Epilepsy Research (2015) 114, 2—12

journal homepage: www.elsevier.com/locate/epilepsyres

REVIEW

Juvenile myoclonic epilepsy: A system disorder of the brain Peter Wolf a,b,∗, Elza Márcia Targas Yacubian c, Giuliano Avanzini d, Thomas Sander f, Bettina Schmitz g, Britta Wandschneider e, Matthias Koepp e a

Danish Epilepsy Centre Filadelfia, Dianalund, Denmark Department of Clinical Medicine, Neurological Service, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil c Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil d Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy e UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK f Center for Genomics, University of Cologne, Germany g Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany b

Received 17 March 2015; accepted 14 April 2015 Available online 27 April 2015

KEYWORDS Juvenile myoclonic epilepsy; Generalized epilepsies; System epilepsies; Cognitive systems; Functional anatomy

Summary The prevailing understanding of generalized epilepsy is shaped by the traditional definition that ‘‘the responsible neuronal discharge takes place, if not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides’’. This view is no longer tenable since concurrent findings using multiple methods have accumulated to reveal the role of bilateral networks of distributed and selective cortical and subcortical structures in so-called generalized ictogenesis. Most of this research has been focused on juvenile myoclonic epilepsy (JME), which today is commonly considered the archetypical syndrome of the idiopathic generalized epilepsies. Based upon recent research in the fields of clinical epileptology, neuropsychology and psychiatry, clinical neurophysiology, neuroimaging and epilepsy genetics this article, for the first time, unites these new findings into a comprehensive nosological view. Genetically determined dysfunctions of important cognitive systems like visuomotor coordination and linguistic communication appear now as key mechanisms of seizure generation in JME. This review suggests a new paradigm to consider JME as a system disorder of the brain analogous to other neurological system disorders. © 2015 Elsevier B.V. All rights reserved.

∗

Corresponding author at: Danish Epilepsy Centre, Kolonivej 2, DK — 4293 Dianalund, Denmark. Tel.: +45 35559640. E-mail addresses: pwl@filadelfia.dk (P. Wolf), [email protected] (E.M.T. Yacubian), [email protected] (G. Avanzini), [email protected] (T. Sander), [email protected] (B. Schmitz), [email protected] (B. Wandschneider), [email protected] (M. Koepp). http://dx.doi.org/10.1016/j.eplepsyres.2015.04.008 0920-1211/© 2015 Elsevier B.V. All rights reserved.

Juvenile myoclonic epilepsy as a system epilepsy

3

Contents Introduction ................................................................................................................ The clinical syndrome ...................................................................................................... Endophenotypes: reflex epileptic traits..................................................................................... Photosensitivity........................................................................................................ Eye closure sensitivity ................................................................................................. Orofacial reflex myocloni .............................................................................................. Praxis induction........................................................................................................ Neuropsychology ........................................................................................................... Working memory in JME ............................................................................................... Executive functions in JME............................................................................................. Psychiatric aspects ......................................................................................................... Personality disorder ................................................................................................... Psychiatry co-morbidity and pharmacoresistance ...................................................................... Clinical neurophysiology .................................................................................................... Sleep in JME ........................................................................................................... Cortical hyperexcitability.............................................................................................. Neuroimaging............................................................................................................... Structural imaging in JME.............................................................................................. Positron emission tomography ......................................................................................... EEG-fMRI .............................................................................................................. Network changes and the role of the thalamus ........................................................................ Family findings and genetics ................................................................................................ Familial aggregation ................................................................................................... Genetic predisposition................................................................................................. Genomic variation ..................................................................................................... Conclusions and summary .................................................................................................. Ethical approval ............................................................................................................ Conflict of interest ......................................................................................................... Acknowledgements ......................................................................................................... References .................................................................................................................

Introduction The first patient with what we now call juvenile myoclonic epilepsy (JME) was described in 1867 by Herpin (1867), and the first comprehensive description of the syndrome was given 90 years later by Janz and Christian (1957) who proposed the term ‘‘impulsive petit mal’’. It took some time to gain international recognition but in 1985 it was included in the first proposal for an international classification of epilepsies and epileptic syndromes (Commission for Classification and Terminology of the ILAE, 1985). Still grossly underdiagnosed at that time in many parts of the world it attracted increasing attention over the following 30 years and is now widely recognized as the archetypical syndrome of the idiopathic generalized epilepsies (IGEs). Consequently, the syndrome became the object of research in many diverse fields, which enabled us to better understand its clinical characteristics and pathophysiological features. Here, our aim is to amalgamate this multimodal information into a comprehensive nosological view.

The clinical syndrome The first official definition of JME is included in the ILAE classification of epilepsies and epilepsy syndromes (Commission for Classification and Terminology of the ILAE, 1985): this syndrome appears around puberty and is characterized by

3 3 4 4 4 5 5 5 5 5 6 6 6 6 6 7 8 8 8 8 8 8 8 9 9 9 9 9 9 9

seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Some patients may suddenly fall from a jerk. No disturbance of consciousness is noticeable. The disorder may be inherited, and sex distribution is equal. Often, there are generalized tonic—clonic seizures (GTCS) and, less often, infrequent absences. The seizures usually occur shortly after awakening, and are often precipitated by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular spike-waves and polyspike-waves; there is no close phase correlation between EEG spikes and jerks. Frequently, the patients are photosensitive. Response to appropriate drugs is good. Accordingly, JME includes three seizure types: myoclonic jerks, GTCS and absences. In most patients the epilepsy begins around puberty with myoclonic jerks preceding the first GTCS for a mean period from 1.3 to 3.3 years (Janz, 1989). In approximately 25% GTCS are observed before the myoclonic jerks and in around one third of the cases the major and minor seizures have simultaneous onset (Janz and Christian, 1957). A special type of myocloni, orofacial reflex myocloni (ORM) in response to talking and reading, were described in JME more recently (Mayer et al., 2006). Myoclonic jerks in full consciousness, which are essential for the diagnosis, predominate in the upper limbs. They are spontaneous, brief, sudden, isolated, or occur in brief arrhythmic clusters with characteristic chronodependence, generally defined as ‘‘epilepsy on awakening’’ (Janz, 1985).

