized onset (24/24, p < 0.001). About 42% of hypomotor seizures (26/62) were seen from the frontal lobes (p < 0.001). On the contrary, hypermotor seizures had most commonly onset from the temporal lobe or from multiple lobes (p < 0.05 and p < 0.001, respectively). Atonic, myoclonic seizures and epileptic spasms had almost exclusively generalized onset (47/55, 50/66, 33/39, respectively, p < 0.001). There were five gelastic seizures and all had generalized EEG onset. Dyscognitive seizures had most commonly generalized (44/78) or Table 1 Characteristics of seizures and epilepsy. Seizures per patient (n) 1 13 (mean 4.5; median 4; SD 2.45) EEG seizure Localization (n of patients) Generalized 67 Frontal 29 Temporal 29 Parieto-occipital 9 Multilobar 91 EEG seizure Localization (n of seizures) Generalized 374 Frontal 118 Temporal 183 Parieto-occipital 84 Multilobar 249 Etiology of epilepsy Unknown 141 Symptomatic (Structural/metabolic/genetic) 84 Specific epilepsy syndromes West syndrome 6 Lennox-Gastaut syndrome 2 Juvenile Myoclonic Epilepsy 2 Childhood Absence Epilepsy 2 Benign focal epilepsy of childhood 1

3 1926 M. Vendrame et al. / Clinical Neurophysiology 122 (2011) Table 2 Ictal onset zone of semiological seizure types. Semiology Generalized Frontal Temporal Parietal Occipital Multilobar Total Aura 20 * *** ** 152 Clonic 35 *** * Tonic 84 *** *** 201 Tonic-clonic 24 *** Automatism *** Hypermotor * *** 118 Gelastic 5 *** Dyscognitive 44 *** 5 28 *** Atonic 47 *** Hypomotor *** Myoclonic 50 *** Versive *** 35 Epileptic spasms 33 *** * p < 0.05 (Binomial test). ** p < 0.01 (Binomial test). *** p < (Binomial test). temporal (28/78) onset (both p < 0.001). Versive seizures had a strong association with multi-lobar onset (26/35 p < 0.001). 4. Discussion We were able to relate different seizure semiologies to specific ictal onset zones as confirmed on VEM. Generalized onset was seen primarily in clonic, tonic, tonic-clonic, dyscognitive (mainly absence seizures), atonic, myoclonic seizures and epileptic spasms; temporal lobe onset was seen primarily in auras, automotor, dyscognitive (other than absence) and hypermotor seizures; frontal onset was seen in hypomotor seizures. In the present study we took into account the initial clinical manifestation of the seizure, and not its complete evolution, partially accounting for some discrepancies with prior literature. The relationship of clonic, tonic and tonic-clonic seizures, as well as atonic and myoclonic seizures, to generalized onset appears to be in congruence with prior literature (Hrachovy and Frost, 2006; Nordli, 2002; Panayiotopoulos, 2001) and seizure classifications (Loddenkemper et al., 2006). Generalized epileptiform discharges in these seizures are thought to arise from the synchronous activity of subcortical generators, such as the thalami, and spread to cortical areas through thalamo-cortical networks (Hrachovy and Frost, 2006; Blume, 1995). Although the pathophysiology of myoclonic seizures is not well studied, they may be cortically generated via a polysynaptic mechanism involving the motor and sensory cortices (Auvin et al., 2008; Manganotti et al., 2001). Similarly, in patients with idiopathic generalized epilepsies (IGE), electrophysiological studies have indicated that generalized epileptiform activity may be generated in the superior frontal cortex (Rodin and Ancheta, 1987; Niedermeyer, 1996). Semiological, electrographical and imaging investigations have yielded additional information on focal features in patients with IGE (Woermann et al., 1998, 1999). Overall, these considerations anticipate the emerging concept of a continuum between focal and generalized epilepsies, and its importance with respect to both medical and surgical therapy (Luders et al., 2009). Nonetheless, it has to be taken into account that generalized EEG patterns are not synonymous with IGE, and generalized ictal EEG patterns associated with the above seizure types were seen in the setting of symptomatic generalized epilepsy, not IGE. Furthermore, in the present study, a proportion of generalized seizures seen on scalp