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Generalized epileptic disorders are characterized by seizures in which there are symptoms of bilateral cerebral involvement, and an electroencephalogram in which synchronous abnormal activity is recorded in both hemispheres at seizure onset (1). Generalized epilepsies result from alterations in the function of the whole brain or of major brain systems, and are often the expression of inborn errors in which the molecular etiology can be identified through genetic approaches. Thus, insights gained from genetic studies of the generalized epilepsies are beginning to answer the age-old question: "What is the cause of epilepsy?" Indeed, concepts of pathogenesis developed in generalized epilepsies may provide clues to the etiologies of the more common focal epileptic disorders. Having passed what is truly a milestone event in epilepsy research—the cloning of the first human idiopathic generalized epilepsy genes (see 2,3)—it seemed an opportune time to review the scope of research progress on the generalized epilepsies. We begin with a brief summary of the clinical features of the generalized epilepsies and then describe new developments in the genetics of these disorders. Current understanding of the cellular and network mechanisms leading to some forms of generalized seizures also are considered. Finally, drug treatment is discussed in the context of the pathophysiologic mechanisms. This review originated at Focus on Epilepsy V, an international symposium held in Quebec City in May 1999. A list of the faculty that participated in this conference is given later (4,5). Generalized epilepsy syndromes are often classified as idiopathic or symptomatic. Idiopathic epilepsies have been described as disorders "not preceded or occasioned by another" (i.e., with no underlying cause other than a possible hereditary predisposition). Idiopathic epilepsies are categorized according to the age at onset, clinical and EEG characteristics, and genetic etiology (4). According to the International League Against Epilepsy (ILAE) definition, idiopathic generalized epilepsies include the following forms: (a) benign neonatal (familial) convulsions, (b) benign myoclonic epilepsy in infancy, (c) childhood (pyknolepsy) and juvenile absence epilepsies, (d) juvenile myoclonic epilepsy, (e) epilepsy with grand mal seizures on awakening, and (f) seizures precipitated by specific modes of activation. However, even this rather extensive list does not encompass all the situations that can be encountered in clinical practice. For instance, some idiopathic epilepsies with generalized tonic–clonic convulsions, such as sleep grand mal or grand mal at random, do not yet have well-defined syndromic definitions. Typical absence seizures characterized by a short lapse of consciousness with no (or minimal) motor and autonomic manifestations are the most innocuous type of generalized seizure. At the other extreme are generalized tonic–clonic seizures with dramatic motor manifestations and impairments in autonomic function that may be life threatening. However, idiopathic generalized tonic–clonic seizures are highly sensitive to antiepileptic drugs (AEDs), and thus the clinical outcome is usually favorable. Conversely, seizures characterized by less dramatic motor manifestations, such as atonic or akinetic seizures, are often resistant to drug therapy and can severely impair the patient's quality of life. In symptomatic generalized epilepsies, seizures occur in conjunction with a spectrum of other neurologic and systemic symptoms, and are usually associated with structural brain lesions or alterations in brain metabolism. In those cases in which the genetic defects have been identified, the mutations perturb brain development, energy production, or other important aspects of brain function. However, the specific ways in which these defects result in seizures has not yet been elucidated. In contrast to the idiopathic epilepsies, symptomatic epilepsies are usually less sensitive to AEDs and are often associated with severe neurologic or psychological impairment. Some forms (e.g., West and Lennox–Gastaut syndromes, epilepsy with myoclonic–astatic seizures or myoclonic absences) can be either cryptogenic or symptomatic of different inborn disorders, whereas early myoclonic encephalopathy and infantile epileptic encephalopathy with suppression burst are always symptomatic of metabolic or malformative encephalopathies. Although the true generalized nature of the discharges accompanying many of the symptomatic generalized epilepsies is debated, the syndromes are nevertheless currently classified among the generalized epilepsies. The ILAE classification has a number of drawbacks. First, its clinical value is uneven: some diagnoses, such as juvenile myoclonic epilepsy, identify a definite type of epilepsy, whereas others, such as myoclonic–astatic epilepsy, correspond to a composite spectrum of clinical forms whose boundaries are not universally agreed on. Second, the definitions of idiopathic and cryptogenic forms with their different implications, but ill-defined boundaries, are not fully satisfactory. Third, it is becoming apparent that certain idiopathic generalized epilepsy syndromes, which appear clinically to be pure epilepsy phenotypes, are in fact genetically heterogeneous. Despite these reservations, the 1989 ILAE classification provides the clinician with a useful diagnostic framework and a guide to natural history, symptoms, and prognosis; in addition, it represents a starting point for genetic studies. The past decade has witnessed the genetic identification of several symptomatic generalized epilepsies, and recently, of a few rare idiopathic epilepsies. Examples of symptomatic generalized epilepsy syndromes with an established genetic defect include (a) myoclonic epilepsy and ragged red fiber disease (MERRF), in which alterations in mitochondrial oxidative phosphorylation are caused by mutations in the mitochondrial gene that codes for tRNA(Lys) (5); (b) Miller–Dieker lissencephaly, in which cortical maldevelopment is associated with a defect in the LIS-1 gene (6) encoding platelet-activating factor acetylhydrolase (7); and (c) progressive myoclonus epilepsy of the Unverricht–Lundborg type (EPM1), in which there is a mutation in the gene for cystatin B, a protein inhibitor of cysteine proteases (8–10). Recently the role of the cystatin B gene defect in the production of myoclonic seizures was confirmed by studies in which the cystatin B gene was disrupted in mice with a gene-targeting strategy (11). Cystatin B–deficient mice exhibited myoclonic seizures (but not tonic–clonic seizures as in human EPM1) and ataxia associated with apoptotic degeneration of cerebellar granule cells. However, cerebellar degeneration is unlikely to account for the myoclonic seizures because other mouse mutants with cerebellar degeneration lack such seizures. The genetic defects in several other progressive myoclonus epilepsies including Lafora disease (EPM2) and certain forms of neuronal ceroid lipofuscinoses (Batten disease) also have been identified. These myoclonus epilepsies are associated with intracellular inclusion bodies in a wide variety of cell types. In EPM2, there is a defect in a gene encoding the protein laforin, which has a consensus amino acid sequence indicative of a protein tyrosine phosphatase (12,13). Mutational inactivation of such an enzyme is presumed to affect the control of glycogen metabolism. At least eight genes underlie the neuronal ceroid lipofuscinoses (CLN1-8), of which four have been characterized (CLN1, CLN2, CLN3, CLN5). It is now generally believed that the neuronal ceroid lipofuscinoses represent a new class of lysosomal storage disorders (14–16). An additional symptomatic generalized epilepsy syndrome, the Angelman syndrome, results from a complex defect affecting imprinted genes on maternal chromosome 15q11-q13. Angelman syndrome can be produced by gene deletions, paternal uniparental disomy, or mutations disrupting the imprinting mechanism (17). Abrogation of the UBE3A gene, which codes for E6-AP ubiquitin protein ligase (also known as ubiquitin ligase 3A), an enzyme involved in protein degradation and processing, is believed to be the cause of Angelman syndrome. However, recent evidence suggests that defects in associated γ-aminobutyric acid subtype A (GABAA)-receptor genes may play an important modifier role (18). Although the most common form of Angelman syndrome (type 1A) is produced by an ∼4-Mb deletion in maternal 15q11-13, a small number (4–6%) of Angelman syndrome patients (type IV) have a point mutation affecting the UBE3A gene. In extended families with such mutations, heterozygotes are normal if the mutant chromosome is inherited from the father, but are affected if it is inherited from the mother. This occurs because the UBE3A gene is maternally imprinted in a brain-specific fashion; that is, in certain neuronal types including Purkinje cells, hippocampal neurons, and olfactory mitral cells, only the copy of the gene inherited from the mother is expressed. Such imprinting does not occur in most other neuronal types or in somatic tissues. Type IV Angelman syndrome patients exhibit many of the neurobehavioral features associated with the type 1A form of the disorder, but they may be less severe. In particular, individuals