4 More common after morning awakening, especially after lack of sleep or premature awakening, they may also occur in relaxation periods later in the day. Grossly symmetrical, they may make the patient drop or throw objects, usually those of morning hygiene or breakfast. As praxisinduced reflex seizures they may predominate in the arm that executes the movement, in general involving the dominant hand. Myoclonic jerks may remain the only seizure type as observed from 8% to 17% of the cases (Janz, 1985); however, this number is probably underestimated since most of these patients might never seek medical advice. The first GTCS, which causes medical referral in most patients, is usually triggered by an accumulation of precipitating factors. GTCS are present in 80—95% of patients and may follow a prolonged cluster of myoclonic jerks, with increasing amplitude and frequency, in a sequence that culminates in the tonic phase of an intense and particularly long GTCS. This was called ‘‘impulsive grand mal’’ (Janz and Christian, 1957) or clonic—tonic—clonic seizure (Delgado-Escueta and EnrileBacsal, 1984). Absences have been described in 31.9% of JME patients (in 12.8% beginning in the first decade of life and in 19.1% with juvenile onset). In general, they are infrequent and short, and may be ignored by the patients due to incomplete, if any, impairment of consciousness (Panayiotopoulos et al., 1989). Rarely, between 4.6% and 15% of cases, childhood absence epilepsy evolves into JME (Janz, 1985; Wirrell et al., 1996). A good therapeutic response is part of the definition but could not always be confirmed. (Guaranha et al., 2011) On the other hand, there is a common belief (e.g. Wikipedia article Juvenile Myoclonic Epilepsy December 25, 2014) that JME requires lifelong treatment because of an extremely high rate of relapse at attempts to terminate medication (Delgado-Escueta and Enrile-Bacsal, 1984). However, this concept has not been supported by a series of recent investigations looking at long-term prognosis (Baykan et al., 2008; Camfield and Camfield, 2009; Geithner et al., 2012; Senf et al., 2013; Höfler et al., 2014; Syvertsen et al., 2014). JME is now often believed to be a heterogeneous condition with a need to define endophenotypes that could better predict therapeutic response. Some diagnostic criteria for JME (e.g. strict chronodependence, focal EEG features, abnormal MRI results) have been discussed, and two international meetings (Avignon 2011, and The Hague 2012) concluded that the symptom obligatory for a diagnosis of JME is the occurrence of myoclonic jerks without loss of consciousness, predominantly occurring after awakening. Two diagnostic groups could then be established, one narrower and one wider. Class I criteria encompass (1) myoclonic jerks without loss of consciousness exclusively occurring on or up to 2 h after awakening; (2) EEG with normal background and typical ictal generalized high amplitude polyspike and slow waves accompanying myoclonic jerks; (3) normal intelligence; and (4) age of onset between 10 and 25 years. The Class II set of criteria included (1) myoclonic jerks predominantly occurring after awakening; (2) myoclonic jerks facilitated by sleep deprivation and stress and provoked by visual stimuli or praxis or GTCSs preceded by myoclonic jerks; (3) normal background on EEG and at least one occurrence of interictal generalized spike or polyspike and waves, with some asymmetry

P. Wolf et al. allowed, with or without recording of myoclonic jerks; (4) no mental retardation or deterioration; and (5) age at onset of 6—25 years (Kasteleijn-Nolst Trenité et al., 2013). These definitions still do not provide unequivocal endophenotypes; the only ones presently available are associated with reflex epileptic traits.

Endophenotypes: reflex epileptic traits Four reflex epileptic traits are common in JME.

Photosensitivity Photosensitivity is the most frequent type of reflex epilepsy and is genetically determined. Its close relation to JME was established by Wolf and Goosses (1986). Photosensitivity is defined by the ‘‘photoparoxysmal response’’ (PPR), which is the provocation of spike-and-wave (SW) discharge by intermittent light stimulation (ILS). These typically have an occipital onset and preponderance. Depending on age and treatment, ILS with common parameters produces a PPR in up to 50% of JME patients but 90% of patients were reported photosensitive with more intense and prolonged stimulation (Appleton et al., 2000). This suggests that photosensitivity expresses a basic mechanism of JME, the clarification of which would be highly important. Moeller et al. have shown, using EEG-triggered fMRI, that the PPR is a transcortical phenomenon involving parts of the frontal, parietal and occipital cortex but not the thalamus, which is central to the generation of spontaneous SW discharges (Moeller et al., 2009). These typically have a frontal onset and preponderance (Sperling and Clancy, 2008). Using magnetencephalography (MEG), Parra et al. (2003) investigated synchronization of oscillations in the ␥ band (30—120 hz), which normally are involved in the processing of sensory stimuli. They showed that enhanced synchrony occurs in response to ILS if it is followed by a PPR but not in control subjects or in the same patients if no PPR is provoked. This hypersynchrony was most pronounced in the frontal and central areas if the patients had myoclonic seizures and in the parietal region if they had absences. Varotto et al. (2012) found enhanced frontocentral EEG connectivity in the ␤ and ␥ band in photosensitive patients with IGE. Visual cortex hyperexcitability appears to be another component, as was demonstrated by Brigo et al. (2013) who investigated the phosphene threshold to transcranial magnetic stimulation (TMS). In summary, the PPR appears to express upregulation of the occipito-frontal pathways and their further connections in response to the processing of visual stimuli. This mechanism could underlie other reflex epileptic traits of JME.

Eye closure sensitivity Eye closure sensitivity defined as appearance of spike and wave discharge (SW) within 2 s after eye closure, is an often overlooked reflex epileptic trait which is pathognomonic for Jeavons syndrome (Covanis, 2010). The clinical presentation is eyelid myocloni which may be accompanied by absence seizures. In JME it occurs in 15—20% of cases (Beniczky et al.,

Juvenile myoclonic epilepsy as a system epilepsy 2012; Guaranha et al., 2011). It overlaps with photosensitivity where eye closure during ILS enhances the provocative effect but is not identical with it (Fabian and Wolf, 1987). Vaudano et al. (2014) studied eye closure sensitivity with fMRI in Jeavons syndrome and believe that the epileptic response is generated in the occipital cortex. However, their findings are interictal and may be explained by all patients being photosensitive. Also eye closure sensitivity occurs only with slow (voluntary or involuntary) eye closure and not with automatic or reflex blinking, which points to the supplementary motor area (SMA) as the region of origin interacting with the visual system (da Conceic ¸ão et al., 2015).

Orofacial reflex myocloni Orofacial reflex myocloni are small, lightning-like myocloni in the perioral muscles, tongue, throat and jaw which are precipitated by language-related activities, particularly by reading and talking. They are the hallmark of primary reading epilepsy (Wolf, 1992), but occur in 25—30% of patients with JME (Guaranha et al., 2011; Mayer et al., 2006). Ictogenesis occurs in the widespread bihemispheric cognitive system underlying linguistic communication, including transformation of written into spoken language. Difficult and emotional linguistic performances increase provocation. The response occurs with some delay indicating that a certain amount of hyperexcitation of the network must be reached for the myoclonic response to occur. This reflex epileptic trait was investigated with EEG-fMRI by Salek-Haddadi et al. (2009) who concluded that it requires a critical mass of neurons within cortico-reticular and cortico-cortical circuitry subserving normal functions to be activated by the stimulation.

Praxis induction Praxis induction was reviewed in detail by Yacubian and Wolf (2014). It is defined by myoclonic seizures precipitated by complex, cognition-guided motor tasks. The close relation of this reflex epileptic trait to JME was established by Matsuoka et al. who found it in 47% of their JME patients (Matsuoka et al., 2000). In non-Japanese patients PI was present in 24—29% (Guaranha et al., 2009; Mayer et al., 2006). Although they did not focus on PI, the working memory fMRI study of Vollmar et al. provides an excellent explanation of this reflex epileptic trait (Vollmar et al., 2011). They used a demanding frontal lobe test of visuomotor coordination and working memory where patients performed as well as controls but presented increased functional connectivity between the motor system and frontoparietal cognitive networks as well as impaired deactivation of the default mode network. Together, these findings provide an explanation as to how cognitive effort can cause myoclonic jerks in JME. In summary, the reflex epileptic traits of JME reveal interactions of cerebral functional anatomic networks or subsystems strongly supporting the concept of JME as a system disorder of the brain (Avanzini et al., 2012).