EEGs may have a focal onset on intracranial recordings (Alarcon et al., 2001; Waziri et al., 2009). Epileptic spasms corresponded to generalized ictal EEG patterns in most of our seizures (33 out of 39 spasms recorded). The term epileptic spasms comprise infantile spasms and spasms occurring after infancy (Blume et al., 2001). According to the latest ILAE report on seizure and epilepsies terminology and organization, there is inadequate information to decide whether epileptic spasms should be classified as focal or generalized, and thus they have been placed into an independent group (named unknown ) (Berg et al., 2010). Several neuro-imaging studies have suggested that infantile spasms may be generated subcortically (Chugani, 2002; Chugani et al., 1992). In particular, their pathogenesis may involve the brain stem raphe nuclei, raphe- cortical pathways, raphe-striatal pathways and descending spinal pathways (Juhasz et al., 2001). Dyscognitive seizures present with alteration of cognition (perception, attention, emotion, memory, and executive function) as the main clinical features, independent of ictal EEG manifestations (Blume et al., 2001). In concordance to the literature (Berman et al., 2010; Tatum et al., 2010; Englot and Blumenfeld, 2009; Cavanna and Monaco, 2009), we observed dyscognitive seizures mainly with generalized onset (absences) (56%) and with focal temporal onset (36%). A video-eeg study on patients with focal epilepsies has shown that normal functioning of the left or both temporal lobes is important for preservation of consciousness (verbal and non-verbal behavior, speech and post-ictal memory) (Lux et al., 2002). Thus, temporal onset or early temporal involvement of ictal activity, as found in our study, may explain the observed cognitive alterations during seizure onset. In the present series, absence seizures were included into this category and likely accounted for most of the generalized EEG descriptions. Complex partial seizures without automatisms and dyscognitive auras were also included into this category and likely accounted for most of the temporal EEG patterns. Similar to our results, different types of auras have been localized to the temporal lobe, including olfactory aura (Acharya et al., 1998; Chen et al., 2003), gustatory and olfactory auras (Ebner and Kerdar, 2000), pharyngeal dysesthesia (Carmant et al., 1996), feeling of chills (Kotagal et al., 2003), and experiential auras (Palmini and Gloor, 1992). Visual auras, and other auras related to visual phenomena, such as simple and complex visual hallucinations, visual illusion and pallinopsia, have been related to seizures arising from the occipital and/or parietal lobes (Obeid et al., 2009; Anand and Geller, 2000; Maillard et al., 2004; Salanova et al., 1992; Williamson et al., 1992), with the exception of complex visual hallucinations, which are primarily seen with temporal lobe seizures (Anand and Geller, 2000). In the present study, most of the auras arose out of the temporal lobes (60 out of 152 auras), although there were also 57 auras with generalized or multi-lobar onset. To this effect, auras in patients with IGE have been previously reported, with frequencies up to 70% of cases studied (Boylan et al., 2006). Visual auras have also described in patients with IGE, and

4 M. Vendrame et al. / Clinical Neurophysiology 122 (2011) they tend to be described as very brief flashing sensations (Gelisse et al., 2008). Seizures with automatisms are thought to arise from the temporal and frontal lobe. In particular, upper extremities automatisms (Kotagal et al., 1989; Chee et al., 1993; Marks and Laxer, 1998) and oral automatisms (Kotagal et al., 2000) have been related to temporal lobe epilepsy, while proximal automatisms (i.e. bicycling) has been related to frontal lobe epilepsy (Obeid et al., 2009). In congruence with the literature, more than 50% of automotor seizures had EEG onset from the temporal lobes, although only 12 of the 82 recorded automotor seizures had frontal onset. During automatisms, frontal regions may constitute the symptomatogenic zone (i.e. the