with UBE3A mutations may have fewer apparent EEG abnormalities and few if any seizures (19). Interestingly, there is a cluster of GABAA-receptor genes within the region deleted in type IA Angelman syndrome. When one of these genes GABRB3 (encoding the GABAA receptor β3 subunit) is deleted in the mouse, the animals have seizures and other features of the Angelman syndrome (20). Deficiency of GABRB3 may function as a modifier of the epilepsy phenotype, accounting for the greater severity in the deletion cases. Thus, type IA Angelman syndrome may represent the first form of human epilepsy in which a genetic defect affecting brain GABAergic function plays a clearly identified pathogenetic role. Major progress has recently been made in understanding the pathogenesis of certain idiopathic generalized epilepsies. In two such disorders—benign familial neonatal convulsion (BFNC) and generalized epilepsy with febrile seizures plus (GEFS+)—defects have been identified in genes coding for subunits of voltage-gated ion channels. Thus, at least some idiopathic generalized epilepsies appear to be members of a growing class of channelopathies that include a broad range of paroxysmal disorders, including certain cardiac arrhythmias, episodic ataxias, periodic paralyses, congenital myotonias, and migraine (2,21). It has long been recognized that genetic factors play a role in the idiopathic generalized epilepsies (22). However, for the most common forms, including childhood absence epilepsy (incidence, one in 1,000), juvenile myoclonic epilepsy (incidence, one in 2,000), and juvenile absence epilepsy (incidence, one in 3,000), linkage studies have so far failed to reveal replicable susceptibility loci. Identification of the genetic basis of these disorders has been challenging because inheritance occurs in a complex (nonmendelian) fashion, and the syndromes may be genetically heterogeneous. It also remains to be determined whether major gene effects or multiple minor susceptibility alleles contribute to the genetic variation (23). In the case of the far less common BFNCs (incidence, one in 100,000), inheritance usually occurs in an autosomal dominant fashion with high (85%), but not complete penetrance (24). This has allowed the genetic basis of this idiopathic generalized epilepsy syndrome to be identified with a positional cloning strategy. BFNC occurs in two genetic forms: (a) EBN1, whose gene has been localized to chromosome 20q13.3; and (b) EBN2, a rarer form to date conclusively identified in only one pedigree, in which the gene is on chromosome 8q24 (25,26). The genes affected in EBN1 and EBN2 have recently been identified and shown to encode the two novel homologous voltage-gated K+ channels KCNQ2 and KCNQ3. Evidence indicates that KCNQ2 and KCNQ3 coassemble to form heteromeric K+ channels. BFNC mutations in either KCNQ2 or KCNQ3 result in a small (∼20–30%) reduction in the current amplitude, which is believed to be sufficient to cause the disorder. The dominant inheritance seems to result from haploinsufficiency rather than from a dominant negative effect produced by the mutant channel subunits (as is the case in the long QT syndrome) (27). A characteristic feature of BFNC is that seizures are expressed mainly during the first several weeks or months of life. In the majority of affected individuals, long-term development is normal, and only ∼16% of patients have epileptic seizures later in life (28,29). It may be postulated that the expression of KCNQ2/KCNQ3 channels is at a critical level in infancy but that there is redundancy in these or related K+ channels later in life, accounting for the disappearance of symptoms in most affected individuals. Alternatively, changes in other brain excitability mechanisms could be responsible for the age-dependent resolution of the seizure phenotype. Evidence has been presented that KCNQ2/KCNQ3 heteromers represent a member of the M-current family of K+ channels (30,31). The M currents are low-threshold, slowly activating K+ currents that exert inhibitory control over neuronal excitability (32). Opening of M-current channels is suppressed by neurotransmitters acting on G protein–linked receptors, including muscarinic cholinergic receptors. Inhibition of M currents result in membrane depolarization and an increase in neuronal input resistance, making the cell more likely to fire actions potentials. Thus, it is not surprising that a defect in M current in BFNC would be associated with enhanced seizure susceptibility. Recently voltage-activated Na+ channels have been implicated in seizure susceptibility in the complex syndrome referred to as "generalized epilepsy with febrile seizures plus" (GEFS+), a phenotypically diverse disorder in which there are febrile seizures in childhood and afebrile seizures later in life. (The syndrome is distinct from common benign febrile seizures.) Two genetically distinct forms of GEFS+ have been described, the first associated with mutations in the auxiliary β1 Na+-channel subunit SCN1B (GEFS+1) (33), and the second with the principal α Na+ channel subunit SCN1A (GEFS+2) (34). Both of these disorders are inherited in an autosomal dominant fashion. Functional studies of expressed Na+ channels composed of mutant subunits are beginning to provide insight into how the genetic defects in these generalized epilepsy syndromes lead to seizure susceptibility. The β1 protein implicated in GEFS+1 regulates the kinetic properties of the main Na+ channel α subunit, causing speeding of inactivation and acceleration in recovery from inactivation. In GEFS+1, there is a C→G transversion within the coding region of the SCN1B gene. The mutation changes a conserved cysteine residue to tryptophan, thus disrupting a putative disulfide bridge, which maintains an extracellular immunoglobulin-like fold of the β1 subunit. The immunoglobulin motif normally allows the β1 to associate with the α subunit, and this interaction is presumably perturbed by the mutation. The mutant β1 subunit no longer speeds the Na+-channel kinetics but instead slightly prolongs inactivation and slows recovery from inactivation. Precisely how these alterations in gating result in febrile seizures is not well understood. One idea is that the mutant β1 subunit could result in greater persistent Na+ current, which would lead to enhanced neuronal bursting, as has been shown in neocortical pyramidal neurons (35). If this effect becomes more significant at higher temperatures, it could explain the temperature dependence of the seizures. To date, mutations in two highly conserved residues in the S4 voltage-sensing region of SCN1A have been associated with GEFS+2. Based on analogies with the effects of induced mutations in a related Na+ channel, it has been suggested that the mutations in GEFS+2 could also modify Na+-channel inactivation, leading to enhanced bursting. An important question raised by the identification of defects in K+ and Na+ channels in rare monogenic idiopathic generalized epilepsies is whether genetic variation in the same genes represents a contributory factor for the more common idiopathic generalized epilepsy syndromes. A recent analysis of the gene structure of the KCNQ2 gene revealed that the gene consists of at least 18 exons that can occur in alternatively spliced forms (29). In addition, a single nucleotide polymorphism resulting in an amino acid substitution T752N was identified. The polymorphism is not a functionally important mutation that contributes to the BFNC phenotype. Nevertheless, such allelic variation could theoretically confer susceptibility to epilepsy, either by itself or in combination with other susceptibility loci. However, the results to date do not implicate this particular polymorphism as a source of susceptibility for idiopathic generalized epilepsy (36). Apart from KCNQ2 and KCNQ3, an enormous diversity of K+ channels contributes to the regulation of brain excitability (37). Pharmacologic inhibition of K+ channels is a potent convulsant stimulus (38). In addition, mice with induced deletions of various K+-channel genes exhibit seizures (39,40). K+-channel genes therefore represent significant candidates in the search for epilepsy susceptibility genes. Indeed, defects in the KCNA1 (Kv1.1) voltage-dependent K+-channel gene in episodic ataxia type 1 are associated with a 10-fold increase in the frequency of epilepsy (41). Similarly, the identification of Na+-channel defects in GEFS+ confirms the importance of the Na+-channel genes as candidates. In retrospect, it seems logical that defects in K+ and Na+ channels, the key mediators of excitability in the nervous system, would be critical to the pathogenesis of some forms of generalized epilepsy. Future genetic studies should logically focus on the role of K+ and Na+ channels as well as other ion channel types in susceptibility to idiopathic generalized epilepsies. The 3-Hz spike-and-wave discharge associated with a generalized absence attack represents the most stereotyped seizure pattern in clinical electroencephalography. These seizures, first described by Gibbs et al. (42), occur in individuals with a normal interictal EEG and originate bilaterally, do not evolve in time, and are not associated with postictal depression (Fig. 1A). Generalized spike-and-wave–like discharges were later reproduced experimentally by Jasper and Droogleever-Fortuyn (43) during