5

Neuropsychology Behavioural peculiarities of many patients with JME were already described in detail by Janz and Christian (1957) as unsteadiness, lack of discipline, hedonism and indifference towards their disease. According to these authors, their mood changes rapidly and frequently. They are easy to encourage and to discourage, gullible and unreliable, promise more than they can deliver. Their behaviour often has effects on their therapy as they will declare that they adhere to all prescriptions, but in fact forget to attend control visits and to take their medication regularly. Recent neuropsychological research has provided better insight in these old observations. Though JME patients have average intellectual abilities (Hommet et al., 2006), even longterm seizure-free patients present ‘real-world problems’ (Thomas et al., 2014), leading to poorer socioeconomic outcomes, such as higher unemployment rates (Camfield and Camfield, 2009). There is increasing evidence that an impairment of thalamofrontocortical network function leads to impairment of higher frontal lobe functions, such as working memory (WM), planning and risk-taking behaviour (Wandschneider et al., 2013; Zamarian et al., 2013). Other cognitive functions, e.g. hippocampal-related episodic memory, are relatively preserved, although there have been reports on more widespread cognitive impairment (Lin et al., 2013).

Working memory in JME The first study of WM performance in JME (Swartz et al., 1994) investigated visual WM in patients with frontal lobe epilepsy (FLE) and used JME patients as a patient control group. Surprisingly, JME patients had similarly impaired WM function as FLE patients when compared to healthy controls. A subsequent 18 FDG-PET study employing the same cognitive task showed widespread decreased 18 FDG-uptake in the ventral premotor cortex, caudate and dorsolateral prefrontal cortex at resting state (Swartz et al., 1996). This was consistent with the poor performance on the WM task. More recent fMRI WM studies reported varying results: Roebling et al. (2009) employed the Sternberg Item Recognition Test, a visual-spatial WM task, and found no differences in performance and activation patterns between JME patients (n = 19) and controls. Vollmar et al. (2011) investigated a larger (n = 30) JME patient population with a more challenging visual spatial n-back WM task. Though performance again did not differ between groups, patients displayed abnormal motor cortex co-activation with fronto-parietal WM networks during increasing cognitive demand. Subsequent combined functional and structural connectivity analyses showed decreased connectivity between prefrontal and fronto-polar regions, possibly accounting for dysfunction of cognitive frontal lobe functions, and increased connectivity between the motor and prefrontal cortex. These observations may help to explain cognitively triggered myoclonic jerks in JME (Vollmar et al., 2012).

Executive functions in JME Studies on executive functions, such as planning, response inhibition, cognitive flexibility and verbal fluency describe

6 varying degrees of impairment. Amongst these, verbal fluency is most consistently affected (Devinsky et al., 1997; O’Muircheartaigh et al., 2011; Pascalicchio et al., 2007; Piazzini et al., 2008; Sonmez et al., 2004; Thomas et al., 2014; Wandschneider et al., 2012a). Two recent studies report poor experience-related learning leading to impulsive decision-making (Wandschneider et al., 2013; Zamarian et al., 2013). In one of these studies, impulsivity was associated with abnormal fMRI WM network activations (Wandschneider et al., 2013). Cognitive impairment may correlate with more active disease (Pascalicchio et al., 2007; Thomas et al., 2014; Vollmar et al., 2011; Wandschneider et al., 2013; Zamarian et al., 2013) and response to valproate may be beneficial for cognitive network restoration (Vollmar et al., 2011). However, there is growing evidence that cognitive dysfunction is part of the JME phenotype and that JME may represent a genetically determined neurodevelopmental disorder: Similar frontal lobe impairment patterns (Iqbal et al., 2009; Levav et al., 2002; Wandschneider et al., 2012a) and abnormal fMRI WM network activation (Wandschneider et al., 2014) have been reported in siblings of JME patients who do not suffer from epilepsy. A recent longitudinal study in new-onset JME reports poorer cognitive performance in patients compared to their healthy peers and altered brain development trajectories in JME, particularly affecting higher-association fronto-parietal-temporal regions (Lin et al., 2014).

Psychiatric aspects The psychosocial prognosis of JME may be poorer than expected. Maladaptive behaviours include alcohol and substance abuse, divorces, abortions, unemployment, and even criminal records (Camfield and Camfield, 2009; Syvertsen et al., 2014). Besides executive dysfunction, psychiatric comorbidity may contribute to poorer social outcome. The prevalence of clinically relevant psychiatric disorders in various series of consecutive JME patients ranges between 22 and 36% (Gélisse et al., 2001; Jayalakshmi et al., 2014; Perini et al., 1996; Syvertsen et al., 2014; Trinka et al., 2006). It is unclear as yet whether psychiatric disorders are the cause or consequence of social problems.

Personality disorder Most common are personality (Cluster B) and anxiety disorders (de Araujo Filho and Yacubian, 2013; Gélisse et al., 2001; Perini et al., 1996). Another frequent problem is substance abuse (Camfield and Camfield, 2009; Syvertsen et al., 2014). Walsh et al. (2014) demonstrated a link between neuropsychological findings and psychiatric comorbidity. Patients with personality disorders exhibited the greatest level of executive impairment, confirming that maladaptive behaviour is related to executive dysfunction. Cluster B personality disorders (PD), characterized as emotional instability, immaturity, lack of discipline, and rapid mood changes, were associated with prefrontal cortical abnormalities in a MRI study (de Araujo Filho et al., 2013). The relationship between neuropsychological findings and social adjustment was evaluated in 42 JME patients and

P. Wolf et al. controls (Moschetta and Valente, 2013). They found significantly poorer social adjustment in JME patients, especially in the domains of work and family relationships. This was significantly associated with impulsive traits and higher novelty seeking scores.

Psychiatry co-morbidity and pharmacoresistance Psychiatric comorbidity has been associated with poorer quality of life and poor seizure control in several studies (de Araujo Filho et al., 2013; Gélisse et al., 2001; Guaranha et al., 2011; Trinka et al., 2006). Jayalakshmi et al. (2014) divided 201 JME patients into a group of VPA responders and nonresponders (19%). Psychiatric comorbidity was the strongest predictor for pharmacoresistance and increased the risk for VPA-non-responsiveness by a factor of 5.54. Premature death has also been associated with psychiatric comorbidity (Genton and Gélisse, 2001). Psychopathology seems to be closely related to poor adherence. While the latter may sometimes appear as a rather typical juvenile weakness it may be associated with risky and unhealthy behaviours (such as substance abuse) leading to negative and, sometimes, irreversible social consequences. Further, poor social outcome may be linked to circadian dysrhythmia typical for JME (Pung and Schmitz, 2006) and can be so severe and socially disruptive that patients become isolated from people who follow a regular, externally structured sleep-wake scheme. It thus appears that there is a continuum from no or mild cognitive deficits in the majority of JME patients up to severe dysexecutive impairment and maladjustive behaviour in a small subgroup of pharmacoresistent patients.

Clinical neurophysiology The main neurophysiological finding of JME is the EEG feature of short discharges of generalized spike-wave (SW) or polyspike-wave (PSW) complexes associated with epileptic myoclonus. Myoclonic jerks occur in brief irregular bursts (Fig. 1). Ictal and interictal epileptic paroxysms, as well as myoclonic jerks, are usually bilaterally synchronous but not necessarily symmetrical (Oguni et al., 1994). Scalp EEG often also shows focal EEG abnormalities, and clear frontocentral predominance of ictal EEG activity recorded with the myoclonic jerks has been repeatedly reported (Aliberti et al., 1994). After the initial recognition of JME, a number of studies investigated its pathophysiology and electrographic features.