eloquent area that produces the observed symptoms during a seizure) (Datta and Loddenkemper, 2010), which may be activated after spreading from the epileptogenic zone, likely located within the temporal (or other) lobes of origin. Hypermotor seizures include repetitive coarse upper extremity movements, complex motor and hypermotor activity with complete loss of consciousness, and have been thought to be frontal in origin (Kotagal et al., 2003; Williamson et al., 1985; Chauvel et al., 1995). Most studies have related hypermotor seizures to the frontal lobe, although these seizures can certainly be seen in patients with temporal lobe epilepsies, especially in the pediatric population (Williamson et al., 1985; Manford et al., 1996; Ray and Kotagal, 2005). In particular, Ray and Kotagal have shown that temporal lobe epilepsy in very young infants may exhibit prominent motor manifestations, which decrease with increasing age and are less prevalent in adults (Ray and Kotagal, 2005). In our series, hypermotor seizures had primarily multi-lobar onset, but also frequently originated from the frontal and temporal lobes (22 and 25 cases respectively, out of 118 seizures recorded). One of the reasons for the discrepancy between our current data and other prior observations is that we took into account only the initial clinical manifestation, while prior reports have examined seizure semiology in their evolution, thereby taking into account the spreading of the seizures into different lobes (Williamson et al., 1985; Manford et al., 1996). The other reason which may account for the observed discrepancy is that other studies have included only patients who became seizure free after surgery, i.e. patients in whom the epileptogenic zone was confirmed by resection and seizure freedom, with a high degree of certainty of the ictal onset, while in the present study the ictal onset zone was estimated only by EEG analysis (Williamson et al., 1985; Manford et al., 1996). Hypomotor seizures are characterized by diminished behavioral activity with indeterminate level of consciousness (also termed behavioral/motor arrest ) and are thought to be either generalized or focal, arising from the temporal or parietal lobes (Kallen et al., 2002). In the study by Kallen et al., of the 110 seizures reviewed, 71 had onset from the temporal and/or parietal lobes, and 39 had generalized onset (Kallen et al., 2002). Others have shown that hypomotor seizures can arise from temporal, temporo-parietal, and also temporo-occipital and parieto-occipital regions (Acharya et al., 1997). In the present study, we found an additional association between hypomotor seizures and frontal lobe involvement, with 26 of the 62 analyzed seizures arising from the frontal lobes. There appears to be a discrepancy between the prior studies by Kallen et al. and Acharya et al. and the present one. One explanation may relate to the fact that we did not take into account the semiological evolution of seizures, but only the earliest clinical manifestation at the time of EEG onset. To this effect, in the prior studies, the observed hypomotor seizures were also associated with motor and automotor features in post-onset phases, indicating the subsequent spread to other brain regions (Kallen et al., 2002; Acharya et al., 1997) Another reason could be the fact that the seizures studied by Kallen et al. and Acharya et al. were restricted to patients who became seizure free after resection, and therefore patients with generalized electro-clinical features, and patients deemed to be unsuitable for resective surgery or patients who failed epilepsy surgery were not included. An additional explanation may be related to the variability of hypomotor symptoms: hypomotor seizures may present in response to multiple possibilities including not only a seizure-related interruption of motor activity or behavioral consciousness, but also while experiencing an aura. Versive semiology of seizures refers to a sustained and forced eye, head and/or truncal rotation or lateral deviation from the midline (Blume et al., 2001). Versive seizures have