low-frequency stimulation of midline and intralaminar thalamic nuclei in the cat, suggesting that they may have a subcortical origin ("centrencephalic hypothesis"). However, some years later, this view was challenged by the discovery that bilateral application of convulsants to the frontal cerebral cortex of cats and monkeys could produce a similar pattern of generalized, 3-Hz spike-and-wave activity (44,45). At approximately the same time, studies of the photosensitive Senegalese baboon Papio papio, which exhibits generalized seizures, demonstrated a cortical origin of the electrographic activity recorded in this genetic model of primary generalized epilepsy (46,47). This evidence, along with an extensive review of clinical data, led Gloor (48,49) to propose the term "generalized corticoreticular epilepsy" to reconcile the centrencephalic and cortical mechanisms. This concept assigned essential roles to both thalamus and cortex in the elaboration of generalized 3-Hz spike-and-wave discharges. Electrographic characteristics of generalized spike-and-wave discharges recorded in a patient (A), in a cat injected with i.m. penicillin injection (B), and in a WAG/Rij epileptic rat (C). Note the similarities that include generalization at onset and throughout the discharge, a nonprogressive feature of the electrographic pattern, and the absence of postictal depression. L, left; R, right; F, frontal; C, central; P, posterior; O, occipital; Cx, cortex (A, from ref. 117; B,118; C,56, with permission). The validity of the corticoreticular hypothesis has been tested over the years in several models of absence attacks with generalized spike-and-wave discharges (50–56). These studies have demonstrated a similarity between the synchronized activity occurring in thalamocortical during sleep and the spike-and-wave discharges of absence epilepsy in the In addition, it has been shown that which is for the generalized nature of the discharge over broad of the two is by and It should be that synchronous spike-and-wave discharges in animals exhibit that are higher than the in Nevertheless, as in the spike-and-wave discharges in models exhibit generalization at seizure onset and throughout the discharge, a nonprogressive electrographic pattern, and absence of postictal depression (Fig. the of spike-and-wave discharges in these animals consists of by minor motor manifestations as and as is the case in with absence of the early evidence thalamocortical to spike-and-wave discharges was in studies in cats injected with penicillin In this in model of absence seizures, depression of thalamic activity by of both and spike-and-wave discharges (Fig. In addition, the thalamus is of with the (e.g., spike-and-wave discharges are not (Fig. Finally, spike-and-wave discharges in the cat brain are in both thalamic nuclei and by cortical excitability is by depression Thus, the and of thalamus and cortex is for generalized spike-and-wave discharges in the penicillin have been from studies with various rat that exhibit seizures of the thalamic activity induced by a of is by disappearance of generalized spike-and-wave discharges induced by i.m. injection of activity is most at the of the cortical and thalamic spike-and-wave and with of normal thalamic EEG from the thalamus of a cat, and i.m. injection of Note that spike-and-wave discharges are not in the posterior; R, right; L, left; P, (A, from ref. with permission). extracellular and intracellular have insight into the cellular mechanisms underlying the spike-and-wave discharge in models of absence seizures. the of the spike-and-wave there is a increase in in and whereas during the the is to (Fig. and A similar pattern of burst activity has been in of the thalamus and during spike-and-wave discharges in genetic models (Fig. from neocortical neurons have also demonstrated that the of the spike-and-wave complex in the penicillin model represents an induced by thalamocortical (Fig. In the is associated with to A similar sequence of intracellular has been recorded in cortical and thalamic neurons in genetic absence epilepsy of during spike-and-wave discharges (Fig. It is, whether the of the that with the of the spike-and-wave complex occurs through inhibitory mechanisms. for a cortical and a thalamocortical during spike-and-wave discharges recorded in a cat injected with i.m. of the EEG and EEG and of single activity by the negative of the cortical EEG Note that both cortical and thalamic with between increase in during the and a reduction of this of to during the of the spike-and-wave discharges recorded in a genetic absence epilepsy of rat from in the thalamus and in the cortex and from the the of and activity at an time (A, from ref. B, EEG and intracellular recorded during a spike-and-wave discharge in a cat injected i.m. with Note that the is associated with a depolarization that whereas the of the spike-and-wave complex is associated with a of the are in the intracellular at membrane from a cortical during the of a spike-and-wave discharge recorded in the EEG from a genetic absence epilepsy of (A, from ref. with permission). The most important source only one in of inhibition on thalamocortical is the thalamic which is composed of GABAergic thalamic neurons are with a current, which can The activity produced by such can sleep In the model of absence seizures, lesions of thalamic spike-and-wave discharges neurons from may have enhanced current The along the cell and inhibitory in the membrane of the neurons the a current is that of In addition, a may with the current in the of Thus, spike-and-wave discharges are by of in thalamic principal neurons, which cortical cells, which in neurons within the is through mechanisms that may burst in thalamocortical to characteristic of the spike-and-wave discharges during an absence seizure. This view is by evidence in brain from mice in which the β3 subunit of the GABAA receptor was deleted In the the β3 subunit is mainly to the a in the β3 inhibition is in these neurons (but not in thalamocortical This results in a dramatic increase of the of thalamocortical neurons to the inhibition of cells. evidence in of a role of mechanisms in the of spike-and-wave discharges from with a drug that and EEG alterations similar to those during absence attacks receptors, causing membrane which to of channels The result is, activity and burst in thalamocortical The of thalamic and cortical during generalized spike-and-wave also has been in In these the burst of thalamic neurons as well as the properties of have been shown to be critical in spike-and-wave discharges similar have been to thalamocortical spike-and-wave discharges with different (i.e., in in These have shown that the

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It has been known for more than a century that flickering sunlight can provoke epileptic seizures in susceptible patients 1. However, the modern technologic environment has led to a dramatic increase in exposure to potential trigger stimuli. Outbreaks of visually induced seizures were reported after the introduction of the television set 2, of video games 3, and of television commercials and programs 4, 5. Other provocative visual stimuli in the contemporary environment include discotheque lighting, rolling escalators (a moving, striped pattern), and rotating helicopter blades 6-9. Such epidemics of visually induced seizures have been a source of great concern to the general public 10. Although much research has been undertaken since the 1950s 4, 8, 11-14, many questions concerning underlying basic mechanisms and clinical semiology remain unanswered, and the terminology of clinical and EEG phenomena is not yet standardized. An initial step has been taken through the publication of proposed international standards for intermittent photic stimulation (IPS) 15. We present a proposal for the terminology and classification of clinical and neurophysiologic phenomena relating to visual sensitivity. It aims to standardize the use of clinical terms and definitions. This proposal is divided into four main areas: Clinical symptoms of visual sensitivity. Classification of the EEG responses to IPS. Classification of electroclinical phenomena. Syndromic classification. Commonly used terms such as photosensitive, photogenic, and photoconvulsive, which have different and inconsistently used connotations, have not been used to avoid any misunderstanding. A distinction has been made between the epileptiform EEG responses to IPS [so-called photoparoxysmal responses (PPRs)] and clinical signs and symptoms, evoked either by IPS or by visual stimuli in daily life. If a PPR is found, the patient is considered IPS sensitive. Visual sensitivity is defined as the susceptibility toward experiencing seizures, which are triggered by the physical characteristics of visual stimuli and not by their perceptual properties (i.e., reflex seizures induced by the cognitive effects of visual stimuli). A combination of these data with a clinical seizure history and imaging results will assist identification of the various syndromes, thus leading to an assessment of risk factors and prognosis in the various patient groups. Visual-induced epilepsy has a strong genetic component. Siblings of children with generalized PPRs are much more likely to show a similar abnormality than are siblings of control subjects (19.3 vs. 3.4%) 16. A PPR is also significantly more common in 5- to 10-year-old siblings of proband offspring of a parent with a PPR (50%) than in siblings of PPR-positive children of parents without a PPR (14%) 17. Studies performed in humans and in experimental animal models, especially the Papio papio baboons, which respond to IPS at 25 Hz with epileptic seizures resembling those of photosensitive patients, indicate that the cerebral cortex plays a primary role in the genesis of electroclinical manifestations of visual-sensitive epilepsy 18. The frontorolandic cortex and the occipital cortex seem to be the most involved in generating the abnormal response in both species. Unitary recording in the baboon shows that the photoparoxysmal EEG response originates from the frontorolandic cortex 19. Generalized seizures appear to result from spread of seizure activity, which is initiated by IPS in the frontorolandic cortex 18. Blockade of frontorolandic discharges by local γ-aminobutyric acid (GABA) infusion also blocks IPS-induced grand mal seizures 20. However, visual afferents to the frontorolandic cortex are controlled by the occipital cortex, which can generate epileptic activity on its own if made hyperexcitable by a decrease in the level of GABA by alloglycine injections 21. Depressants of photosensitivity in the baboon such as valproic acid (VPA) also are active in humans. Despite many striking similarities, the relationship between the IPS-sensitive baboon and patients with photic-induced seizures has been questioned 22, 23. Neurophysiologic studies in patients with photic reflex myoclonus 24-26 show that the contralateral occipital cortex is activated first and that impulses spread to the primary motor cortex to produce myoclonic jerks. In addition, numerous reports indicate that in a considerable number of individuals with visually induced seizures, ictal activity originates from the occipital cortex 13, 27, 28. Subsequent spread to the suprasylvian cortex often results in generalized tonic–clonic seizures (GTCSs), whereas infrasylvian spread produces complex partial seizures (see also partial seizure section). Studies in pattern-sensitive epilepsy revealed that the two hemispheres can have a different threshold; that a critical area of the visual cortex should be stimulated, and that synchronization of neural activity is necessary to elicit a PPR 29. The corpus callosum is critical for interhemispheric synchronization and generalization of EEG discharges 30. Visually evoked potentials (VEPs) of different contrast show that for stimuli of low to medium frequency, the contrast dependence of VEP amplitude and latency is remarkably abnormal for luminance-contrast, but not so for chromatic-contrast stimuli 14. These data indicate that patients with visually induced seizures lack the normal mechanisms of cortical gain control for pattern stimuli of low temporal frequency and high luminance. Suppression of contrast gain control may be experimentally induced in the cat by local application of bicuculline 31, indicating that reduced GABAergic transmission plays a role in visual cortex hyperexcitability. In patients with progressive myoclonus epilepsy, the mechanism of visual sensitivity has been related to deficit in dopaminergic transmission, because apomorphine, a dopaminergic agonist, abolished the PPRs 32. Many antiepileptic drugs (AEDs), developed for partial and generalized seizures, have reduced or abolished PPRs in humans, suggesting that a variety of neurotransmitters and channel blockers could be involved 33, 34. Some individuals may complain of subjective symptoms when they are exposed to photic stimuli, especially IPS 35. Some of these symptoms are normal phenomena, due to the effect of intense light stimuli. They consist of seeing zigzag lines or colors not actually present in the stimuli. Other symptoms include dizziness, eye pain, dragging sensations in one eye, epigastric discomfort, nausea, or simple visual hallucinations. These manifestations may be unrelated to epileptic activity or they may result from an ictal discharge arising in the occipital cortex 27, 36 or in the mesial temporal structures 37. An accurate clinical diagnosis regarding the nature of mild subjective symptoms can be very difficult if the duration is short and their occurrence infrequent. Some of these subjective manifestations may be definitely ictal but still remain isolated symptoms, which is sustained as long as the triggering stimulus is sustained. On other occasions, they may be part of a more complex ictal episode, if a self-sustained ictal discharge arises and spread occurs (see Partial seizures section). Frontopolar, recruiting, photomyogenic, and photooculoclonic responses are synonymous with orbitofrontal photomyoclonus. The triggering stimulus is IPS. The frequency range of flashes effective in triggering this response is usually between 8 and 20 Hz. It is rarely seen in children, but constitutes a normal finding in adults and, in particular, in the elderly. Patients have rapid myoclonic jerking of the periorbital muscles, which produces eyelid fluttering and blinking, synchronous with the flashes. There may be vertical oscillations of the eyeballs. Amplitude of the response increases progressively during the first flashes, reaching a maximum within a few seconds. The maximal amount of muscle activity is initially observed in the inferior orbicularis oculi muscles, with subsequent irradiation to other facial muscles, the frontal and occipital areas, and the neck 38. Further spread may be seen if IPS stimulation continues. The likelihood of eliciting this response is increased by muscular tension, for instance, if one were to instruct the subject to screw up the eyes and clench the jaws. This response is bilateral and time-locked to the stimulus. Latency between each flash and the corresponding muscle contraction is ∼50–60 ms. Response is blocked when the eyes are opened, and it stops immediately when the stimulation is terminated. Although the physiology and significance of this response have been disputed for a number of years, our current understanding indicates it to be an expression of cortical response 39 within the spectrum of photic cortical reflex myoclonus 25, 26. Eyelid myoclonus may occur either as a very short event lasting ∼1–2 s without any detectable impairment of consciousness or as in Absences with eyelid myoclonus, be prolonged and accompany an absence seizure 40. Eyelid myoclonus must be differentiated from the orbitofrontal photomyoclonus (OPM, see earlier), because its clinical and electrographic relation to epilepsy is obvious. The delay between the stimulus and ensuing eyelid jerking is longer than that seen in the photomyogenic response and is more variable 41. In some patients, myoclonic jerking of the eyelids appears in the context of a complex repetitive self-stimulation habit with deliberate fluttering of the eyes and hyperextension of the head in front of any bright light source, including IPS. Under these circumstances, attempting to draw any distinction between eyelid myoclonus and self-inducing behavior may be particularly difficult. In exceptional cases, focal myoclonic (FM) jerks (e.g., in one hand, arm, or hemiface) can be evoked by IPS 35, 42. Consciousness is retained. Generalized myoclonic jerks are usually symmetric and predominate in the upper limbs. In most cases, they are mild, producing only nodding of the head and slight arm abduction. More generalized jerks, involving the face, trunk, and legs, may occasionally cause the patient to fall. The relationship of myoclonic jerks to the stimulus is complex. Sometimes there is no definite time relationship. On other occasions, the jerks may be repeated rhythmically with the same frequency as the stimulus or at one of its subharmonics 11. Isolated myoclonic jerks occur without impairment of consciousness. However, generalized jerks may be repeated, especially if the stimulus continues. In this situation, consciousness may be impaired, and a GTCS may follow. On rare occasions IPS has been shown to produce version of the eyes and the head toward one side. The versive posture (TVP) may be sustained as long as the triggering stimulus is continued 43, representing a stimulus-dependent localized ictal phenomenon. It may also outlast the stimulus as a feature of a simple partial seizure that may then evolve to complex partial or to a GTCS. In this case, it indicates that focal seizure activity precedes seizure generalization. A small subgroup of patients has loss of awareness as the only symptom. When stimulation is performed with the eyes being held closed, the absences may be manifested only by opening the eyes. Mean age at onset is ∼12 years 4. Absences may outlast the stimulus. A mild myoclonic component and evolution into a GTCS are possible. These are usually, but not always, triggered after sustained exposure to photic stimuli. They may follow an absence, a myoclonic jerk, a series of jerks, or a partial seizure, but can occur without any preceding phenomenon. Secondary generalization may be slow or very fast, after mild clinical signs such as head deviation or visual symptoms, which could possibly indicate generalization of an initially focal, possibly occipital seizure. In up to 65% of patients with photic-induced seizures, focal ictal onset, usually in the occipital neocortex, is clinically demonstrable 27, 28. Photically induced PS is often characterized by a sequence of visual and vegetative symptoms, sometimes accompanied by headache 36, 44. These seizures can be mistaken for migraine, especially if motor manifestations are not recognizable. Clinical seizure semiology is similar to that of spontaneous occipital-onset seizures. Spread may be rapid, but it must be stressed that it can also be remarkably slow, occurring after many minutes of ictal activity limited to the occipital lobe 13, 18, 45, 46. Most patients experiencing subjective symptoms describe visual phenomena as the initial ictal manifestation. These are usually reported as bright, multicolored, or occasionally manifesting dark rings, spots, or simple geometric forms, which are continuous or flashing. Location is usually, but not necessarily, in the periphery of the visual field, crossing to the opposite side while rotating or moving slowly 36, 44, 47. Ictal amaurosis, blindness, or of limited to one or involving the visual field, may follow the visual but may occasionally the first It can be to between ictal and More complex visual may include often related to and may be accompanied by or of or as or moving or also may include in the or of a in manifested by or of More complex may result in an of in or Ictal (i.e., the or of visual the of is no longer is reported this often with there may be in the two Visual phenomena are often accompanied or by eye, or eye and head usually toward the side of the initial visual it may be to eye and head are manifestations of the seizure or they are by the patient to follow and Eyelid fluttering or with a dragging in one eye other seizure manifestations that have been to occipital of seizure Visual phenomena, both and may spread to the visual of seizure activity to structures is and accompanied by of temporal lobe The most ictal pattern is a sequence of epigastric discomfort, and Some patients which to be particularly during the of prolonged seizures triggered by photic stimulation 36, 44. to the motor cortex is accompanied by focal motor or activity and to the cortex by In exceptional cases, it has been that visual stimuli can simple with vegetative symptoms or an epigastric without any preceding visual to stimuli producing a activity at the flash frequency, as as the stimulus terminated. This is a normal activity at a or of the flash frequency, in with the stimulus It is often with at the flash It is normal and of no clinical significance if In of patients, an abnormal response in can be by stimuli producing a activity at the flash frequency, which as as the stimulus is terminated. It first as a response by and by 38. The are of arising in the orbicularis oculi and in particular, and are maximal at the front of the A cerebral component of frontal lobe may also be present to are known as and include the four of the classification of and of the responses and of the It is still to the finding of one of these responses is related to risk of visually induced seizures, because from of age and of also have on the of However, a generalized response at a range of is considered to be of clinical of or high Some have clinical for instance, occipital after of generalized PPR by and in to or maximal at the of the head and not at the flash frequency or at a The and activity and epileptiform responses that outlast the stimulus These often many and may evolve to an seizure. or activity, which are but may be of amplitude at the front or of the It is a response by and to response of Generalized PPR after This may not be the stimulus is as as a generalized PPR is It by and and has a strong with epilepsy and visually induced seizures in patients for clinical EEG in general is but in of by photic stimulation may an cortex, which is also IPS could then also elicit a seizure by usually area It is this should be considered a and it not in We for only that if the response to IPS is the likelihood of epilepsy from to and the likelihood of visually induced seizures is The risk of seizures is in patients with PPR but without spontaneous epileptiform EEG discharges The only contemporary on other of induced responses is a on the of photosensitivity and epilepsy 17. They that the seizure risk siblings of years were not to IPS and were of The risk IPS-sensitive siblings of age range with a PPR in one of their jerking evoked by IPS is related to a clinical history of epileptic seizures the We a to a distinction between the various groups. an evolution of the clinical or the of more clinical patients could from one to the In due the number of could be The PPR can be by individuals with headache or or because of a with epilepsy or photosensitivity Studies performed in the 1950s and in normal subjects revealed a of abnormal EEG responses to IPS between and and If the response is a generalized the likelihood of epileptic seizures is in the of for EEG In of patients than years being for general EEG head headache the occurrence of a generalized PPR related to a history of epileptic seizures for an abnormal response to IPS and slow activity and without generalization. the of visually induced seizures (see earlier), a clinical history should be taken with the on subjective discomfort, such as in the eyes or of can be considered an ictal 35. A distinction between an ictal visual and such as and seeing can be difficult to If in the patient can be in this with as a When a PPR is in a the to IPS may increase during leading to a clinical seizure A PPR can be in epilepsy (see seizures are should be concerning the in which seizures It may be to the patient on possibly provocative visual stimuli (e.g., sunlight through flashes, striped in to a clinical history of spontaneous seizures, clinical signs are seen during the the patient is considered to have visually induced and spontaneous seizures, with or without a PPR in the EEG see This a seizure in front of the in the while a and so or not (e.g., On such it be to the seizure visually subsequent could of these These patients have a history of seizures often myoclonic jerks and in response to a visual stimulus. The finding of a PPR is on the IPS as as on the age of the patient and the and of A combination of both visually induced and spontaneous seizures may be either in children with epileptic and photosensitivity or in normal children and The Classification of not visual sensitivity or IPS sensitivity as of any epileptic it that the of a There is and that and IPS sensitivity to various of a a PPR or can be in generalized or or and within the context of seizures. A PPR may occur in patients with epilepsy as a finding with no and with no relationship to the seizure (see However, such are In most patients with epilepsy and a the of the PPR is significantly related to the and clinical of the epilepsy and has the and prognosis of such are not on this The most between IPS and epilepsy occurs in generalized Visual sensitivity is particularly in in which it can be in different age but it is most common in children and of There is a patients with and The triggering role of visual stimuli to decrease through the PPR may on repeated EEG myoclonic epilepsy in is the of with It is characterized by onset the age of Generalized discharges are with myoclonic jerks and can be by IPS. absence epilepsy in its is with PPRs and in of no is between those with and without a A of is seen in both absence epilepsy is accompanied by or PPRs in of patients myoclonic epilepsy is the of epilepsy that has the with to of patients to of a the of clinical visual sensitivity may be It is this IPS-sensitive subgroup also has a occurrence and a high after a of with GTCS on is accompanied by a PPR in of the patients, but this is in with GTCS that not occur at epilepsy, as of epilepsy, is considered to be related to It is with evoked by IPS or pattern in than of Visual in which is with including absences on light stimulation and absences with eyelid myoclonus 40. there is a subgroup of patients with seizures by triggering and is the most common of such Many of these patients be to a main of but with the other of many characteristics including sensitivity and such patients can be as a visual-sensitive it is not at this time this to the of different genetic or to a Visual sensitivity is not common in patients with the and other of or generalized an being epilepsy of Although in this of epilepsy, a PPR is often during is known its clinical and are often both clinically and as an EEG it may be the first of the It is often with and the most of in which an abnormal response to IPS is an include clinically and which can be in very patients, but also in Visual sensitivity is especially in the and This may be characterized by a but particularly by high amplitude of responses to and evoked potentials to flashes. Patients with progressive loss of and may decrease during the of the is a the In this is often with spontaneous focal occipital seizures is a and EEG that to after the or of evolution the clinical of the is variable and between epilepsy and the clinical spectrum is and may occur A PPR has been in a so with and seizures In the abnormal responses to IPS have been A has been on and A PPR can be in focal with various of and also in A of occipital lobe epilepsy to visual stimuli has been reported occurs in or with a pattern of visually induced occipital lobe seizures that may spread This of epilepsy is often mistaken for This is with a PPR in of which are often accompanied by myoclonic jerks. The of clinical is not as children may visually induced myoclonic jerks or absence in front of complex stimuli. may be very for in the first years of life. clinical and EEG of may during the In a variety of circumstances, seizures, usually can be by visual stimuli in patients be considered as The most to strong visual stimuli in patients may have a genetic of with other factors such as or or may cause as can the use of drugs such as and has also been with of and PPRs are the different of epilepsy and are significantly with a variety of epileptic of different Further on and prognosis are The in the in made by an from were We the loss of our and made a to this

1. Jana E. Jones, PhD* 2. Joan K. Austin, DNS, RN† 3. Rochelle Caplan, MD‡ 4. David Dunn, MD§ 5. Sigita Plioplys, MD** 6. Jay A. Salpekar, MD¶ 1. *Assistant Professor, Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisc 2. †Distinguished Professor of Nursing, Indiana University School of Nursing, Indianapolis, Ind 3. ‡Professor, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Calif 4. §Arthur B. Richter Professor of Child Psychiatry, Indiana University, Indianapolis, Ind 5. **Assistant Professor, Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Ill 6. ¶Assistant Professor of Psychiatry and Pediatrics, George Washington University School of Medicine, Washington, DC Epilepsy occurs in approximately 1% of the population. It is the third most common neurologic disorder in the United States after Alzheimer disease and stroke. The prevalence of epilepsy is equal to the combined prevalence of cerebral palsy, multiple sclerosis, and Parkinson disease. Epilepsy is the most common childhood neurologic disorder, affecting 0.5% to 1.0% of children younger than age 16 years. (1) More than 326,000 children younger than age 15 years have epilepsy, and approximately 90,000 have seizures that are not controlled completely by treatment. Epilepsy often occurs in conjunction with other conditions, including autism spectrum disorder, cerebral palsy, Down syndrome, and intellectual disability. Although seizures are the most readily identifiable feature of epilepsy, behavior and cognitive functioning also are affected negatively in a substantial number of children. The prevalence of psychiatric comorbidity in epilepsy is significantly higher than in healthy controls or in children who have other chronic health conditions. This article reviews the current knowledge of coexisting psychiatric disorders in children who have epilepsy and discusses diagnostic and treatment issues. Two epidemiologic investigations, conducted in the United Kingdom 3 decades apart, demonstrate that psychiatric comorbidity is overrepresented in pediatric epilepsy. In the classic Isle of Wight study, Rutter and associates (2) reported that 7% of children in the general population exhibited a mental health problem compared with 12% of children who had non-neurologic physical disorders. Significantly higher rates were reported in those having epilepsy, including 29% in children who had uncomplicated (idiopathic and cryptogenic) epilepsy and 58% in those who had complicated epilepsy (seizures in the context of structural central nervous system abnormalities). Strikingly similar findings were reported in a recent United Kingdom epidemiologic investigation by Davies and colleagues. (3) Among children ages 5 to 15 years of age, psychiatric disorders were found in 9.3% of the …

PURPOSE: To examine potential risk factors for poor health-related quality of life (HRQOL) among adolescents with epilepsy by using the newly developed QOLIE-AD-48. Risk factors were derived from sociodemographic, social, academic, and epilepsy- and health-related domains. METHODS: The QOLIE-AD-48 was administered to 197 English-speaking adolescents (age 11-17 years from >20 sites in the United States and in Canada). The self-report instrument yields an overall HRQOL score and eight subscale scores. Other data were obtained from family interviews, physician reports, and health records. Multiple regression analyses were conducted to study risk factors for impairment of HRQOL. RESULTS: Older adolescents (age 14-17 years), those with more severe epilepsy and more symptoms of neurotoxicity, and those living in households with lower socioeconomic status were more likely to report poor overall HRQOL. Risk factors in the eight HRQOL domains were found as follows: (a) Epilepsy Impact: older age in adolescence, more severe epilepsy and neurotoxicity, more hospitalizations during the past year, and fewer hours of extracurricular activities; (b) Memory and Concentration: longer duration of epilepsy, special education classes, and history of repeating a grade in school; (c) Attitude Toward Illness: older age, female gender, and more severe epilepsy and neurotoxicity; (d) Social Support: younger age, male gender, and fewer hospitalizations in the last year; (e) Stigma: lower socioeconomic status and special-education classes; and (f) Health Perceptions: older age, female gender, and lower socioeconomic status. None of the factors examined was significantly associated with HRQOL in (g) Physical Functioning or (h) School Behavior subscales. CONCLUSIONS: We identified several risk factors for poor HRQOL outcomes in adolescents with epilepsy. Age, increased seizure severity, and neurotoxicity were most consistently associated with poor HRQOL across domains. Older adolescents, independent of epilepsy severity, reported worse overall HRQOL than did their younger counterparts. Older adolescents also were more likely to perceive a greater negative impact on life and general health, and had more negative attitudes toward epilepsy. Adolescent boys and girls may show different sensitivities to various quality-of-life domains.

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Scientists have created a powerful new way to control quantum systems, achieving the first-ever demonstration of quadsqueezing—an elusive fourth-order quantum effect。 By combining simple forces in a clever way, they made previously hidden quantum behaviors visible and usable, opening new frontiers for quantum technology

Quantum physics once shocked scientists by revealing that particles can behave like waves—and now, that strange behavior has been pushed even further。 For the first time, researchers have observed wave-like interference in positronium, an exotic “atom” made of an electron and its antimatter partner, a positron。 This breakthrough not only strengthen

In a major breakthrough, scientists have observed electrons in graphene flowing like a nearly frictionless liquid, defying a core law of physics。 This exotic quantum state not only reveals new fundamental behavior but could also unlock powerful future technologies

Crabs’ famous sideways walk may trace back to a single evolutionary moment 200 million years ago。 Researchers found that most modern crabs inherited this trait from one ancestor—and never looked back。 The movement likely gave them an edge, helping them dodge predators with quick, unpredictable bursts

For the first time, scientists have watched a subduction zone literally fall apart beneath the ocean floor。 Using advanced seismic imaging, they found the Juan de Fuca plate splitting into fragments as it sinks beneath North America。 Rather than collapsing all at once, the plate is tearing piece by piece, like a train slowly derailing

[In this section, we present a lead paper followed by a set of comment articles that have been invited by the editors. Our goal is to present different or opposing views on topical issues. Articles and comments are commissioned in the spirit of encouraging discussion and debate in a format that will stimulate thought and further research.] For myself I shall be well satisfied if I have made it appear probable to you that there does exist a form of epilepsy in children which is distinguishable by its clinical features and in which the prognosis is always good Adie (1924) differentiating “pyknolepsy” (syndrome) from “petit mal” (seizures) This commentary outlines clinical and electroencephalography (EEG) aspects of typical absence seizures (TAS) and related epileptic syndromes in order to identify areas of consensus as well as areas of uncertainty that may indicate directions for future research. This may also assist the International League Against Epilepsy (ILAE) Commission, which is currently working on establishing scientifically rigorous criteria for the identification of specific epileptic seizures and syndromes using an evidence-based approach (Engel, 2006). Relevant ILAE definitions and classifications are shown in Table 1. TAS and related epileptic syndromes were thoroughly assessed by leading clinicians and researchers in this area during a 3-day symposium in 1994 in London (Duncan & Panayiotopoulos, 1995). Consensus was achieved in the definition and semiology of TAS and controversies in their syndromic classification comprehensively debated (Reynolds et al., 1995). The report by Sadleir and colleagues (Sadleir et al., 2008) and its related predecessor on childhood absence epilepsy (CAE) (Sadleir et al., 2006) is assessed in the context of this debate. TAS are generalized seizures of sudden onset and termination, lasting for seconds. They are fundamentally different from other seizures and they are pharmacologically unique (Panayiotopoulos, 2005a). TAS have two requisite components: Clinically, the transient impairment of consciousness (TIC) (absence) EEG generalized >2.5 Hz spike- or polyspike-slow wave discharges (S-PWD). TAS usually occur in the context of idiopathic generalized epilepsies (IGE). The prefix “typical” is to differentiate them from atypical absences rather than to characterize them as “classical” or characteristic of any particular syndrome. Atypical absence seizures occurring in the context of mainly symptomatic epilepsies and with slow <2.5 Hz S-PWD are beyond the scope of this commentary. The clinical and EEG manifestations of TAS have been well-characterized through video EEG studies (Penry et al., 1975; Stefan, 1982, 1983; Holmes et al., 1987; Panayiotopoulos et al., 1989a, 1989b, 1997; Capovilla et al., 2001; Poblano et al., 2001; Guilhoto et al., 2003; Sadleir et al., 2008). The clinical manifestations vary significantly between patients (Tables 2 and 3). TIC may be the only clinical symptom (simple TAS), but this is often combined with other manifestations (complex TAS). In recognition of this diversity, the ILAE has recently recognized four types of TAS (Table 1) probably of different pathophysiology and syndromic significance: (1) the classical TAS, (2) myoclonic absence seizures, (3) phantom TAS and (4) eyelid myoclonia with absence (EMA) (Engel, 2006). TIC is a mandatory symptom of TAS and may be severe, moderate, or mild. In routine EEG practice, TIC is commonly assessed by the ability of a patient to recall a verbal test stimulus (a phrase, number, or rhyme) during S-PWD. By examining TIC in an all or none fashion, this test detects only severe TIC. When TIC is mild, the patient often recalls the test stimulus (Fig. 1D, 1I, and 1J). Furthermore in brief S-PWD, the test is often given or continues after these have ended. Asking the patient to count his/her breaths during hyperventilation (BCH) was the most reliable and practical means for the detection of TIC during S-PWD among various methods that we evaluated (Panayiotopoulos et al., 1989b). We have validated BCH (Giannakodimos et al., 1995) and use it as a standardized method in our studies of TAS, which is how we have identified phantom absences that manifest with cessation, delay, hesitation, or errors in counting (Fig. 1D) (Panayiotopoulos et al., 1997; Koutroumanidis et al., 2008). BCH is powerful because it simultaneously tests attention, concentration, memory, sequential accuracy, and language function. Illustrative EEG from video EEG samples to exemplify important matters to consider in the diagnosis and the syndromic classification of TAS. The actual video EEG of most of these and many other patients can be viewed in the companion CD of our publications, which also include many years of follow-up (Panayiotopoulos, 2005b; Panayiotopoulos, 2007b). Cases A–E are from a video EEG at first presentation of children with TAS before age 10 years. Only case A was CAE. All others had other than CAE syndromes that were predicted from the first EEG with significant implications on prognosis and management. Case B had classical myoclonic TAS, and at last follow-up at aged 8 years is neurocognitively impaired with intractable GTCS and myoclonic TAS. Case C had marked myoclonic components through the whole length of TAS, photosensitivity, multiple spikes, and irregular S-PWD. At age 12 years, TAS are worse with an evolution similar to her mother (case K). Case D had very mild (phantom TAS) and absence status epilepticus as previously reported with video EEG sequences (Panayiotopoulos et al., 2001). Case E had moderate and severe TAS, with multiple spikes and irregular S-PWD, similar to her older sister (case F), who had onset of TAS at age 11 years. Two years later, she had a GTCS in front of the TV. These sisters illustrate well the problem of classifying syndromes of TAS by age at onset; accordingly case E would be classified as CAE and case F as JAE. Case G had S-PWD concurrent with myoclonic and atonic symptoms without TIC. These features, which are not TAS, confirmed the diagnosis of myoclonic-astatic epilepsy. Case H had severe and lengthy TAS of JAE. The patient also had GTCS and myoclonic jerks. Case I demonstrates TAS with mild TIC in two young women with JME. TIC was documented only with breath counting during hyperventilation. In all other occasions, the patients were able to recall the verbal test-stimulus during S-PWD. Case J is from EMA patients whose seizures manifest with mainly eyelid myoclonia that may be associated with minor TIC. Case K from video EEG of the mother of case C. TAS and photosensitivity started at age 6 years, GTCS occurred at age 14, and premenstrual myoclonic jerks appeared later; all continue in adult life and are resistant to medication. There is no consensus on the extent and clinical significance of other more elaborate psychological testing for the detection of TIC during S-PWD that may appear clinically silent. This is a matter that divides opinions not only for S-PWD but also for any other type of EEG epileptiform activity that may be associated with TIC (Aarts et al., 1984; Aldenkamp and Arends, 2004). Many types of psychological testing have been used during S-PWD since 1939 (Schwab, 1939). These generally show that impairment of response may start just before the onset of S-PWD, tend to get worse with longer duration of S-PWD, but improve during the latter part of it (Mirsky and van Buren, 1965; Goode et al., 1970; Sellden, 1971; Porter & Penry, 1973; Browne et al., 1974). The ictal EEG of TAS consists of generalized >2.5 Hz S-PWD, which are often of higher amplitude in the anterior regions (Fig. 1, A–K). By consensus, spike-wave frequency is higher than 2.5 Hz, mainly 3–4.5 Hz, but there are no recommendations on how these measurements should be made. Frequency is usually variable and faster in the first second (opening phase), becomes more regular and stable in the subsequent 3 s (initial phase), and slows down towards the terminal phase of longer S-PWD (Fig. 1) (Panayiotopoulos et al., 1989b). This is why our practice is to estimate mean frequency of the initial phase of S-PWD and not at the first second of S-PWD used by other authors (Holmes et al., 1987; Sadleir et al., 2006). S-PWD also show significant qualitative variations that are clinically significant when examined systematically; they may be fragmented, multiple spikes may predominate, and the relationship between spike/multiple and slow wave fluctuates (Fig. 1). Duration is easy to measure and commonly is from 3 to 30 s. Hyperventilation induces TAS in nearly all untreated patients. Intermittent photic stimulation may precipitate or facilitate S-PWD in any type of TAS (Fig. 1C, 1J, and 1K); eyelid myoclonia is a common clinical accompaniment. Generalized >2.5 Hz S-PWD is the EEG marker of TAS but may also be clinically silent or manifest with symptoms other than TIC (Fig. 1G) (Dalby, 1969; Genton, 1995; Koutroumanidis & Panayiotopoulos, 2008). Sadlier and coworkers (2006, 2008) define as absence seizure any type of >2.5 Hz S-PWD associated with clinical signs even if this is not associated with TIC. However, the latter could be either TAS with undetectable TIC (which is a matter of methodological sensitivity) or other that TAS epileptic seizures (Fig. 1G). The syndromic classification of IGE with TAS is controversial (Reynolds et al., 1995). One view is that all presentations are one disease or a biological continuum (Berkovic et al., 1987). Another view, which we support, is that IGE with TAS comprise distinct epileptic syndromes, four of which are recognized by the ILAE. These are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), epilepsy with myoclonic absences (MAE), and juvenile myoclonic epilepsy (JME) (Tables 1 and 3). CAE, first described in the pre-EEG era by Adie (1924) as pyknolepsy, manifests with numerous severe TAS and good prognosis as subsequently confirmed with EEG, video EEG and long follow-up studies (Loiseau & Panayiotopoulos, 2004). There remain many areas of uncertainty of what is CAE. The ILAE broadly defines it as a syndrome with frequent (several to many per day) and severe absences (see ILAE definition of TAS), school age at onset (peak at 6–7 years), and common remission (Table 1). Exclusion criteria have been introduced (Loiseau & Panayiotopoulos, 2004). The ILAE, by accepting MAE and JME as separate syndromes, probably exclude myoclonic TAS and mild TAS from CAE (Commission, 1989). It is by this logic that EMA (which are primarily myoclonic) may also be an exclusion criterion. Further, by accepting reflex TAS as a distinct category, the ILAE indicates that these too may not be part of CAE. That perioral myoclonia or single violent jerks occurring in the course (not at onset) of TAS is an exclusion criterion may be debatable; however, their presence indicates worse prognosis (Panayiotopoulos, 2007a). The same applies for multiple spikes and fragmented S-PWD that also indicate a bad prognosis, coexistent myoclonic jerks, or generalized tonic–clonic seizures (GTCS) (Panayiotopoulos et al., 1989b; Fakhoury & Abou-Khalil, 1999). A simplistic but unsatisfactory practice is to label as CAE any child with onset of daily TAS at ≤10 years and to as early as 2 years (Sadleir et al., 2006). The 10 years of age cut off is arbitrary and not a decisive “gold standard” to define what is and what is not CAE. Further, TAS of recognized syndromes, such as MAE or JME, may start before that age, and TAS of early childhood onset (<4 years of age) are heterogeneous and often entirely different to those of CAE (Doose, 1994). The arbitrary limit of 10 years is mainly based on the pioneering work of Doose and Janz who found that pyknoleptic absences usually start before the age of 10 years, while nonpyknoleptic absences usually start after this age (Doose, 1994; Janz et al., 1994). If diagnosis by age at onset is to be followed, the study population should be correctly defined as “childhood absence seizures,” rather CAE which is a subset of it. Such a distinction is particularly important in view of the current National Institute of Neurological Disorders and Stroke supported study of CAE from which initial published results refer to “a high incidence of adverse behavioral and cognitive outcomes in CAE” (O'Deil et al., 2006). Is this CAE or childhood absence seizures? Classical studies have shown significant differences between “childhood absence seizures” and CAE (see details and citations in Sander, 1995). This syndrome is now well-defined, but the course is variable (Bureau & Tassinari, 2005; Engel, Jr., 2006). Myoclonic absences manifest with bilateral clonic jerks often with a tonic contraction (Fig. 1B). TIC is of variable severity. Onset ranges from 1 to 12 years (peak 7 years). Etiologically, myoclonic TAS are sometimes idiopathic and of good prognosis, but two-thirds are cryptogenic or symptomatic, which are resistant to treatment, and may progress to epileptic encephalopathies. MAE offers a good argument against diagnosing syndromes of TAS by age at onset. That simple TAS may also occur and sometimes precede the characteristic myoclonic absences (Bureau & Tassinari, 2005) is another concern to consider in validating the reports of Sadleir et al. (2006, 2008); such children could easily have been categorized as CAE without appropriate follow-up. There are many areas of uncertainty regarding the precise definition of JAE, but all authorities agree that TAS with severe TIC is its main seizure type. These TAS in many respects are similar to those of CAE, although often less frequent, with less severe TIC, and more polyspikes in the EEG S-PWD (Fig. 1E, 1F, and 1H). TAS continue into adult life often with GTCS. One-fifth of patients also have myoclonic jerks (Commission, 1989; Wolf, 1992; Obeid, 1994), which are erroneously considered an exclusion criterion by Sadleir et al. (2008). Myoclonic jerks on awakening with peak age at onset in the mid-teens are the defining seizures of JME. GTCS are probably unavoidable in untreated patients. TAS occurring in 30% of patients are usually simple with mild TIC (Fig. 1I) (Berkovic et al., 1987). One-third of TAS in JME appear at ≤10 years, often predate myoclonic jerks, and may be more severe than those of later onset (Commission, 1989; Panayiotopoulos et al., 1989a, 1989b; Wirrell et al., 1996; Delgado-Escueta et al., 1999). We are in need of longitudinal studies to determine their features and how they develop in time (which is not possible without follow-up) rather than arbitrarily including them in CAE as per Sadleir et al. (2006, 2008). Other proposed syndromes of IGE with TAS need further consideration and study. The following brief presentation of some of them is to emphasize key features of their TAS (recognized by the ILAE), which are important to consider in any analysis and differential diagnosis. EMA (the seizure) consists of brief (3–6 s), marked, rhythmic, and fast jerks of the eyelids which may occur alone (eyelid myoclonia) or followed by mild TIC (eyelid myoclonia with absence) (Fig. 1J) (Giannakodimos & Panayiotopoulos, 1996). They may occur in idiopathic, cryptogenic, or symptomatic epilepsies. In the idiopathic syndrome of Jeavons, EMA occur mainly after eye closure, usually start in childhood, and all patients are photosensitive. Infrequent GTCS and limb myoclonic jerks are common, usually occurring after the onset of EMA. The syndrome is commonly lifelong and resistant to pharmacologic treatment. This syndrome, characterized by phantom absences (Fig. 1D), becomes clinically apparent only when GTCS and often absence status epilepticus occur, usually in adulthood (Panayiotopoulos et al., 1997, 2001; Koutroumanidis et al., 2008). Reflex TAS to photic, pattern, emotional upset, and thinking are well described. TAS associated with clinical photosensitivity (Fig. 1C, 1J, and 1K) are unlikely to occur in CAE, and they are likely to continue in adult life (Hirsch & Marescaux, 1994; Loiseau et al., 1995). It is apparent from the above descriptions that, with the exception of CAE, nearly all other syndromes of IGE with TAS are lifelong and also manifest with myoclonic jerks and GTCS (Table 3). Absence status epilepticus occur in one-third of patients, and this predominates in IGE with phantom absences or perioral myoclonia TAS (Agathonikou et al., 1998). Features of TAS, as with any other type of seizure, depend on brain maturity, the sleep-wake cycle, provocation, and a variety of other factors (Fisher et al., 2005). Overall, children have TAS with severe TIC and lengthier duration more often than adults. Spontaneous eyes opening (when not caused by motor events of TAS), like all other automatisms, occurs only when TIC is severely impaired (see definitions of automatisms in Table 2). The variability of TIC and duration of TAS by age also contributes to shaping the clinical presentation of syndromes of IGE-TAS that, as with many other epileptic syndromes (rolandic epilepsy for example), may be age-dependent and age-limited. Conversely, even age-influenced individual TAS features are also syndrome-related as indicated by the fact that children may also have brief and mild TAS (Fig. 1C and 1D), and conversely also manifest with severe and lengthy TAS (Fig. 1H). studies have shown that TAS of IGE with age, but this may be for such as in JME and EMA (Panayiotopoulos, 2007a). the clinical and EEG features of TAS, S-PWD are usually and usually of clinical in those patients who have numerous clinical seizures during the et al., The syndromes of IGE with TAS, like all other and epileptic rigorous and for their individual EEG or even a type of seizure does not an epileptic rather it is the of and video EEG symptoms and signs that a syndrome (Commission, 1989). studies are particularly important in children syndromes often progress to seizures other than those in the initial presentation or years. In our studies on IGE with TAS, we a and patient with TAS is assessed clinically and with video EEG from the time of first to as long as is This is for recognized patients. However, significant are also from of reliable by and (Panayiotopoulos, 2007a). Sadleir and (2006, 2008) should be for patients at the first of their They have a video EEG analysis of clinical associated with >2.5 Hz S-PWD to reports However, to this beyond a study and the are because of the of any follow-up with definitions and arbitrary that, to their not with the ILAE CAE is not with TAS at age ≤10 years, myoclonic jerks are not an exclusion criterion for JAE, and TAS of JME were only when onset was at years, which means that JME with onset of TAS between years were either or in CAE. For a analysis to the assessed should be thoroughly examined and which does not appear to be the case in the current report of Sadleir et al. (2008). of the progress of the study population first between may important assessed in this commentary. patients classified as CAE should now be in remission or will have features of other IGE-TAS syndromes with TAS in childhood as per the Table there is a of many years in studies that may to on these issues. These be and particular to important differences between individual reports in patient or length of and other study them as in the reports of Sadleir et al. (2006, 2008) their and TAS and related epileptic syndromes are a significant progress made in their and video EEG classification is a work in and we should all remain to future We are in need of studies with precise definitions and of the these may and our in the spirit of work with an and the clinical of view, even if IGE syndromes with TAS were a continuum or the same (which is unlikely current in and their has significant and This may sometimes be in clinical practice, but it is not in are identified on the of In current good practice recommendations an epileptic syndrome and treatment. This progress has been achieved through against the of all of them in have been to this and we should be to this I to colleagues who have with their and their of this particularly who also in the various to its of I that I have the on in and that this report is with those The has no of to The has a with and an for a of a of The on

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A mysterious magnetic material once thought to host an exotic “quantum spin liquid” has turned out to be something entirely different—and possibly just as intriguing。 Scientists studying cerium magnesium hexalluminate found it showed the hallmark signs of this elusive quantum state, like a lack of magnetic order and a spread of energy states。 But a

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