Sleep in JME Because of the susceptibility of JME patients to sleep deprivation and because myoclonic jerks typically occur after awakening, various studies have looked at sleep architecture in JME. Abnormalities have been observed despite adequate seizure control, including reduced sleep efficiency, increased sleep latency and total NREM sleep (Krishnan et al., 2014). Moreover, studies of sleep phasic patterns have found an explicit relationship between EEG epileptiform abnormalities and cyclic alternating patterns (CAPs)

Juvenile myoclonic epilepsy as a system epilepsy

7

Figure 1 Typical EEG features in a patient with JME. A brief discharge of PSW occurs when the patient is awake (A), as well in association with a K complex in non-REM sleep (B). A strong activation of paroxysmal discharges, often associated with myoclonic jerks, occurs at awakening (C).

phase A, which corresponds to transient activation of arousal (Avanzini et al., 2000; Gigli et al., 1992). These observations suggest that phasic sleep phenomena that relate to arousal stimuli (K complexes, vertex waves, or abrupt shifts to alpha rhythm) may significantly facilitate the appearance of epileptic discharge (Fig. 1B).

Cortical hyperexcitability With respect to other forms of idiopathic generalized epilepsies, JME presents with predominant myoclonic jerks. This observation led investigators to hypothesize a prominent hyperexcitability of motor cortex, which has been addressed by various studies. Transcranial magnetic stimulation paradigms clearly demonstrated increased excitability in the motor cortex in patients with JME, which is accentuated after sleep deprivation and more pronounced in the morning than in the afternoon (Badawy et al., 2009; Manganotti et al., 2006). The decisive role of motor cortex hyperexcitability in the generation of myoclonic jerks is further supported by a study performed by using jerk-locked back averaging of EEG. This

study revealed a positive-negative EEG transient with maximal amplitude in the frontal leads, which preceded the myoclonic jerk by about 10 ms, with an interhemispheric delay of 9.5 ms between the jerk-locked positive peaks detected in the frontal EEG leads. A comparable time lag between the onset of myoclonic jerks in the two deltoid muscles suggested a unilateral cortical generation of myoclonic jerks in JME, followed by a bilateral synchronization (Panzica et al., 2001). Further clarifications on the cortical networks involved in JME have recently been provided by an analysis of EEG functional connectivity, which demonstrated a hypercoupled state among the cingulate, superior and medial frontal gyri and paracentral lobule during the interictal and preictal phases (Clemens et al., 2013). A key role for SW generation has been attributed to precuneus (Lee et al., 2014). This conclusion does not rule out the role of subcortical (namely thalamic) structures in pacing the bilateral SW/PSW discharges, as recently confirmed by MEG studies (Hamandi et al., 2011; Stefan et al., 2009). Neurophysiological evaluation has detected a prominent hyperexcitability of motor circuitry. However, premotor frontal regions appear also to be significantly involved, since EEG generalized SW and PSW typically show a

8 frontocentral maximum (review by Serafini et al., 2013) and the neuropsychological and neuroimaging investigations discussed above indicated abnormalities involving frontal lobes (Wandschneider et al., 2012a,b). Neurophysiological findings with photosensitive JME patients are discussed in the section Endophenotypes (Brigo et al., 2013; Parra et al., 2003; Varotto et al., 2012).

Neuroimaging Dieter Janz first emphasized in his monograph age-relation as an important taxonomic principle (Janz, 1969). During adolescence, dramatic changes occur in brain development with grey matter reduction of both cortical and subcortical structures following a general increase in cortical development during childhood (Wierenga et al., 2014). In JME, defective pruning may cause excessive hyperexcitable synapses, aberrant circuitry, and migration disturbances due to delayed apoptosis of excitatory neurons, reported as ‘‘microdysgenesis’’ (Meencke and Janz, 1984). These developmental changes are under genetic influence, and may lead to excessive neuronal density and, subsequently, aberrant hyperexcitable circuits (Tamnes et al., 2010).

Structural imaging in JME Quantitative and voxel-based MR studies showed increased grey matter with the maximum mesio-frontal in the SMA (Woermann et al., 1999). Imaging studies of the microarchitecture in JME reveal reduced structural and altered functional connectivity of the anterior SMA, motor cortex and frontoparietal cognitive networks (Vollmar et al., 2011). Such increased functional coupling between the motor system and cognitive networks provide an explanatory framework for how cognitive effort or praxis can cause myoclonic jerks and for several clinical observations like ‘‘frontal’’ cognitive and behavioural profiles in JME (O’Muircheartaigh et al., 2012; Vollmar et al., 2012).

Positron emission tomography In line with changes in cortical thickness, positron emission tomography (PET) studies were the first imaging modality to demonstrate evidence for increased neuronal density and GABA-ergic receptor binding (Koepp et al., 1997). These changes are most pronounced in the dorsolateral prefrontal cortex but there is also brainstem and basal ganglia involvement in addition to the commonly implicated thalamo-cortical systems (Koepp and Duncan, 2000).

EEG-fMRI Simultaneous EEG-fMRI, primarily used to study generalized spike-wave activity, has identified thalamic activations occurring several seconds before EEG spike wave activity (Bai et al., 2010; Moeller et al., 2010), followed by widespread ‘‘deactivations’’ of association cortex affecting frontal, parietal and cingulate areas, the so called ‘default mode’ network (Aghakhani et al., 2004; Archer et al., 2003;

P. Wolf et al. Gotman et al., 2005; Hamandi et al., 2006; Laufs et al., 2007).

Network changes and the role of the thalamus New-onset patients with JME have shown delayed cortical maturation with higher cortical volume in parts of the fronto-thalamocortical networks implicated in crosssectional imaging investigations of adults with chronic JME, including mesial frontal, supplementary motor and posterior cingulate cortex (Lin et al., 2014). A clinically significant disruption of the thalamo-frontocortical circuitry early in the course of the condition could lead to both seizures and neuro-cognitive deficits. The degree of connectivity between SMA and thalamus has been correlated with scores in word naming tasks and expression scores. Posterior cingulate cortex volume changes and thalamic connectivity predict cognitive inhibition scores on the mental flexibility task (O’Muircheartaigh et al., 2011). Similar changes, together with thalamic volume loss and reduced NAA/Cr signal ratio on MRSpectroscopy (MRS), have been observed within 12 months of seizure onset. This is unlikely the result of chronic seizures (Pulsipher et al., 2009). Thalamic changes in medial frontal lobes and thalamus appear to be progressive (Lin et al., 2009). Progressive thalamic volume loss has been correlated not only with age and disease duration but also with personality traits (Betting et al., 2006; Kim et al., 2007; Tae et al., 2007). This suggests that individuals with the greatest degree of neuronal dysfunction have more severe epilepsy and more significant personality disorders (de Araujo Filho et al., 2009).

Family findings and genetics Twin and family studies suggest that JME is a heritable IGE syndrome (Peljto et al., 2014; Vadlamudi et al., 2014; Zifkin et al., 2005). About 5% of first-degree relatives of JME patients are affected by epilepsy. Almost all of them exhibit some common IGE syndrome with an increased prevalence of JME (≈45% with JME, ≈30% with CAE/JAE and ≈30% idiopathic epilepsies with GTCS alone) (Schmitz et al., 2000; Winawer et al., 2005) suggesting that shared but also specific genetic risk configurations contribute to the overlapping phenotypic expression of this spectrum of syndromes (Janz et al., 1992).

Familial aggregation The individual manifestation of both absence and myoclonic seizures in about 30% of patients with JME and the familial aggregation of various IGE syndromes support the current view that JME and related IGE syndromes, specifically CAE, JAE and EGTCS on awakening, constitute a family of system disorders characterized by an abnormally bilateral synchronous hyperexcitability of thalamo-cortical and various transcortical networks (Avanzini et al., 2012; Blumenfeld, 2005; Schmitz et al., 2000; Wolf, 2015). This system model postulates that the variable phenotypic expression of different generalized seizure types and associated reflex traits

Juvenile myoclonic epilepsy as a system epilepsy is generated by an age-related spatial expression of synchronized oscillations in selective thalamo-cortical and transcortical circuits, which vary in their constitutional cortical connectivity. (Blumenfeld, 2005; Wandschneider et al., 2012a,b, 2014). It has not yet been possible to relate these variations to specific genetic alterations.

Genetic predisposition Despite heritability estimates of up to 70% (Vadlamudi et al., 2014) the majority of genetic factors predisposing to the JME-related system epilepsies are still unknown due to their complex genetic predisposition and extensive genetic heterogeneity (Dibbens et al., 2007). The genetic architecture is likely to display a neurogenetic spectrum, in which a small fraction (1—2%) is mainly determined by single gene defects, whereas the vast majority of patients presumably display an oligo-/polygenic predisposition (Ottman, 2005). Several Mendelian JME-associated genes have been identified by positional candidate gene analyses, specifically CACNB4, CASR, GABRA1, GABRD and EFHC1 (Delgado-Escueta et al., 2013). In addition, allelic associations of JME with single nucleotide polymorphisms in three genes (BRD2, CX36, and ME2) have been reported to confer susceptibility of JME (for review see Delgado-Escueta et al., 2013).

Genomic variation Recently, pathogenic structural genomic variations have been identified in up to 5% of patients with JME-related system epilepsies (Scheffer et al., 2014). In particular, recurrent microdeletions at genomic rearrangement hotspot regions (15q11.2/CYFIP1, 15q13.3/CHRNA7, 16p13.11/NDE1, 16p11.2/PRRT2, and 22q11/SNAP29) (de Kovel et al., 2010; Mefford et al., 2010) and microdeletions affecting genes (e.g. GEPHN, NRXN1, RBFOX1) (Dejanovic et al., 2014; Lal et al., 2013; Møller et al., 2013) previously implicated in a wide range of neurodevelopmental disorders, have been noted to be significantly enriched in patients with JME-related system epilepsies compared to population controls (Lal et al., 2015). The most prominent microdeletion at 15q13.3 exhibits a 50-fold increased risk for IGE compared to population controls (de Kovel et al., 2010; Helbig et al., 2009). Interestingly, the same recurrent microdeletions increase the risk of a broad spectrum of neuropsychiatric disorders (Watson et al., 2012). These findings suggest a shared genetic predisposition of JME-related system epilepsies with apparently unrelated neuropsychiatric disorders and highlight the strong impact of fundamental neurodevelopmental processes.

Conclusions and summary The prevailing understanding of generalized epileptic seizures is shaped by the traditional definition that ‘‘the responsible neuronal discharge takes place, if not throughout the entire grey matter, then at least in the greater part of it and simultaneously on both sides’’ (Commission for Classification and Terminology of the International League Against Epilepsy, 1970). Accumulating concurrent findings

9 with multiple methods, however, have revealed the role of bilateral networks of distributed and selective cortical and subcortical structures in so-called generalized ictogenesis. The inappropriateness of the term ‘‘generalized’’ for epileptic seizures and syndromes has therefore increasingly been recognized (McNally and Blumenfeld, 2004; Wolf, 1994, 2006, 2010). The ictogenic networks are not individual but disease-specific. In JME they appear to be largely identical with functional-anatomical subsystems of the brain supporting central cognitive functions like visuomotor coordination and linguistic communication (Vollmar et al., 2012). Abuse of these physiological subsystems based on genetically determined hyperexcitability and hyperconnectivity seems to be a basic ictogenic mechanism of JME. It is therefore worthwhile to consider JME as one of the prototypes of the new concept of system epilepsies (Avanzini et al., 2012). This, in turn, may lead to an improved nosological understanding. Deficits in the related cognitive performance of both JME patients and siblings unaffected by seizures (Wandschneider et al., 2012a) suggest that JME is a neurological system disorder in a broad sense.

Ethical approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflict of interest None of the authors has any conflict of interest relevant to this research activity to disclose.

Acknowledgements This work is dedicated to Prof. Dieter Janz who in 1957 first described Juvenile Myoclonic Epilepsy, on the occasion of his 95th anniversary. Drs. S. Franceschetti and F. Panzica, Milan, are thanked for their contributions to the section on clinical neurophysiology.

References Aghakhani, Y., Bagshaw, A.P., Benar, C.G., et al., 2004. fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. Brain 127, 1127—1144. Aliberti, V., Grunewald, R.A., Panayiotopoulos, C.P., Chroni, E., 1994. Focal electroencephalographic abnormalities in juvenile myoclonic epilepsy. Epilepsia 35, 297—301. Appleton, R., Beirne, M., Acomb, B., 2000. Photosensitivity in juvenile myoclonic epilepsy. Seizure 9, 108—111. Archer, J.S., Abbott, D.F., Waites, A.B., Jackson, G.D., 2003. fMRI ‘‘deactivation’’ of the posterior cingulate during generalized spike and wave. Neuroimage 20, 1915—1922. Avanzini, G., Binelli, S., Franceschetti, S., et al., 2000. Pathophysiology on myoclonus in Janz Syndrome. In: Schmitz, B., Sander, T. (Eds.), Juvenile Myoclonic Epilepsy: The Janz Syndrome. Wrightson Biomedical Publishing Ltd, pp. 57—71. Avanzini, G., Manganotti, P., Meletti, S., et al., 2012. The system epilepsies: a pathophysiological hypothesis. Epilepsia 53, 771—778.

10 Badawy, R.A., Macdonell, R.A., Jackson, G.D., Berkovic, S.F., 2009. Why do seizures in generalized epilepsy often occur in the morning. Neurology 73, 218—222. Bai, X., Vestal, M., Berman, R., et al., 2010. Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging. J. Neurosci. 30, 5884. Baykan, B., Altindag, E.A., Bebek, N., et al., 2008. Myoclonic seizures subside in the fourth decade in juvenile myoclonic epilepsy. Neurology 70, 2123—2129. Beniczky, S., Guaranha, M.S.B., Conradsen, I., et al., 2012. Modulation of epileptiform discharges in juvenile myoclonic epilepsy: an investigation of reflex epileptic traits. Epilepsia 53, 832—839. Betting, L.E., Mory, S.B., Li, L.M., et al., 2006. Voxel-based morphometry in patients with idiopathic generalized epilepsies. Neuroimage 32, 498—550. Blumenfeld, H., 2005. Cellular and network mechanisms of spikewave seizures. Epilepsia 46 (Suppl. 9), 21—33. Brigo, F., Bongiovanni, L.G., Nardone, R., et al., 2013. Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study. Epilepsy Behav. 27, 301—306. Camfield, C.S., Camfield, P.R., 2009. JME 25 years after seizure onset. A population-based study. Neurology 73, 1041—1046. Clemens, B., Puskás, S., Besenyei, M., et al., 2013. Neurophysiology of juvenile myoclonic epilepsy: EEG-based network and graph analysis of the interictal and immediate preictal states. Epilepsy Res. 106, 357—369. Commission for Classification and Terminology of the International League Against Epilepsy, 1970. Clinical and electroencephalographical classification of epileptic seizures. Epilepsia 11, 102—113. Commission for Classification and Terminology of the International League Against Epilepsy, 1985. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 26, 268—278. Covanis, A., 2010. Jeavons syndrome. In: Panayiotopoulos, C.P. (Ed.), Atlas of Epilepsies. Springer, London, pp. 1080— 1091. da Conceic ¸ão, P.O., Guaranha, M.S.B., Uchida, C.G.P., et al., 2015. Blinking and eyelid myoclonia: characteristics and correlation of eylid movements. Seizure 24, 12—16. de Araujo Filho, G.M., Lin, K., Lin, J., et al., 2009. Are personality traits of juvenile myoclonic epilepsy related to frontal lobe dysfunctions? A proton MRS study. Epilepsia 50, 1201—1209. de Araujo Filho, G.M., de Araujo, T.B., Sato, J.R., et al., 2013. Personality traits in juvenile myoclonic epilepsy: evidence of cortical abnormalities from a surface morphometry study. Epilepsy Behav. 27, 385—392. de Araujo Filho, G.M., Yacubian, E.M., 2013. Juvenile myoclonic epilepsy: psychiatric comorbidity and impact on outcome. Epilepsy Behav. 28 (Suppl. 1), S74—S80. de Kovel, C.G., Trucks, H., Helbig, I., et al., 2010. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133, 23—32. Dejanovic, B., Lal, D., Catarino, C.B., et al., 2014. Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. Neurobiol. Dis. 67, 88—96. Delgado-Escueta, A.V., Enrile-Bacsal, F., 1984. Juvenile myoclonic epilepsy of Janz. Neurology 34, 285—294. Delgado-Escueta, A.V., Koeleman, B.P., et al., 2013. The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 28 (July (Suppl. 1)), S52—S57. Devinsky, O., Gershengorn, J., Brown, E., et al., 1997. Frontal functions in juvenile myoclonic epilepsy. Neuropsychiatry Neuropsychol. Behav. Neurol. 10, 243—246. Dibbens, L.M., Heron, S.E., Mulley, J.C., 2007. A polygenic heterogeneity model for common epilepsies with complex genetics. Genes Brain Behav. 6, 593—597.

P. Wolf et al. Fabian, A., Wolf, P., 1987. Epileptic discharge after eye closure: relation to photosensitivity. In: Wolf, P., Dam, M., Janz, D., Dreifuss, F.E. (Eds.), Adv. in Epileptology. XVIth Epilepsy International Symposium. Raven, New York, pp. 259—264. Geithner, J., Schneider, F., Wang, Z., et al., 2012. Predictors for long-term seizure outcome in juvenile myoclonic epilepsy: 25—63 years of follow-up. Epilepsia 53, 1379— 1386. Gélisse, P., Genton, P., Samuelian, J.C., et al., 2001. Psychiatric disorders in juvenile myoclonic epilepsy. Rev. Neurol. 157, 297—302. Genton, P., Gélisse, P., 2001. Premature death in juvenile myoclonic epilepsy. Acta Neurol. Scand. 104, 125—129. Gigli, G.L., Calia, E., Marciani, M.G., et al., 1992. Sleep microstructure and EEG epileptiform activity in patients with juvenile myoclonic epilepsy. Epilepsia 33, 799—804. Gotman, J., Grova, C., Bagshaw, A., et al., 2005. Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. Proc. Natl. Acad. Sci. U.S.A. 102, 15236—15240. Guaranha, M.S.B., Araújo Filho, G.M.de, Lin, K., et al., 2011. Prognosis of juvenile myoclonic epilepsy is related to endophenotypes. Seizure 20, 42—48. Guaranha, M.S.B., Sousa, P.d.S., Araújo Filho, G.M., et al., 2009. Provocative and inhibitory effects of a video-EEG neuropsychologic protocol in juvenile myoclonic epilepsy. Epilepsia 50, 2446—2455. Hamandi, K., Salek-Haddadi, A., Laufs, H., et al., 2006. EEG-fMRI of idiopathic and secondarily generalized epilepsies. Neuroimage 31, 1700—1710. Hamandi, K., Singh, K.D., Muthukumaraswamy, S., 2011. Reduced movement-related ␤ desynchronisation in juvenile myoclonic epilepsy: a MEG study of task specific cortical modulation. Clin. Neurophysiol. 122, 2128—2138. Helbig, I., Mefford, H.C., Sharp, A.J., et al., 2009. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41, 160—162. Herpin, Th., 1867. Des accés incomplets d’épilepsie. Baillière, Paris. Höfler, J., Unterberger, I., Dobesberger, J., et al., 2014. Seizure outcome in 175 patients with juvenile myoclonic epilepsy — a long-term observational study. Epilepsy Res. 108, 1817— 1824. Hommet, C., Sauerwein, H.C., De, T.B., Lassonde, M., 2006. Idiopathic epileptic syndromes and cognition. Neurosci. Biobehav. Rev. 30, 85—96. Iqbal, N., Caswell, H.L., Hare, D.J., et al., 2009. Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: a preliminary controlled experimental video-EEG case series. Epilepsy Behav. 14, 516—521. Janz, D., 1969. Die Epilepsien. Spezielle Pathologie und Therapie. Thieme, Stuttgart. Janz, D., 1985. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol. Scand. 72, 449—459. Janz, D., 1989. Juvenile myoclonic epilepsy. Cleve. Clin. J. Med. 56 (Suppl.), S23—S33. Janz, D., Christian, W., 1957. Impulsiv — Petit mal. J. Neurol. 176, 346—386. Janz, D., Beck-Mannagetta, G., Sander, T., 1992. Do idiopathic generalized epilepsies share a common susceptibility gene. Neurology 42 (Suppl. 5), 48—55. Jayalakshmi, S., Vooturi, S., Bana, A.K., et al., 2014. Factors associated with lack of response to valproic acid monotherapy in juvenile myoclonic epilepsy. Seizure 23, 527—532. Kasteleijn-Nolst Trenité, D.G., Schmitz, B., Janz, D., et al., 2013. Consensus on diagnosis and management of JME: from founder’s observations to current trends. Epilepsy Behav. 28 (July (Suppl. 1)), S87—S90.

Juvenile myoclonic epilepsy as a system epilepsy Kim, J.H., Lee, J.K., Koh, S.B., et al., 2007. Regional grey matter abnormalities in juvenile myoclonic epilepsy: a voxel-based morphometry study. Neuroimage 37, 1132—1137. Koepp, M.J., Duncan, J.S., 2000. Positron emission tomography in idiopathic generalized epilepsy: imaging beyond structure. In: Schmitz, B., Sander, T. (Eds.), Juvenile Myoclonic Epilepsy: The Janz Syndrome. Wrightson, Petersfied, pp. 91—99. Koepp, M.J., Richardson, M.P., Brooks, D.J., et al., 1997. Central benzodiazepine/gamma-aminobutyric acid A receptors in idiopathic generalized epilepsy: an [11C] flumazenil positron emission tomography study. Epilepsia 38, 1089—1097. Krishnan, P., Sinha, S., Taly, A.B., et al., 2014. Altered polysomnographic profile in juvenile myoclonic epilepsy. Epilepsy Res. 108, 459—467. Lal, D., Trucks, H., Møller, R.S., et al., 2013. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 54, 265—271. Lal, D., Trucks, H., de Kovel, C.G., et al., 2015. Genome-wide burden analysis of rare deletions suggests a strong impact of neurodevelopmental genes in the aetiology of genetic generalised epilepsies. PLoS Genet., http://dx.doi.org/10.1371/ journal.pgen.1005226 (in press). Laufs, H., Hamandi, K., Salek-Haddadi, A., et al., 2007. Temporal lobe interictal epileptic discharges affect cerebral activity in ‘‘default mode’’ brain regions. Hum. Brain Mapp. 28, 1023—1032. Lee, C., Kim, S.M., Jung, Y.J., et al., 2014. Causal influence of epileptic network during spike-and-wave discharge in juvenile myoclonic epilepsy. Epilepsy Res. 108, 257—266. Levav, M., Mirsky, A.F., Herault, J., et al., 2002. Familial association of neuropsychological traits in patients with generalized and partial seizure disorders. J. Clin. Exp. Neuropsychol. 24, 311—326. Lin, J.J., Dabbs, K., Riley, J.D., et al., 2014. Neurodevelopment in new-onset juvenile myoclonic epilepsy over the first 2 years. Ann. Neurol. 76, 660—668. Lin, K., Carrete Jr., H., Lin, J., et al., 2009. Magnetic resonance spectroscopy reveals an epileptic network in juvenile myoclonic epilepsy. Epilepsia 50, 1191—1200. Lin, K., de Araujo Filho, G.M., Pascalicchio, T.F., et al., 2013. Hippocampal atrophy and memory dysfunction in patients with juvenile myoclonic epilepsy. Epilepsy Behav. 29, 245—247. Manganotti, P., Bongiovanni, L.G., Fuggetta, G., et al., 2006. Effects of sleep deprivation on cortical excitability in patients affected by juvenile myoclonic epilepsy: a combined transcranial magnetic stimulation and EEG study. J. Neurol. Neurosurg. Psychiatry 77, 56—60. Matsuoka, H., Takahashi, T., Sasaki, M., Matsumoto, K., Yoshida, S., Numachi, Y., Saito, H., Ueno, T., Sato, M., 2000. Neuropsychological EEG activation in patients with epilepsy. Brain 123, 318—330. Mayer, T.A., Schroeder, F., May, T.W., Wolf, P.T., 2006. Perioral reflex myoclonias: a controlled study in patients with JME and focal epilepsies. Epilepsia 47, 1059—1067. McNally, K.A., Blumenfeld, H., 2004. Focal network involvement in generalized seizures: new insights from electroconvulsive therapy. Epilepsy Behav. 5, 3—12. Meencke, H.J., Janz, D., 1984. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 25, 8—21. Mefford, H.C., Muhle, H., Ostertag, P., et al., 2010. (2010) Genomewide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 6, e1000962. Moeller, F., LeVan, P., Muhle, H., et al., 2010. Absence seizures: individual patterns revealed by EEG-fMRI. Epilepsia 51, 2000—2010.

11 Moeller, F., Siebner, H.R., Ahlgrimm, N., et al., 2009. fMRI activation during spike and wave discharges evoked by photic stimulation. Neuroimage 48, 682—695. Møller, R.S., Weber, Y.G., Klitten, L.L., et al., 2013. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy. Epilepsia 54, 256—264. Moschetta, S., Valente, K.D., 2013. Impulsivity and seizure frequency, but not cognitive deficits, impact social adjustment in patients with juvenile myoclonic epilepsy. Epilepsia 54, 866—870. Oguni, H., Mukahira, K., Oguni, M., et al., 1994. Video-polygraphic analysis of myoclonic seizures in juvenile myoclonic epilepsy. Epilepsia 35, 307—316. O’Muircheartaigh, J., Vollmar, C., Barker, G.J., et al., 2012. Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy. Brain 135, 3635—3644. O’Muircheartaigh, J., Vollmar, C., Barker, G.J., et al., 2011. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 76, 34—40. Ottman, R., 2005. Analysis of genetically complex epilepsies. Epilepsia 46 (Suppl. 10), 7—14. Panayiotopoulos, C.P., Obeid, T., Waheed, G., 1989. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann. Neurol. 25, 391—397. Panzica, F., Rubboli, G., Franceschetti, S., et al., 2001. Cortical myoclonus in Janz syndrome. Clin. Neurophysiol. 112 (October (10)), 1803—1809. Parra, J., Kalitzin, S.N., Iriarte, J., et al., 2003. Gamma-band phase clustering and photosensitivity: is there an underlying mechanism common to photosensitive epilepsy and visual perception. Brain 126, 1164—1172. Pascalicchio, T.F., de Araujo Filho, G.M., da Silva Noffs, M.H., et al., 2007. Neuropsychological profile of patients with juvenile myoclonic epilepsy: a controlled study of 50 patients. Epilepsy Behav. 10, 263—267. Peljto, A.L., Barker-Cummings, C., Vasoli, V.M., et al., 2014. Familial risk of epilepsy: a population-based study. Brain 137, 795—805. Perini, G.I., Tosin, C., Carraro, C., et al., 1996. Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy. J. Neurol. Neurosurg. Psychiatry 6, 601—605. Piazzini, A., Turner, K., Vignoli, A., et al., 2008. Frontal cognitive dysfunction in juvenile myoclonic epilepsy. Epilepsia 49, 657—662. Pulsipher, D.T., Seidenberg, M., Guidotti, L., et al., 2009. Thalamofrontal circuitry and executive dysfunction in recent-onset juvenile myoclonic epilepsy. Epilepsia 50, 1210—1219. Pung, T., Schmitz, B., 2006. Circadian rhythm and personality profile in juvenile myoclonic epilepsy. Epilepsia 47 (Suppl. 2), 111—114. Roebling, R., Scheerer, N., Uttner, I., et al., 2009. Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy. Epilepsia 50, 2456—2465. Salek-Haddadi, A., Mayer, T., Hamandi, K., et al., 2009. Imaging seizure activity: a combined EEG/EMG-fMRI study in reading epilepsy. Epilepsia 50, 256—264. Scheffer, I.E., Mefford, H.C., 2014. Epilepsy beyond the single nucleotide variant in epilepsy genetics. Nat. Rev. Neurol. 10, 490—491. Schmitz, B., Sailer, U., Sander, T., et al., 2000. Clinical genetics of idiopathic generalized epilepsies. In: Schmitz, B., Sander, T. (Eds.), Juvenile Myoclonic Epilepsy: The Janz Syndrome. Wrightson, Petersfield, pp. 129—144. Senf, P., Schmitz, B., Holtkamp, M., Janz, D., 2013. Prognosis of juvenile myoclonic epilepsy 45 years after onset. Neurology 81, 1—6.

12 Serafini, A., Rubboli, G., Gigli, G.L., Koutroumanidis, M., Gelisse, P., 2013. Neurophysiology of juvenile myoclonic epilepsy. Epilepsy Behav. (July (Suppl. 1)), S30—S39. Sonmez, F., Atakli, D., Sari, H., et al., 2004. Cognitive function in juvenile myoclonic epilepsy. Epilepsy Behav. 5, 329—336. Sperling, M.R., Clancy, R.R., 2008. Ictal electroencephalogram. In: Engel, J., Pedley, T.A. (Eds.), Epilepsy. A Comprehensive Textbook, vol. 1, 2nd ed. Wolters Kluwer, Philadelphia, pp. 825—854. Stefan, H., Paulini-Ruf, A., Hopfengärtner, R., et al., 2009. Network characteristics of idiopathic generalized epilepsies in combined MEG/EEG. Epilepsy Res. 85, 187—198. Swartz, B.E., Halgren, E., Simpkins, F., Syndulko, K., 1994. Primary memory in patients with frontal and primary generalized epilepsy. J. Epilepsy 7, 232—241. Swartz, B.E., Simpkins, F., Halgren, E., et al., 1996. Visual working memory in primary generalized epilepsy: an 18 FDG-PET study. Neurology 47, 1203—1212. Syvertsen, M.R., Thuve, S., Stordrange, B.S., Brodtkorb, E., 2014. Clinical heterogeneity of juvenile myoclonic epilepsy: follow-up after an interval of more than 20 yrs. Seizure, 344—348. Tae, W.S., Joo, E.Y., Han, S.J., et al., 2007. CBF changes in drug naive juvenile myoclonic epilepsy patients. J. Neurol. 254, 1073—1080. Tamnes, C.K., Ostby, Y., Fjell, A.M., et al., 2010. Brain maturation in adolescence and young adulthood: regional age-related changes in cortical thickness and white matter volume and microstructure. Cereb. Cortex 20, 534—548. Thomas, R.H., Walsh, J., Church, C., et al., 2014. A comprehensive neuropsychological description of cognition in drug-refractory juvenile myoclonic epilepsy. Epilepsy Behav. 36, 124—129. Trinka, E., Kienpointner, G., Unterberger, I., et al., 2006. Psychiatric comorbidity in juvenile myoclonic epilepsy. Epilepsia 47, 2086—2091. Vadlamudi, L., Milne, R.L., Lawrence, K., et al., 2014. Genetics of epilepsy: the testimony of twins in the molecular era. Neurology 83, 1042—1048. Varotto, G., Visani, E., Canafoglia, L., et al., 2012. Enhanced frontocentral EEG connectivity in photosensitive generalized epilepsies: a partial directed coherence study. Epilepsia 53, 359—367. Vaudano, A.E., Ruggieri, A., Tondelli, M., et al., 2014. The visual system in eyelid myoclonia with absences. Ann. Neurol. 76, 412—427. Vollmar, C., O’Muircheartaigh, J., Barker, G.J., et al., 2011. Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study. Brain 134, 1710—1719. Vollmar, C., O’Muircheartaigh, J., Symms, M.R., et al., 2012. Altered microstructural connectivity in juvenile myoclonic epilepsy: the missing link. Neurology 78, 1555—1559. Walsh, J., Thomas, R.H., Church, C., et al., 2014. Executive functions and psychiatric symptoms in drug-refractory juvenile myoclonic epilepsy. Epilepsy Behav. 35, 72—77. Wandschneider, B., Centeno, M., Vollmar, C., Symms, M., Thompson, P.J., Duncan, J.S., Koepp, M.J., 2014. Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype? Brain 137, 2469—2479.

P. Wolf et al. Wandschneider, B., Centeno, M., Vollmar, C., Stretton, J., O’Muircheartaigh, J., Thompson, P.J., Kumari, V., Symms, M., Barker, G.J., Duncan, J.S., Richardson, M.P., Koepp, M.J., 2013. Risk-taking behavior in juvenile myoclonic epilepsy. Epilepsia 54, 2158—2165. Wandschneider, B., Kopp, U.A., Kliegel, M., Stephani, U., Kurlemann, G., Janz, D., Schmitz, B., 2012a. Prospective memory in patients with juvenile myoclonic epilepsy and their healthy siblings. Neurology 75, 2161—2167. Wandschneider, B., Thompson, P.J., Vollmar, C., Koepp, M.J., 2012b. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 53, 2091—2098. Watson, C.T., Marques-Bonet, T., Sharp, A.J., Mefford, H.C., 2012. The genetics of microdeletion and microduplication syndromes: an update. Annu. Rev. Genomics Hum. Genet. 15, 215—244. Wierenga, L.M., Langen, M., Oranje, B., Durston, S., 2014. Unique developmental trajectories of cortical thickness and surface area. Neuroimage 87, 120—126. Winawer, M.R., Marini, C., Grinton, B.E., Rabinowitz, D., Berkovic, S.F., Scheffer, I.E., Ottman, R., 2005. Familial clustering of seizure types within the idiopathic generalized epilepsies. Neurology 65, 523—528. Wirrell, E.C., Camfield, C.S., Camfield, P.R., Gordon, K.E., Dooley, J.M., 1996. Long-term prognosis of typical childhood absence epilepsy. Neurology 47, 912—918. Woermann, F.G., Free, S.L., Koepp, M.J., Sisodiya, S.M., Duncan, J.S., 1999. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 122, 2101—2108. Wolf, P., 1992. Reading epilepsy. In: Roger, J., Bureau, M., Dravet Ch, Dreifuss, F.E., Perret, A., Wolf, P. (Eds.), Epileptic Syndromes in Infancy, Childhood and Adolescence. , 2nd ed. J. Libbey, London, pp. 281—298. Wolf, P., 1994. Epileptic seizures and syndromes: terms and concepts. In: Wolf, P. (Ed.), Epileptic Seizures and Syndromes, With Some of their Theoretical Implications. J. Libbey, London, pp. 3—7. Wolf, P., 2006. Basic principles of the ILAE syndrome classification. Epilepsy Res. 70 (Suppl. 1), 20—26. Wolf, P., 2010. Much ado about nothing? Epilepsia 51, 717—718. Wolf, P., 2015. Reflex epileptic mechanisms in humans: lessons about natural ictogenesis. Epilepsy Behav., http://dx.doi.org/10.1016/j.yebeh.2015.01.009. Wolf, P., Goosses, R., 1986. Relation of photosensitivity to epileptic syndromes. J. Neurol. Neurosurg. Psychiatry 49, 1386— 1391. Yacubian, E.M., Wolf, P., 2014. Praxis induction. Definition, relation to epilepsy syndromes, nosological and prognostic significance: a focused review. Seizure 23, 247—251. Zamarian, L., Höfler, J., Kuchukhidze, G., Delazer, M., Bonatti, E., Kemmler, G., Trinka, E., 2013. Decision making in juvenile myoclonic epilepsy. J. Neurol. 260, 839—846. Zifkin, B., Andermann, E., Andermann, F., 2005. Mechanisms, genetics, and pathogenesis of juvenile myoclonic epilepsy. Curr. Opin. Neurol. 18, 147—153.