been mostly related to temporal and frontal lobe seizures (Wyllie et al., 1986; McLachlan, 1987; Shukla et al., 2002; O Dwyer et al., 2007). In concordance with a higher frequency of non-focal EEG correlate for versive seizures in our series, Leutmezer and colleagues found focal clinical signs in relationship to generalized or obscured ictal EEG patterns and/or focal interictal abnormalities in patients with IGE. (Leutmezer et al., 2002). Versive seizures in IGE accompanied by generalized EEG discharges have been described by others (Ferrie, 2005; Usui et al., 2005). To this effect, it is important to take into account that our analysis was based exclusively on the initial manifestation of the seizure. For example, versive seizures evolving into a generalized tonic-clonic phase would be classified as versive. Although this may make the comparison with other studies difficult, it has to be pointed out that there is a general lack of guidelines and consensus regarding which phase of a multi-phasic seizure should be accounted for analysis. Our results need to be interpreted in the clinical context of the retrospective data acquisition and setting at a VEM unit of a tertiary epilepsy center. Taking our findings together, there is no one to one correlation between seizure types and ictal EEG seizure patterns (Berg et al., 2010; Blume et al., 2001). Although the majority of seizures are either generalized or focal, some seizures are not exclusively generalized or exclusively focal in origin. Not all myoclonic seizures are necessarily generalized, and not all seizures with staring can immediately be distinguished as absence or other subtypes of dyscognitive seizures (Cavanna and Monaco, 2009; Lux et al., 2002; Leutmezer et al., 2002; Usui et al., 2005). To date, several papers have approached this problem from a localization-related or a symptom-related perspective, and both approaches may have been biased by selection. We did not restrict our study group to patients who underwent successful resective epilepsy surgery, thus not maintaining the gold-standard of seizure-freedom after resection for localization of seizure-onset. However, this enabled us to include patients with presumed generalized epilepsies as well as other patients who may not have been considered candidates for epilepsy surgery. Inclusion of generalized epilepsies and inclusion of a heterogenous, wide spectrum of clinical seizures appeared to be the most feasible approach to demonstrate the overlap between semiological features in the presence of focal and generalized EEG seizure patterns. It is also important to take into account that the present series included only pediatric patients, and semiology in children may not be identical to seizure semiology in adults. For example, hypermotor seizures in this series were found to have onset from the temporal lobes, which is consistent with prior observations reporting prominent motor manifestations in temporal lobe epilepsy in children compared to adults (Ray and Kotagal, 2005). In summary, different seizure semiologies relate to specific brain regions with overlap between focal and generalized seizure types. Our findings may contribute to a better understanding of the mechanisms of nonrandom distribution of seizures, and may provide information for individualized treatment options. Our findings support the feasibility of the recent separation of seizure semiology and epilepsy localization by the ILAE and suggest expansion of this concept (Berg et al., 2010).

5 1928 M. Vendrame et al. / Clinical Neurophysiology 122 (2011) Disclosure There are no financial interests and no funding sources supporting this work. References Acharya JN, Wyllie E, Luders HO, Kotagal P, Lancman M, Coelho M. Seizure symptomatology in infants with localization-related epilepsy. Neurology 1997;48: Acharya V, Acharya J, Luders H. Olfactory epileptic auras. Neurology 1998;51: Alarcon G, Kissani N, Dad M, Elwes RDC, Ekanayake J, Hennessy MJ, et al. Lateralizing and localizing values of ictal onset recorded on the scalp: evidence from simultaneous recordings with intracranial foramen ovale electrodes. Epilepsia 2001;42: Anand I, Geller E. Visual auras. In: SS LudersHO, editor. Epileptic Seizures: Pathophysiology and Clinical Semiology. Philadelphia: Churchill Livingstone; p Auvin S, Derambure P, Cassim F, Vallee L. Myoclonus and epilepsy: diagnosis and pathophysiology. Rev Neurol (Paris) 2008;164:3 11. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, Epilepsia 2010;51: Berman R, Negishi M, Vestal M, Spann M, Chung MH, Bai X, et al. Simultaneous EEG, fmri, and behavior in typical childhood absence seizures. Epilpsia 2010;51: Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel Jr J. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42: Blume WT. Physiology of atonic seizures. Adv Neurol 1995;67: Boylan LS, Labovitz DL, Jackson SC, Starner K, Devinsky O. Auras are frequent in idiopathic generalized epilepsy. Neurology 2006;67: Carmant L, Carrazana E, Kramer U, Helmers SL, Holmes GL, Black PM, et al. Pharyngeal dysesthesia as an aura in temporal lobe epilepsy. Epilepsia 1996;37: Cavanna AE, Monaco F. Brain mechanisms of altered conscious states during epileptic seizures. Nat Rev Neurol 2009;5: Chauvel P, Kliemann F, Vignal JP, Chodkiewicz JP, Talairach J, Bancaud J. The clinical signs and symptoms of frontal lobe seizures. Phenomenology and classification. Adv Neurol 1995;66: discussion Chee MW, Kotagal P, Van Ness PC, Gragg L, Murphy D, Luders HO. Lateralizing signs in intractable partial epilepsy: blinded multiple-observer analysis. Neurology 1993;43: Chen C, Shih YH, Yen DJ, Lirng JF, Guo YC, Yu HY, et al. Olfactory auras in patients with temporal lobe epilepsy. Epilepsia 2003;44: Chugani HT, Shewmon DA, Sankar R, Chen BC, Phelps ME. Infantile spasms: II. Lenticular nuclei and brain stem activation on positron emission tomography. Ann Neurol 1992;31: Chugani HT. Pathophysiology of infantile spasms. Adv Exp Med Biol 2002;497: Datta A, Loddenkemper T. The epileptogenic zone. In: Wyllie E, Cascino G, Gidal B, Goodkin H, editors. Wyllie s Treatment of Epilepsy. Principles & Practice. 5th Edition. Lippincott, Williams & Wilkins: Philadelphia; p Ebner A, Kerdar M. Olfactory and gustatory auras. In: S LHN, editor. Epileptic Seizures, Pathophysiology and Clinical Semiology: Churchill Livingstone; p Engel Jr J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42: Englot DJ, Blumenfeld H. Consciousness and epilepsy: why are complex-partial seizures complex? Prog Brain Res 2009;177: Ferrie CD. Idiopathic generalized epilepsies imitating focal epilepsies. Epilepsia 2005;46(Suppl 9):91 5. Gelisse P, Coubes P, Crespel A. Visual auras in idiopathic generalized epilepsy. Rev Neurol (Paris) 2008;164: Hrachovy RA, Frost Jr JD. The EEG in selected generalized seizures. J Clin Neurophysiol 2006;23: Juhasz C, Chugani HT, Muzik O, Chugani DC. Neuroradiological assessment of brain structure and function and its implication in the pathogenesis of West syndrome. Brain Dev 2001;23: Kallen K, Wyllie E, Luders HO, Lachhwani D, Kotagal P. Hypomotor seizures in infants and children. Epilepsia 2002;43: Kellinghaus C, Loddenkemper T, Najm IM, Wyllie E, Lineweaver T, Nair DR, et al. Specific epileptic syndromes are rare even in tertiary epilepsy centers: a patient-oriented approach to epilepsy classification. Epilepsia 2004;45: Kotagal P, Arunkumar G, Hammel J, Mascha E. Complex partial seizures of frontal lobe onset statistical analysis of ictal semiology. Seizure 2003;12: Kotagal P, Bleasel A, Geller E, Kankirawatana P, Moorjani BI, Rybicki L. Lateralizing value of asymmetric tonic limb posturing observed in secondarily generalized tonic-clonic seizures. Epilepsia 2000;41: Kotagal P, Lüders H, Morris HH, Dinner DS, Wyllie E, Godoy J, et al. Dystonic posturing in complex partial seizures of temporal lobe onset: a new lateralizing sign. Neurology 1989;39: Leutmezer F, Lurger S, Baumgartner C. Focal features in patients with idiopathic generalized epilepsy. Epilepsy Res 2002;50: Loddenkemper T, Kellinghaus C, Wyllie E, Najm IM, Gupta A, Rosenow F, et al. A proposal for a five-dimensional patient-oriented epilepsy classification. Epileptic Disord 2005;7: Loddenkemper T, Kotagal P. Lateralizing signs during seizures in focal epilepsy. Epilepsy Behav 2005;7:1 17. Loddenkemper T, Luders H, Najm I, Wyllie E. Classification of the epilepsies. In: Wyllie E, editor. The treatment of epilepsy. Philadelphia: Lippincott Williams and Wilkins; Luders H, Acharya J, Baumgartner C, Benbadis S, Bleasel A, Burgess R, et al. Semiological seizure classification. Epilepsia 1998;39: Luders HO, Burgess R, Noachtar S. Expanding the international classification of seizures to provide localization information. Neurology 1993;43: Luders HO, Turnbull J, Kaffashi F. Are the dichotomies generalized versus focal epilepsies and idiopathic versus symptomatic epilepsies still valid in modern epileptology? Epilepsia 2009;50: Lux S, Kurthen M, Helmstaedter C, Hartje W, Reuber M, Elger CE. The localizing value of ictal consciousness and its constituent functions: a video-eeg study in patients with focal epilepsy. Brain 2002;125: Maillard L, Vignal JP, Anxionnat R, TaillandierVespignani L. Semiologic value of ictal autoscopy. Epilepsia 2004;45: Manford M, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119(Pt 1): Manganotti P, Tamburin S, Zanette G, Fiaschi A. Hyperexcitable cortical responses in progressive myoclonic epilepsy: a TMS study. Neurology 2001;57: Marks Jr WJ, Laxer KD. Semiology of temporal lobe seizures: value in lateralizing the seizure focus. Epilepsia 1998;39: McLachlan RS. The significance of head and eye turning in seizures. Neurology 1987;37: Niedermeyer E. Primary (idiopathic) generalized epilepsy and underlying mechanisms. Clin Electroencephalogr 1996;27:1 21. Nordli Jr DR. Infantile seizures and epilepsy syndromes. Epilepsia 2002;43(Suppl 3):11 6. Obeid M, Wyllie E, Rahi AC, Mikati MA. Approach to pediatric epilepsy surgery: State of the art, Part I: General principles and presurgical workup. Eur J Paediatr Neurol 2009;13: O Dwyer R, Silva Cunha JP, Vollmar C, Mauerer C, Feddersen B, Burgess RC, et al. Lateralizing significance of quantitative analysis of head movements before secondary generalization of seizures of patients with temporal lobe epilepsy. Epilepsia 2007;48: Palmini A, Gloor P. The localizing value of auras in partial seizures: a prospective and retrospective study. Neurology 1992;42: Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3: Ray A, Kotagal P. Temporal lobe epilepsy in children: overview of clinical semiology. Epileptic Disord 2005;7: Rodin E, Ancheta O. Cerebral electrical fields during petit mal absences. Electroencephalogr Clin Neurophysiol 1987;66: Rosenow F, Luders H. Presurgical evaluation of epilepsy. Brain 2001;124: Salanova V, Andermann F, Olivier A, Rasmussen T, Quesney LF. Occipital lobe epilepsy: electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and Surgery of occipital lobe epilepsy. Brain 1992;115(Pt 6): Shukla G, Bhatia M, Gaekwad SB, Singh VP, Jain S, Maheshwari MC. The lateralizing significance of version of head and dystonic limb posturing in epileptic seizures. Neurol India 2002;50:33 6. Tatum WO, Ho S, Benbadis SR. Polyspike ictal onset absence seizures. J Clin Neurophysiol 2010;27:93 9. Usui N, Kotagal P, Matsumoto R, Kellinghaus C, Luders HO. Focal semiologic and electroencephalographic features in patients with juvenile myoclonic epilepsy. Epilepsia 2005;46: Waziri A, Claassen J, Stuart RM, Arif H, Schmidt JM, Mayer SA, et al. Intracortical electroencephalography in acute brain injury. Ann Neurol 2009;66: Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial seizures of frontal lobe origin. Ann Neurol 1985;18: Williamson PD, Thadani VM, Darcey TM, Spencer DD, Spencer SS, Mattson RH. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery. Ann Neurol 1992;31:3 13. Woermann FG, Free SL, Koepp MJ, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999;122(Pt 11): Woermann FG, Sisodiya SM, Free SL, Duncan JS. Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes. Brain 1998;121(Pt 9): Wyllie E, Luders H, Morris HH, Lesser RP, Dinner DS. The lateralizing significance of versive head and eye movements during epileptic seizures. Neurology 1986;36: