D:JLEissueEPD1818(3)ArticlesMNT JLE JOURNAL EPD 0839 … · 2018. 4. 3. · Journal Identiﬁcation = EPD Article Identiﬁcation = 0839 Date: August 17, 2016 Time: 2:18pm 254 Epileptic

Journal Identification = EPD Article Identification = 0839 Date: August 17, 2016 Time: 2:18 pm

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Review articleEpileptic Disord 2016; 18 (3): 252-88

Idiopathic focal epilepsies:the “lost tribe”*

Deb K. Pal 1,2, Colin Ferrie 3, Laura Addis 1, Tomoyuki Akiyama 4,Giuseppe Capovilla 5, Roberto Caraballo 6,Anne de Saint-Martin 7, Natalio Fejerman 6, Renzo Guerrini 8,Khalid Hamandi 9, Ingo Helbig 10, Andreas A. Ioannides 11,Katsuhiro Kobayashi 4, Dennis Lal 12, Gaetan Lesca 13,Hiltrud Muhle 14, Bernd A. Neubauer 15, Tiziana Pisano 8,Gabrielle Rudolf 16, Caroline Seegmuller 17, Takashi Shibata 4,Anna Smith 18, Pasquale Striano 19, Lisa J. Strug 20,Pierre Szepetowski 21, Thalia Valeta 22, Harumi Yoshinaga 4,Michalis Koutroumanidis 23

1 Department of Basic & Clinical Neuroscience, Institute of Psychiatry,Psychology & Neuroscience, King’s College London, UK2 Kings College and Evelina Children’s Hospitals, London, UK3 Leeds General Infirmary, Paediatric Neurology, Leeds, UK4 Department of Child Neurology, Okayama University Graduate Schools of Medicine,Dentistry, and Pharmaceutical Sciences, Okayama, Japan5 Child Neuropsychiatry and Epilepsy Center, C. Poma Hospital, Mantova, Italy6 Neurology Department. Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”,Buenos Aires, Argentina7 Centre Référent des Epilepsies Rares associé, Centre référent des troubles du langageet des apprentissages, Hôpitaux Universitaires de Strasbourg, Strasbourg, France8 Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-Universityof Florence, Firenze, Italy9 The Alan Richens Welsh Epilepsy Centre, University Hospital of Wales; CardiffUniversity Brain Research Imaging Centre, School of Psychology, Cardiff University,Cardiff, UK10 Department of Neuropediatrics, University Medical Center Schleswig-Holstein(UKSH), Kiel, Germany11 Laboratory for Human Brain Dynamics, AAI Scientific Cultural Services Ltd., Nicosia,Cyprus12 Cologne Center for Genomics, University of Cologne, Cologne; Department ofNeuropediatrics, University Medical Center Giessen and Marburg Giessen; CologneExcellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD),University of Cologne, Cologne, Germany13 Department of Genetics, University Hospitals of Lyon; Claude Bernard Lyon I

iences de Lyon, CNRS UMR5292, INSERM

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University; Centre de Recherche en Neurosc

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.2016.0839

52 Epileptic Disord, Vol. 18, No. 3, September 2016

orrespondence:eb K. Palepartment of Basic & Clinicaleuroscience, Institute of Psychiatry,

sychology & Neuroscience,ing’s Collegeondon, [email protected]>

U1028, Lyon, France; French Epilepsy, Language and Development (EPILAND) network14 Department of Neuropediatrics, University Medical Center Schleswig-Holstein(UKSH), Kiel, Germany15 Department of Neuropediatrics, University Medical Center Giessen and Marburg,Giessen, Germany

∗This review article is the updated result, edited by M. Koutroumanidis, C. Ferrie and D.Pal, of the Waterloo International Symposium on Idiopathic Focal Epilepsies: Phenotypeto Genotype,held at Somerset House, London on 29th September 2012.

mailto:[email protected]


E

Idiopathic Focal Epilepsies: state-of-the-art

16 Department of Neurology, Strasbourg University Hospital; Strasbourg University;UMR S INSERM U1119, Strasbourg, France; French Epilepsy,Language and Development (EPILAND) network17 Centre Référent des Epilepsies Rares associé, Service medico-chirurgicaldes epilepsies, Hôpitaux Universitaires de Strasbourg, Strasbourg, France18 Dept of Basic and Clinical Neuroscience, Institute of Psychiatry,Psychology & Neuroscience, Kings College, London, UK19 Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences,Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health,University of Genova, Institute “G. Gaslini”, Genova, Italy20 Program in Child Health Evaluative Sciences, The Hospital for Sick Children;University of Toronto, Toronto, ON, Canada21 French Epilepsy, Language and Development (EPILAND) network, Aix-MarseilleUniversity; INSERM UMR_S901; Mediterranean Institute of Neurobiology (INMED),

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Marseille, France22 Department of Clinical neurophysiology, St. Thomas’ Hospital, London, UK23 GSTT, Clin Neurophysiology and Epilepsies, Lambeth Wing, St Thomas’ Hospital,London, UK

Received September 9, 2015; Accepted June 22, 2016

ABSTRACT – The term idiopathic focal epilepsies of childhood (IFE) is notformally recognised by the ILAE in its 2010 revision (Berg et al., 2010), norare its members and boundaries precisely delineated. The IFEs are amongstthe most commonly encountered epilepsy syndromes affecting children.They are fascinating disorders that hold many “treats” for both cliniciansand researchers. For example, the IFEs pose many of the most interestingquestions central to epileptology: how are functional brain networks invol-ved in the manifestation of epilepsy? What are the shared mechanisms ofcomorbidity between epilepsy and neurodevelopmental disorders? Howdo focal EEG discharges impact cognitive functioning? What explains theage-related expression of these syndromes? Why are EEG discharges andseizures so tightly locked to slow-wave sleep?In the last few decades, the clinical symptomatology and the respectivecourses of many IFEs have been described, although they are still notwidely appreciated beyond the specialist community. Most neurologistswould recognise the core syndromes of IFE to comprise: benign epilepsyof childhood with centro-temporal spikes or Rolandic epilepsy (BECTS/RE);Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gas-taut and photosensitive types). The Landau-Kleffner syndrome and therelated (idiopathic) epilepsy with continuous spikes and waves in sleep(CSWS or ESES) are also often included, both as a consequence of the sha-red morphology of the interictal discharges and their potential evolutionfrom core syndromes, for example, CSWS from BECTS. Atypical benignfocal epilepsy of childhood also has shared electro-clinical features warran-ting inclusion. In addition, a number of less well-defined syndromes of IFEhave been proposed, including benign childhood seizures with affectivesymptoms, benign childhood epilepsy with parietal spikes, benign child-hood seizures with frontal or midline spikes, and benign focal seizures ofadolescence.The term “benign” is often used in connection with the IFEs and is increasin-gly being challenged. Certainly most of these disorders are not associatedwith the devastating cognitive and behavioural problems seen with early

pileptic Disord, Vol. 18, No. 3, September 2016 253

childhood epileptic encephalopathies, such as West or Dravet syndromes.However, it is clear that specific, and sometimes persistent, neuropsycholo-gical deficits in attention, language and literacy accompany many of the IFEsthat, when multiplied by the large numbers affected, make up a significantpublic health problem. Understanding the nature, distribution, evolution,risk and management of these is an important area of current research.


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.K. Pal, et al.
A corollary to such questions regarding comorbidities is the role of focalinterictal spikes and their enduring impact on cognitive functioning. Whatexplains the paradox that epilepsies characterised by abundant interictalepileptiform abnormalities are often associated with very few clinical sei-zures? This is an exciting area in both clinical and experimental arenasand will eventually have important implications for clinical managementof the whole child, taking into account not just seizures, but also adaptivefunctioning and quality of life. For several decades, we have accepted anevidence-free approach to using or not using antiepileptic drugs in IFEs.There is huge international variation and only a handful of studies exa-mining neurocognitive outcomes. Clearly, this is a situation ready for anoverhaul in practice.Fundamental to understanding treatment is knowledge of aetiology. Inrecent years, there have been several significant discoveries in IFEs from stu-dies of copy number variation, exome sequencing, and linkage that promptreconsideration of the “unknown cause” classification and strongly suggesta genetic aetiology. The IFE are strongly age-related, both with regards toage of seizure onset and remission. Does this time window solely relate toa similar age-related gene expression, or are there epigenetic factors invol-ved that might also explain low observed twin concordance? The genetic(and epigenetic) models for different IFEs, their comorbidities, and theirsimilarities to other neurodevelopmental disorders deserve investigationin the coming years. In so doing, we will probably learn much about normalbrain functioning. This is because these disorders, perhaps more than anyother human brain disease, are disorders of functional brain systems (eventhough these functional networks may not yet be fully defined).In June 2012, an international group of clinical and basic science resear-chers met in London under the auspices of the Waterloo Foundation todiscuss and debate these issues in relation to IFEs. This Waterloo Founda-tion Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotypewitnessed presentations that explored the clinical phenomenology, phe-notypes and endophenotypes, and genetic approaches to investigation ofthese disorders. In parallel, the impact of these epilepsies on children andtheir families was reviewed. The papers in this supplement are based uponthese presentations. They represent an updated state-of-the-art thinkingon the topics explored.The symposium led to the formation of international working groups underthe umbrella of “Luke’s Idiopathic Focal Epilepsy Project” to investigatevarious aspects of the idiopathic focal epilepsies including: semiology andclassification, genetics, cognition, sleep, high-frequency oscillations, andparental resources (see www.childhood-epilepsy.org). The next sponsoredinternational workshop, in June 2014, was on randomised controlled trials


in IFEs and overnight learning outcome measures.

Key words: idiopathic focal epilepsy, Rolandic epilepsy, Panayiotopoulossyndrome, occipital epilepsy (Gastaut type), symptomatic epilepsy, EEG,treatment, prognosis, neuronal circuit, magnetoencephalography, beha-viour, language, genetics


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verlap of the core idiopathic focalpilepsies of childhood with otherocal symptomatic epilepsies

enzo Guerrini, Tiziana Pisano

ocal epilepsies have core clinical and EEG characte-istics that make early recognition possible in mostatients. However, overlap with other focal and pos-ibly symptomatic epilepsy syndromes exists. Somef the features most strongly suggestive of idiopathic

ocal epilepsy (e.g. normal background EEG acti-ity, EEG discharges with stereotyped waveforms andypical topography, and characteristic clinical mani-estations) may also be encountered in symptomaticpilepsies due to structural lesions affecting the Rolan-ic or occipital cortex. The clinical course of focal

diopathic syndromes may be complicated by cog-itive and language impairment. In some cases, theverlap of such core symptoms between idiopathicnd symptomatic epilepsy renders the underlyingause a mystery.linical semiologies and electrographic features thatighlight the focal origin of seizures characterise

he idiopathic focal epilepsies (IFEs) of childhood.hey describe a spectrum of syndromes with nonderlying structural brain lesion or attendant neu-ological signs or symptoms. They are presumed toe genetic and are usually age dependent. Their cha-acteristics imply not just the absence of obviousausative factors, but also specific clinical and EEGndings (Berg et al., 2010). The most common formsre benign childhood epilepsy with centro-temporalpikes or Rolandic epilepsy (BECTS/RE) (Beaussart,972), early-onset benign childhood occipital epilepsyPanayiotopoulos type) (Panayiotopoulos, 1989), andate-onset (Gastaut type) childhood occipital epilepsyGastaut, 1982). Symptomatic epilepsies, on the otherand, have an acquired or genetic cause and aressociated with neuroanatomical or neuropathologi-al abnormalities indicative of an underlying diseaser condition. When a genetic mutation causes arain malformation that results in epilepsy, the epi-

epsy is considered the result of the interposed brainbnormality, rather than the direct consequence ofhe genetic abnormality (Berg et al., 2010). In clini-al practice, however, distinction between idiopathicnd symptomatic focal epilepsies might not always be

pileptic Disord, Vol. 18, No. 3, September 2016

lear or meaningful, especially when they are asso-iated with specific learning and language problemsDeonna, 1993).n the IFE, seizures are usually brief, infrequent, andend to concentrate around preschool or school ages.he EEG background activity and organization of sleepre normal. Focal epileptiform abnormalities have a

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haracteristic “stereotyped” morphology and are mar-edly activated by non-REM sleep (Gregory and Wong,992). Rolandic epilepsy is the most frequent type ofdiopathic focal epilepsy. The age at onset is between-13 years. The seizure prognosis is excellent. Seizuresre simple partial with motor symptoms involving theace and occur during sleep or on awakening. Often,he seizures show symptoms caused by activation ofhe Rolandic or perisylvian sensorimotor cortex. Inter-ctal EEG shows typical high-voltage centro-temporalpikes and sharp-waves that increase during sleep.ccasionally, they may occur only in sleep. In most

hildren, drug treatment is not needed (Ambrosettond Tassinari, 1990).ome of the same features which, in combina-ion, are strongly suggestive of idiopathic focalpilepsy (e.g. normal EEG background activity, epilep-iform discharges with stereotyped wave forms andypical locations, reflex phenomena, and characteris-ic clinical manifestations) may also be encountered inymptomatic epilepsy due to specific structural lesionsffecting the Rolandic or occipital cortex. For example,ortical dysplasia of the Rolandic cortex may causetereotyped rhythmic sharp-waves with phase reversalver the centro-temporal region and motor seizuresffecting one side of the face and the ipsilateral hand,ue to the wide area of cortical representation of

hese body parts. If seizures are not frequent, theEG background may remain normal. In such cir-umstances, especially if seizures occur during sleep,arly distinction from idiopathic RE may be impos-ible without an MR scan (figure 1). Specific syndromesave been described in which, in addition to theore features of RE, affected patients exhibited cli-ical features indicating co-occurring dysfunction inider neuronal networks. For instance, both a fami-

ial syndrome of autosomal dominant RE and speechyspraxia, as well as a recessive syndrome of RE andaroxysmal dyskinesia, have been reported (Scheffert al., 1995, Guerrini et al., 1999, Kugler et al., 2008).t is unknown whether these conditions representolandic epilepsy “plus” syndromes, which maintain

he idiopathic-genetic aetiopathogenic mechanism ofE, or result from “interposed” structural abnormali-

ies affecting the Rolandic cortex as well as additionaleural networks.ome patients with RE show atypical clinical and EEGvolution associated with cognitive dysfunction rela-ed to a marked increment of interictal EEG discharges

255

uring NREM sleep. This phenomenon has beeneported in different syndromes that are thought toelong to the spectrum of RE. Epileptic encepha-

opathy with continuous spikes and waves duringlow-wave sleep (CSWS) is a condition best definedy the associated cognitive or behavioural impair-ents acquired during childhood and not related to


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igure 1. EEG recording of a 4-year-old girl showing normal backegion, and FLAIR MRI showing focal cortical dysplasia involving

ny factor other than the presence of frequent inter-ctal epileptiform discharges during sleep. Althoughhis condition is considered by many authors to beart of the childhood focal epilepsy syndromes, it canlso be observed in a symptomatic context in childrenith structural brain lesions, such as polymicrogy-

ia or perinatal ischaemic insults or hydrocephalusGuerrini et al., 1998; Veggiotti et al., 1999; Guzzetta etl., 2005). Landau-Kleffner syndrome (LKS) is a parti-ular condition in which acquired aphasia is the coreanifestation (Cole et al., 1988). Clinical, neurophysio-

ogical, and cerebral glucose metabolism data supporthe hypothesis that interictal epileptiform dischargeslay a prominent role in the cognitive deficits by inter-

ering with the neuronal networks both at the sitef the epileptic foci and at distant, connected areas

Deonna and Roulet-Perez, 2010). Given that CSWSs an age-dependent EEG pattern, the outcome ofpilepsy is usually good, irrespective of aetiology,hereas the outcomes of cognition, language, andehaviour are variable.hildhood occipital epilepsies manifest with a firsteak onset at around 2 years old and a second lateeak onset between ages 7 to 9 years. In the early-onset

orm (Panayiotopoulos type), seizures are infrequentnd occur at night, usually shortly after the childalls asleep. The episodes typically last a few minutes,ut status epilepticus at onset with neurovegetative

56

ymptoms may occur (Panayiotopoulos, 1989). A com-on clinical pattern is one of vomiting and gazing

oward one side, often evolving to rhythmic muscleontractions on one or both sides of the body. Inhe late-onset type (Gastaut type), some children mayxperience headache and visual symptoms (colou-ed shapes or flashes of light) associated with the

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d activity with superimposed spikes in the left centro-temporaleft Rolandic region.

eizure. The EEG shows sharp waves with maximumccipital negativity, often occurring in long bursts ofpike-wave complexes, and markedly activated by eyelosure (Gastaut, 1982). Childhood idiopathic occipitalpilepsy can be difficult to distinguish from symp-omatic causes with less favourable prognoses. The

ere presence on EEG of continuous spike-wave acti-ity does not guarantee an “idiopathic” origin, sincetructural lesions may cause a similar pattern. Perina-al ischaemic insults and cortical malformations arehe most frequent causes of occipital epilepsy. Corti-al dysplasia, Sturge-Weber syndrome, celiac disease,yperglycaemia (non-ketotic), Lafora disease, Gaucherisease, and mitochondrial disease can also cause occi-ital seizures in children (Guerrini et al., 1995).syndrome of idiopathic photosensitive occipital lobe

pilepsy has been described with onset in adolescenceGuerrini et al., 1995), sometimes overlapping withther types of idiopathic focal epilepsy (Guerrini et al.,997). In this form, prolonged visual seizures are pre-ipitated by visual stimuli, which seem to act throughmechanism of impaired contrast gain control in theccipital cortex (Porciatti et al., 2000). Notably, similareizures may also appear in the early phases of someorms of progressive myoclonic epilepsies (Guerrini etl., 2000).europsychological impairment may occur in chil-ren with idiopathic epilepsy syndromes, possibly due

Epileptic Disord, Vol. 18, No. 3, September 2016

o the active phase of epilepsy. The clinical courseay be complicated by cognitive and language impair-ent or behavioural disturbances, with or withoutSWS. These functional changes may reflect a parti-ular type of epileptic encephalopathy, in which thepileptiform abnormalities themselves contribute tohe progressive disturbance in cerebral function and,


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s in symptomatic forms, the patients develop drug-esistant epilepsy and global regression of cognitiveunction. Some patients, especially those in whomhe epileptic process is localised around the perisyl-ian cortex, present with features of autistic spectrumisorder, but unlike primary autism, there is no loss ofocial interaction (Deonna and Roulet-Perez, 2010).lthough many clinical, EEG, neuroimaging, and neu-

opsychiatric features make it possible to differentiatediopathic from symptomatic focal epilepsy, in some,he number of shared features complicates accuratedentification of the underlying cause. In severe phe-otypes with RE “plus,” new genetic findings aremerging (Lemke et al., 2013a; Lesca et al., 2013)hat might help to fill the gap of knowledge and

odifying the concepts on which the dichotomydiopathic versus symptomatic has traditionally beenased.

typical clinical presentationsf idiopathic focal epilepsies

n childhood

atalio Fejerman, Roberto Caraballo

he concept of “atypical evolution” in idiopathic focalpilepsy refers to both clinical and EEG features thatan be seen in several epilepsy syndromes, includingtypical benign focal epilepsy of childhood (ABFEC),tatus of Rolandic epilepsy, Landau-Kleffner syndromeLKS), and CSWS syndrome. Here, we outline treat-

ent recommendations and discuss prognosis.diopathic focal epilepsies (IFEs) appear across a wideange of ages. Due to space limitations, we are goingo deal neither with benign familial and non-familialnfantile seizures, which are quite frequent, nor withenign focal seizures in adolescents, which are not so

requent, but in our experience are under-diagnosedCaraballo et al., 2003; Caraballo et al., 2007a). The two

ain epilepsy syndromes of the IFE appearing in child-ood are benign focal epilepsy with centro-temporalpikes or Rolandic epilepsy (RE) and Panayiotopou-os syndrome (PS) (Fejerman, 2008, Panayiotopoulost al., 2008). Gastaut type of childhood occipital epi-

epsy is also included in the group of the IFE, but isare (Caraballo et al., 2008).

typical features of RE


typical features of RE may be seen in seizure characte-istics (daytime-only seizures, post-ictal Todd paresis,rolonged seizures, or even status epilepticus) or on

he EEG (atypical spike morphology, unusual loca-ion, absence-like spike-wave discharges, or abnormalackground) (Aicardi, 2000). Early age at seizure onset

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eems to be one of the most important items amonghe atypical features (Kramer et al., 2002; Saltik et al.,005; You et al., 2006; Fejerman et al., 2007a). In a retros-ective study of 126 patients, atypical features were

ound in almost half of the patients (Datta and Sinclair,007). A follow-up study of RE patients reported aigher percentage of learning and behavioural disa-ilities in the group with atypical features (Verrotti etl., 2002). In a prospective study of 44 children withE divided into a typical group (n=28) and an atypicalroup (n=16) on the basis of EEGs showing features,uch as a slow spike-wave focus, synchronous foci, oreneralised 3-Hz spike-wave discharges, the atypicalroup had significant lower full scale IQ and verbal IQMetz-Lutz and Filippini, 2006).

typical evolution of RE

he concept of atypical evolutions does not includehe cases of RE with atypical features, but refers tohe presence of severe neuropsychological impair-

ents that may become persistent. On the EEG, theseases show continuous spikes and waves during slowleep (CSWSS), which seems to be a kind of bilate-al secondary synchrony (Fejerman et al., 2007b). Theeasons why some children develop this EEG patternre still not understood. In some cases, certain anti-pileptic drugs seemed to be responsible (Shields andaslow, 1983; Caraballo et al., 1989; Prats et al., 1998;ejerman et al., 2000). These conditions correspondo the syndromes known as atypical benign focal epi-epsy of childhood (ABFEC), status of RE (lasting daysr weeks) including motor facial seizures and anar-

hria with persistent drooling (Fejerman and Di Blasi,987, Fejerman et al., 2000), Landau-Kleffner syndromeLKS), and CSWSS syndrome (Tassinari et al., 2005). Forxample, the cases of ABFEC described by Aicardi andhevrie (Aicardi and Chevrie, 1982) showed atonic fits

eading to daily falls, and all of our cases presentedith important learning difficulties during the periodsf CSWSS (Fejerman et al., 2007b). Of children withBFEC, all 11 recovered but five have learning diffi-ulties; language difficulties persisted in two out ofhree LKS patients; all seven children with status ofE recovered after 3-14 years of follow-up (Fejermant al., 2000).n spite of being epileptic encephalopathies withinhe spectrum of electrical status epilepticus in sleepESES) syndromes, ABFEC and status of RE do present

257

favourable outcome when appropriate therapeuticeasures are taken (Fejerman, 1996; Fejerman et al.,

000; Fejerman et al., 2007b). Prognosis of LKS andSWSS or ESES syndrome instead, is not so good in

erms of full recovery.evertheless, in a recent series of 28 symptomatic

nd 25 idiopathic cases of focal epilepsies associated


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.K. Pal, et al.

ith encephalopathy related to ESES receiving add-onherapy with sulthiame, the results were quite encou-aging, especially in children with a previous diagnosisf RE or PS (Fejerman et al., 2012). It is interesting toote that a particular group of children with unilate-al polymicrogyria may present with the same atypicallinical and EEG evolutions as the patients with IFEesponding to therapy in the same way (Caraballo et al.,007b). Overall, 25 of 33 patients with ABFEC, status ofE, or ESES syndrome eventually became seizure-free.

re these four conditions (ABFEC, status of RE,KS and CSWS) independent syndromesr part of a continuum related to RE?

bservations regarding the evolution of clinicalnd EEG findings identified during the follow-up ofatients with RE (above) may not be generalisable toll the cases. Patients with PS and Gastaut type ofhildhood occipital epilepsy (COE) may show the sametypical electroclinical course (Fejerman et al., 1991).atients with two types of IFE (i.e. RE and PS or RE andastaut type of COE) may also develop an atypical evo-

ution (Caraballo et al., 2011c). Another patient studiedy our group who had RE and PS and an atypical evo-

ution presented with a mutation in the GRIN2A geneLemke et al., 2013b).

s there a relationship between atypical featuresnd what is considered here as atypical evolutionsf RE?

t is clear that not all the patients with RE showingtypical clinical and EEG features evolve to ABFEC, sta-us of RE, LKS, or CSWS syndrome. In our series of9 idiopathic cases of ABFEC, status of RE, LKS andSWS syndrome appearing after the onset of RE epi-

epsy started at the age of 4 years or less in 25 patientsFejerman et al., 2007b). There is no clear explanationor this repeatedly reported observation (Kramer et al.,002; You et al., 2006). There are also cases of RE whoave prolonged intermittent drooling and oromotoryspraxia associated with a marked increase in centro-

emporal spikes during the episodes (Roulet-Perez etl., 1989). Persistent slurred speech as a single pheno-enon was also reported (Kramer et al., 2002). Shoulde consider these cases as having atypical features oro they represent an atypical evolution of RE?

58

ow to prevent the atypical evolutionsf IFE of childhood?

typical electroclinical features (primarily EEG abnor-alities and early age of onset) should be considered

s risk factors for atypical evolution (Fejerman et al.,

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000; Kramer et al., 2002). Based on an update onhe ESES-CSWSS syndrome, the subject of therapyas reviewed and it was stated that “an agreement

bout the optimal treatment of these conditions is stillacking” (Veggiotti et al., 2012). When the mentionedisks are evident, the recommendation is to avoid thelassic AEDs (phenobarbital, phenytoin, and carbama-epine) and some of the new AEDs, such as oxcar-azepine, lamotrigine, topiramate, and levetiracetam

Catania et al., 1999; Montenegro and Guerreiro, 2002,araballo et al., 2010), and to start treatment with etho-

uximide, benzodiazepines, or sulthiame. In refractoryases, corticosteroids may also be considered.

ay a genetic aetiology be related to atypicalvolutions of IFE?

genetic aetiology has been proposed in patients withBFEC and even in patients with epilepsy associatedith ESES. This is discussed in detail below (Lesca et

l., 2012; Helbig et al., 2014).n conclusion, a future challenge is to determine if thetypical evolutionary potential within IFEs describes aontinuum of expression related to a single geneticetiology, or if this electroclinical picture is caused byistinct epileptic syndromes. In addition to the impor-

ance of the nosological placement, early and correctiagnosis is crucial for optimal therapeutic manage-ent and clinical outcomes.

nvolvement of autonomic,ensorimotor, auditory, vocal, and visualircuits in idiopathic focal epilepsies

iuseppe Capovilla and Pasquale Striano

diopathic focal epilepsies (IFEs) affect over 20% ofhildren with non-febrile seizures and constitute aignificant part of the everyday practice of epilepto-ogists. They have distinctive characteristics but theylso share common clinical and EEG features and itas been suggested that they may be linked together

n a broad, age-related and age-limited, geneticallyetermined, benign childhood seizure susceptibilityyndrome. Although rare, IFEs may be complicatedy a broad range of cognitive problems, behaviouralisturbances, and resistance to medical therapy that


an impact brain maturation and the development ofognitive skills. Recent opinions suggest that IFEs areaused by perturbations of localised processes invol-ing different brain areas, which in some cases canvolve to a global network disturbance.hile IFEs affect over 20% of children with non-febrile

eizures, the category is not specifically recognised


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y the ILAE. This chapter focuses on three electrocli-ical syndromes, subtypes of IFE, recognised by the

nternational League against Epilepsy (ILAE) (Engel,006): Panayiotopoulos syndrome, Rolandic epilepsy,nd occipital epilepsy of Gastaut type. Other putativeorms include: focal epilepsy with parietal spikes/giantomatosensory evoked spikes (de Marco and Tassinari,981) and focal epilepsy with frontal or midline spikesuring sleep (Beaumanoir and Nahory, 1983; Capovillat al., 2006). Each form has distinctive characteristicsut they also share common clinical and EEG features.eizures are infrequent, usually nocturnal and remitithin a few years from onset. Brief or prolonged sei-

ures, even focal status epilepticus, may occur onlynce in the patient’s lifetime. Neurological and cog-itive function, as well as brain imaging, are normal

n patients with IFE. It has been suggested that all ofhese conditions may be linked together in a broad,enetically determined, age-related and age-limitedenign childhood seizure susceptibility syndrome

Panayiotopoulos, 1993; Panayiotopoulos et al., 2008;aggero et al., 2014). Rarely, IFEs may be complicatedy pharmacoresistance, behavioural disturbances, orrange of cognitive impairments, particularly trouble-

ome in childhood given the brain’s developmentallyulnerable state, a time during which neurologicalisturbances can profoundly impact brain maturationnd the development of cognitive skills (Braakmant al., 2011).

nvolvement of autonomic circuits in IFE:anayiotopoulos syndrome

anayiotopoulos syndrome (PS) is a common idio-athic childhood-specific epilepsy. It is characterisedy seizures, often prolonged, with predominantlyutonomic symptoms and shifting and/or mul-iple foci, often with occipital predominance onEG (Panayiotopoulos, 1993; Panayiotopoulos, 2007;anayiotopoulos et al., 2008; Capovilla et al., 2009).nset is from age 2 to 11 years with 76% starting

etween 3 and 6 years. The hallmark of PS is ictalutonomic alterations that may involve any functionf the autonomic system and mainly emesis. Otherutonomic manifestations include pallor, sphinctericncontinence, hypersalivation, cyanosis, mydriasis or

iosis, coughing, abnormalities of intestinal moti-ity, breathing, cardiac irregularities, and syncopal-like


anifestations (Koutroumanidis, 2007). Pure autono-ic seizures or status epilepticus appear to occur

n 10% of patients. However, autonomic manifesta-ions are usually followed by conventional seizureymptoms. Converging evidence from multiple andndependent clinical, EEG, and magnetoencephalo-raphic studies has documented Panayiotopoulos

fimtoOea


yndrome as a model of childhood autonomic epilepsyPanayiotopoulos et al., 2008).utonomic symptoms are usually generated by activa-

ion or inhibition of parts of the central autonomic net-ork that involves the insular cortex, medial prefrontal

ortex, amygdala, hypothalamus, and ventrolateraledulla (Goodman et al., 2008). In PS, the neuroa-

atomical and neurophysiological underpinnings ofutonomic manifestations are unknown, but it haseen suggested that the preferential involvement ofmetic and other autonomic manifestations in PS maye attributed to a maturation-related susceptibility of

he central autonomic network (Panayiotopoulos etl., 2008) which has a lower threshold to epilepto-enic activation than those producing focal corticalemiology. Thus, irrespective of the localisation of theirnset, ictal discharges may activate the lower thresholdutonomic centres (and therefore produce autono-ic manifestations) commonly before other cortical

egions of relatively higher threshold that generateocal cortical symptoms (sensory, motor, visual orther). Seizures remain purely autonomic if ictal neu-onal activation of non-autonomic cortical areas failso reach symptomatogenic threshold; otherwise, theyonsist of autonomic and localisation-related corticalymptoms and signs that may only rarely occur fromnset. This hypothesis may explain why similar auto-omic manifestations may appear from anterior orosterior, or right or left brain onsets. In this sense,s seizures primarily involve a particular system (theutonomic), PS may be considered as an electroclinicalxample of “system epilepsy” (see below).

nvolvement of sensorimotor and auditory vocalircuits in IFE: Rolandic epilepsy

olandic epilepsy (RE) or benign childhood epi-epsy with centro-temporal spikes is the mostommon childhood focal epilepsy (Fejerman, 2008;anayiotopoulos et al., 2008), usually starting betweenand 10 years. The cardinal features are focal sei-

ures consisting of unilateral facial sensory-motorymptoms, oropharyngo-laryngeal symptoms, speechrrest, and hypersalivation (Capovilla et al., 2011).entro-temporal spikes, typically activated by drow-

iness and slow sleep, indicate that the epileptogenicone in Rolandic epilepsy involves neuronal networksithin the Rolandic cortex surrounding the central

259

ssure bilaterally. Indeed, RE reflects an age-relatedaturational instability of the lower Rolandic (soma-

osensory) cortex that represents the face and theropharynx bilaterally (Panayiotopoulos et al., 2008).ver the last years, evidence has accumulated that

ven RE is associated with language impairment,lthough the cerebral mechanism through which


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pileptiform activity in the Rolandic areas may affecthe language system is still unclear. Functional magne-ic resonance imaging (fMRI) data support a functionaleficit of the default mode network (DMN). This dys-

unction is most apparent in the precuneus, a keyegion of the DMN. In particular, children with REhow reduced activation of the DMN during the restondition and a deactivation during cognitive effortBesseling et al., 2013a). In addition, reduced functionalonnectivity was demonstrated between the senso-imotor network and the left inferior frontal gyrusBroca’s area), which might link seizure activity, ori-inating from the sensorimotor cortex to language

mpairment (Oser et al., 2014).t is also well known that RE may rarely evolve to moreevere syndromes with behavioural and neuropsy-hological deficits, such as epilepsy with continuouspike-and-wave during sleep (CSWS) (Patry et al.,971; Striano and Capovilla, 2013) and the broad spec-rum of age-related epileptic conditions characterisedy the EEG pattern of electrical status epilepticusuring sleep, including atypical epilepsy with centro-

emporal spikes and Landau-Kleffner syndrome. Theathophysiological mechanisms underlying this cog-itive derailment are also incompletely understood.he abnormal EEG activity is probably due to thectivation of the reticulo-thalamic-cortical systemith secondary bilateral synchronization through the

orpus callosum, as supported by the activation of epi-eptiform activity during sleep (Striano and Capovilla,013). As the duration of CSWS and the localisationf interictal foci influence the degree and type ofognitive dysfunction, it is likely that the epileptic acti-ity occurring during sleep causes the typical clinicalymptoms by interfering with sleep-related physiolo-ical functions, and possibly neuroplasticity processesediating higher cortical functions, such as learning

nd memory consolidation (Striano and Capovilla,013). fMRI studies also suggest that the neurophysio-ogical effects of CSWS activity are not restricted to thepileptic focus but spread to connected brain areasia a possible mechanism of surrounding and remotenhibition, possibly having long-lasting consequencesn normal brain function, organization, and matura-

ion (Van Bogaert, 2013). Moreover, in patients withSWS, EEG-fMRI results during drug-induced sleep

how a complex pattern of activation involving theerisylvian/prefrontal cortex, the thalamus, and a deac-

ivation of DMN (Siniatchkin et al., 2010). A dysfunction

60

f these networks is a possible explanation for thebserved neuropsychological disorders.andau-Kleffner syndrome (LKS), also known as acqui-ed epileptic aphasia, is an acquired childhoodisorder consisting of auditory agnosia, associatedith focal or multifocal spikes or spike-and-waveischarges, nearly continuous during sleep (Landau

bo(ttCz

nd Kleffner, 1957). Although LKS patients often appearo be deaf, their normal audiograms and auditory evo-ed potentials support the concept that there is annderlying disorder of cortical processing of auditory

nformation, a “verbal-auditory agnosia” (Landau andleffner, 1957). The aphasia in these children may benly one component of a more complex neuropsy-hological disorder associated with other cognitivend behavioural deficits. EEG-fMRI studies suggest thatathophysiological effects associated with CSWS acti-ity are not restricted to the epileptic focus, but spreado connected areas due to remote functional conse-uences, such that the spike-associated deactivationf DMN is a further consequence of the individual

ocus of epileptic activity. This phenomenon has beenefined as the “network inhibition hypothesis”, byhich increased cortical activity in one region inhi-its subcortical arousal systems, leading to widespreadecreased cortical activity, including the DMN (Deiege et al., 2008).

nvolvement of visual circuits in IFE:ccipital epilepsy of Gastaut

ccipital epilepsy of Gastaut is a rare form ofure occipital epilepsy accounting for about 2-7%f benign childhood focal seizures (Gastaut, 1982;anayiotopoulos et al., 2008). The age at onset rangesrom 3 to 15 years with a peak between 8 and 11ears. Elementary visual hallucinations are frequentlyhe first and often the only seizure symptom. Com-lex visual hallucinations such as faces and figures,nd visual illusions such as micropsia, palinopsia andetamorphopsia occur in <10% of patients and mainly

fter the appearance of elementary visual hallucina-ions (Gastaut, 1982; Panayiotopoulos et al., 2008). Thepileptogenic zone involves networks within the occi-ital lobes and this localisation is congruent with theymptomatogenic zone. Little is known about the cor-ical areas involved in spike or seizure generation inhis syndrome, but recent fMRI studies suggest that thepileptogenic area is localised in the medial parietalreas of both hemispheres (Leal et al., 2006).

iscussion

ased on the current knowledge, it is reasonableo state that IFEs are likely to be linked together


y a genetically determined, functional derangementf brain maturation that is mild and age related

Panayiotopoulos et al., 2008). In fact, despite the dis-inctiveness of their core clinical and EEG features,hese syndromes may show significant reciprocity.hildren with RE may present with autonomic sei-ures referable to PS, while others may alternately


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ave autonomic and Rolandic seizures. A small num-er of susceptible children may also have minornd fully reversible neuropsychological symptomshat are rarely clinically overt and can be detectednly by formal neuropsychological testing. However,

n a very limited number of patients, the distur-ance of brain maturation may further evolve into aore aggressive clinical state with enduring neuro-

sychological consequences. Clearly, the spectrum ofeuropsychological disorders depends not only on

he location of the epileptic focus and its duration,ut also on the connected cortical and subcorticalreas, where specific patterns of spike-induced activa-ion (especially in perisylvian and/or prefrontal areas)nd DMN deactivation underlie the dysfunction ofeuropsychological circuitry. Each function and its cor-espondent system needs to be studied with a dynamicpproach that pinpoints how one part of the deve-oping system might interact differently with otherarts and at varying epochs across ontogenesis. Func-

ional connectivity can be measured by correlatinglood-oxygen-dependent oxygenation (BOLD) relatedynamic fluctuations of grey matter activity betweenifferent brain regions, however, additional prospec-

ive studies using functional neuroimaging are neededo better understand the interaction between DMNeactivation and the other systems and its develop-ental milestones (Filippini et al., 2013).

n the last few years, some authors postulated theoncept of “system epilepsies”. Data supporting thisypothesis, that some types of epilepsy depend on theysfunction of specific neural systems, are reviewedlsewhere (Wolf, 2006; Capovilla et al., 2009; Avanzinit al., 2012). Briefly, the “system epilepsy” hypothesis

mplies that some types of epilepsy reflect the patho-ogical expression of an identifiable neural system,

ade up of brain areas, which subserve normal phy-iological functions and that constitute a pre-existingunctional system (as in RE and related syndromesith the involvement of the sensory-motor system),r with the birth of pathological systems as in Westnd Lennox-Gastaut syndrome. According to the “sys-em epilepsy” hypothesis, dysfunction of a single braintructure cannot be solely responsible for the complexanifestations of these epileptic syndromes. Instead,

heir full electroclinical picture requires a pathologicalystem in which different brain areas (the cortex, tha-amic nuclei, and brainstem) work together, activelynd simultaneously participating in the epileptoge-


ic process. When some of these stations are notnvolved in the pathological epileptic process, othernd less complex electroclinical phenotypes develop.MRI studies (Capovilla et al., 2013; Siniatchkin andapovilla, 2013) can help to document the active and

imultaneous participation of these different brainreas and thus allow us to better understand the

BsGsdoo


europathophysiological process. An enriched aware-ess of the basis for cognitive impairment in childrenith epileptic encephalopathies may help with theesign of more effective and targeted therapeutic stra-

egies. As epileptic encephalopathies can complicateFEs, it is vital that the identification and treatmentf developmental, behavioural and psychiatric co-orbidities are not neglected and that a rational,

olistic approach is taken to the management of epi-eptic syndromes in infancy and childhood.

ow useful are individual interictal EEGbnormalities in diagnosing the specificyndrome of idiopathic focal epilepsy?

arumi Yoshinaga, Katsuhiro Kobayashi,omoyuki Akiyama, Takashi Shibata

e consider how useful individual EEG abnormalitiesre in the diagnosis of the main syndromes withinhe spectrum of idiopathic focal epilepsy (IFE), espe-ially Panayiotopoulos syndrome (PS), and in furthernderstanding of the underlying pathophysiology. PSas high dipole stability, similar to that of benignpilepsy in childhood with centro-temporal spikesBECTS). Preceding positive spikes (PPSs) accompanyot only the Rolandic spikes in BECTS, but are alsoetected with the Rolandic spikes observed in PS.owever, they are rarely observed with spikes fromatients with febrile seizures (FS). These electroence-halographic findings indicate a close link between

hese two syndromes. We believe that a source(s) ofhe PPSs and a separate source of the main Rolandicpike, each representing two proximal populations ofeurons in the inferior part of the Rolandic cortex,re necessary for the development of the Rolandiceizures that are characteristic of BECTS, but maylso occur in PS. Epileptic high-frequency oscillationsHFOs) may be related to the neuropsychologicalegression that accompanies the extraordinary EEGbnormalities of epilepsy with continuous spike-wavesuring slow-wave sleep (CSWS). They also appear toorrelate with the severity of IFE (Kobayashi et al., 2010;obayashi et al., 2011). In conclusion, conventionalEGs and advanced EEG analysis techniques are bothseful tools for diagnosing IFE and for investigating theathophysiology of IFE-spectrum syndromes.

261

enign childhood epilepsy with centro-temporalpikes (BECTS) and the occipital lobe epilepsy ofastaut type are representative IFEs. Both have

traightforward electroclinical phenotypes with Rolan-ic spikes and Rolandic seizures in the former andccipital spikes and visual seizures in the latter. On thether hand, Panayiotopoulos syndrome, the youngest


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ember of IFE, manifests with occipital and extra occi-ital spikes. Its characteristic seizures include mainlyutonomic symptoms, which are not referable to dis-inct cortical areas. Conventional EEG cannot fullylarify the electroclinical correlations in PS nor confirmhe EEG characteristics of PS as a distinctive type of IFE.n this report, we evaluate the EEG findings of PS witharious modern techniques including dipole analysis,equential mapping, and HFO analysis, to better deli-eate both its features as an IFE and the mechanisms

hat underlie seizure manifestations.

hat are the common EEG features of idiopathicocal epilepsy (IFE)?

ipole characteristicseveral dipole analysis studies of benign child-ood epilepsy with centro-temporal spikes (BECTS)ave unanimously documented good dipole stability

Wong, 1989; Yoshinaga et al., 1992). Wong (1989) repor-ed greater dipole stability in typical BECTS comparedo atypical BECTS with intellectual disability. He hypo-hesized that even if a common generator were presentn the atypical group, as is the case in typical BECTS,he former would contain additional extraneous inter-ctions and would not show a stable dipole.S is a benign idiopathic epilepsy of early childhoodimilar to BECTS of late childhood (Panayiotopoulost al., 2008). Several reports have suggested thathe two conditions may be linked (Yoshinaga et al.,005; Yoshinaga et al., 2006; Koutroumanidis, 2007;anayiotopoulos et al., 2008). We have previouslyublished a report on dipole analysis in PS and sho-ed intra- and inter-individual dipole stability similar

o BECTS using single spike analysis (Yoshinaga etl., 2005). Moreover, we carried out advanced dipolenalysis using spike selection that was performedbjectively using a computer detection program follo-ed by automatic clustering analyses (Yoshinaga et al.,

006). This program identifies clusters of spikes basedn similar morphology and topography. We compa-ed the dipoles of occipital spikes observed in the PSGroup A) to those observed in other groups (Group). We analysed the dipoles of the averaged spike inach patient. In Group A, the averaged occipital spikes

n each patient showed dense dipole locations in theesial occipital area, while in Group B, dipole loca-

ions were widely scattered. In Group A, the geometricentres of the dipoles at each time point (such as at the

62

ain negative peak and the preceding or followingositive peak) were estimated in the neighbouring

ocations. In contrast, they tended to be scattered inroup B. Our study revealed that PS has high dipole

tability, similar to that of BECTS. From the electroence-halographic point of view, this could indicate a close

ink between these two syndromes.

mgno2Vr

receding positive spikesan der Meij and colleagues (van der Meij et al., 1992)ocused primarily on the preceding positive spikesPPSs) observed in Rolandic spikes, and concluded thathe occurrence of a PPS before the prominent Rolan-ic spike is significantly related to Rolandic seizures

Loiseau and Beaussart, 1973). Their hypothesis is thatPSs originate from a specifically oriented populationf neurons located in a gyrus of the inferior part of theolandic cortex (van der Meij et al., 1993).o clarify the clinical implications of the PPSs within IFE,e analysed PPSs in the Rolandic and occipital spikes

n children with two types of IFE (BECTS and PS), asell as in children with febrile seizures (FS) (Yoshinagat al., 2013). We generated an averaged spike for eachatient from the Rolandic and occipital spikes thatere detected using an automatic spike detection and

lustering system. We compared the PPS ratio amonghe three groups (BECT vs. PS vs. FS) using sequen-ial mapping. We included 25 children with BECTS, 18ith PS, and 15 with FS and Rolandic spikes. PPS in

he averaged Rolandic spikes occurred in 15 childrenith BECTS and nine with PS, but only in four with

S. Three of these four children with FS later develo-ed afebrile seizures, and one of them was diagnosedith PS. We then analysed eight PS and six FS chil-ren with occipital spikes: PPS occurred in five childrenith PS but only in one with FS. This FS patient latereveloped prolonged autonomic febrile seizures. Inonclusion, PPSs are not specific to Rolandic spikes inECTS, but are also detected in Rolandic and occipitalpikes observed in PS, while they are rare in FS. Thesendings suggest a strong correlation of PPSs withpileptogenesis.

hat causes the differences in the clinical featuresetween patients with benign epilepsy withentro-temporal spikes and those withanayiotopoulos syndrome?

he characteristic seizure manifestations of BECTSndicate a sensory motor cortex origin (Loiseau andeaussart, 1973). In contrast, the seizure semiology ofS is characterised mainly by autonomic symptoms,articularly vomiting, which indicate no specific corti-al area as the site of seizure onset (Koutroumanidis,007; Panayiotopoulos et al., 2008). Centro-temporalpikes (also known as Rolandic spikes) are the hall-


ark of BECTS, whereas the interictal EEGs in PS showreater variability in spike topography, with a predomi-ance of occipital spikes and an appreciable numberf Rolandic and other multifocal spikes (Covanis et al.,003; Specchio et al., 2010).an der Meij and colleagues (van der Meij et al., 1993)eported that the source of PPSs was the inferior part of


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he Rolandic cortex, which is located near the sourcef the main Rolandic spikes. They hypothesized that

he presence of the main Rolandic spikes alone wasnsufficient to account for the clinical symptomatologyf Rolandic seizures and that the existence of the PPS-enerating site was necessary for the development ofeizures.owever, as mentioned, our study indicated that PPS

re not specific to Rolandic spikes in BECTS, but arelso detected in Rolandic spikes observed in PS, andarely in those in FS (Yoshinaga et al., 2013). These fin-ings do not support van der Meij and colleagues’ypothesis (van der Meij et al., 1993). Such conflictingvidence motivated us to study the characteristics ofolandic spikes in the two syndromes.

ctal EEGsearly 10% of children with PS develop pureolandic seizures at the same or at a later age

Caraballo et al., 2007). BECTS and PS have differentathophysiologies and seizure types, but share somelinical and EEG features. To further investigatehese relationships, we studied five children whoad experienced both characteristic types of seizureanifestations, namely Rolandic and emetic seizures

Yoshinaga et al., 2015). We found that they all sho-ed Rolandic spikes when they had Rolandic seizures

nd occipital or multifocal spikes when they had eme-ic seizures. We also reported in detail a girl whohowed two different types of ictal EEG pattern: onetarting in the occipital area with associated pro-onged emetic symptoms and one starting from theolandic area, associated with facial twitching. Weave also seen a boy with PS and interictal Rolandicpikes who showed focal slowing over the occipitalrea and posterior spikes one day after an emeticeizure. Based on this evidence, we believe that thearticipation of the occipital area is important in PS,ven when the patient shows Rolandic spikes onheir EEG.

ipole location of Rolandic spikese have performed a preliminary study in whiche compared the dipole location of Rolandic spikesbserved in 21 children with BECTS (Group A) and0 children with PS (Group B). We analysed both thenset dipoles for PPS and the peak dipoles for the mainpikes of the averaged Rolandic spike in each patient


nd found that onset dipoles in both groups wereidely distributed in the Rolandic area without anyarticular differences. In contrast, there was a signi-cant difference in peak dipole locations between the

wo groups, especially in the Y and Z axes. Dipoles inhe BECTS group were located lower and were moreightly clustered than those in the PS group. Thus, peak

epsmaCs


ipoles in BECTS corresponded well to the ictal symp-om of facial twitching. However, peak dipole locationsn PS were more widely distributed in the Rolandicrea, where an actual epileptogenic focus may notxist. Moreover, the migration distance between theain dipoles and the onset dipoles was different bet-een the two syndromes. The main dipoles and thenset dipoles were more closely located in BECT than

n PS, especially in the Z axis direction.o summarise, it appears that the source of the PPSnd the source of the main Rolandic spike representwo proximal populations of neurons in the inferiorart of the Rolandic cortex and are necessary for theevelopment of the characteristic Rolandic seizures,s proposed by van der Meij et al. (1993).

hat determines the individual severityf epilepsy in IFE?

here is a spectrum of paediatric epileptic disor-ers extending from the benign end of BECTS to thencephalopathic end of epilepsy with CSWS (Tassinarit al., 2000), raising the question of what determineshe individual severity of epilepsy in IFE.

e have been trying to detect gamma and high-requency oscillations (HFO) on scalp EEGs inhildhood epilepsies. Because HFOs may affect nor-al brain functions, we examined them in 10 childrenith CSWS (Kobayashi et al., 2010), aged six to nine

ears. We were able to detect HFOs in the time-xpanded EEG tracings during slow-wave sleep, butot after CSWS subsided, leaving random focal spikesn the EEG. During CSWS, the frequency of theigh-frequency peak with the greatest power in eachatient’s spectra ranged from 97.7 to 140.6 Hz.

n another study of children with BECTS (Kobayashit al., 2011), we found that the frequency of HFOs wasimilar to that in CSWS, but their magnitude was muchmaller. Therefore, HFOs of high magnitude are rela-ed to CSWS and their presence may indicate a poorrognosis. We have also found that HFOs are obser-ed during the period of active seizure occurrence.nterictal spikes tend to persist after seizure cessation,ut HFOs disappear and their presence may thereforeeflect epileptogenicity (Kobayashi et al., 2011).hysiological high-frequency activity is believed tolay an important role in higher brain functions, inclu-

263

t al., 2010). We hypothesize that it is unlikely thathysiological and pathological HFOs coexist in theame brain without interaction and that epileptic HFOsay relate to the neuropsychological regression that

ccompanies the extraordinary EEG abnormalities ofSWS. Epileptic HFO also appear to correlate with the

everity of IFE.


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onclusion

onventional EEGs and advanced EEG analysis tech-iques are both useful tools for diagnosing IFE and

or investigating the pathophysiology of IFE-spectrumyndromes. Further investigations are needed to elu-idate the mechanisms underlying the unique clinicaleizure manifestations observed in Panayiotopoulosyndrome.

agnetoencephalography in thediopathic focal epilepsies of childhood

halid Hamandi, Andreas A. Ioannides

agnetoencephalography is an established and now,n light of hardware and software computationaldvances, rapidly developing technology. The idiopa-hic focal epilepsies (IFEs) typically show unilateral,nd occasionally bilateral or multi-focal interictalpileptic discharges on EEG. These readily lend them-elves to more detailed neurophysiological study withagnetoencephalography. This review focuses on the

xisting magnetoencephalography literature in theFEs. Studies show that stable dipolar sources of inter-ctal epileptiform discharges that characterise the IFEsre, in some studies, associated with more detailedhenotypic characteristics. Recently, sample sizes have

ncreased and attention is moving to novel analy-is strategies and time-frequency analysis approaches.he ultimate objective of these studies is a greaternderstanding of the generators of epileptic activitynd their relationship to clinical and neuropsycholo-ical phenotypes.ocal interictal epileptiform discharges (IEDs) definehe IFEs (Legarda et al., 1994). This defining neuro-hysiology motivates studies using magnetoencepha-

ography (MEG) in understanding seizure phenome-ology, exploring aetiology and identifying clinicaliomarkers. This article provides an initial overviewf magnetoencephalography, a review of publishedEG studies on IFE, and a discussion of recent MEGethodological developments and potential future

ontributions.

agnetoencephalography

ackground

64

EG detects the minute changes in the magnetic fieldust outside the head that are generated by coherentlectrical currents within the brain. EEG detects thehanges in electrical potential between scalp elec-rodes generated by the same electrical currents in therain that generate the MEG field. Until the 1990s, onlysingle sensor, or arrays with few sensors covering

tel(csa

nly part of the head, were available. This understan-ably limited the utility of MEG as a diagnostic tool.odern MEG scanners have 300 to 400 channels, arran-

ed in a helmet-like liquid helium dewar, allowingimultaneous whole-head recordings.

ource localisationnumber of methods are available to model the

enerators of EEG and MEG. The single and mul-iple equivalent current dipole (ECD) are models thatpproximate the electrical current generators to oner more point source(s). The single ECD model haseen most commonly used in localising putative epi-

eptic spike sources in epilepsy. A different methodf source localisation uses beamformer techniques.ere, the pattern of sensitivity of each sensor and the

tatistical properties of the signal are used to producespatial filter that extracts an estimate of the signal

rom given points in the brain based on the signal of allensors. A number of beamformer methods exist, theommonest used in MEG is Synthetic Aperture Magne-ometry or SAM (Vrba and Robinson, 2001). SAM cane used to extract the source time course from oner more specified locations. A further adaption of theAM, known as SAMg2, identifies excess kurtosis thatan be generated by the sharp waveform of epilepticpikes (Robinson et al., 2004).AM is part of a wide range of methods that relyn the linearity of the forward problem to reduceource analysis to a matrix inversion operation (e.g.sing the spatial filter in the case of SAM) (figure 2).or different reasons, the ECD and linear methodsan work well when one, or few focal generatorsominate the signal, or some property of the source

sparse nature, distinct oscillatory or spiky pattern)an provide an additional handle that can be incor-orated as a constraint within the linear framework.

n other cases, the source reconstruction problemequires a non-linear approach with magnetic fieldomography (MFT), with optimal properties for tomo-raphic analysis (Taylor et al., 1999). A non-linearpproach to the inverse problem is computationallyntensive and has so far not been widely applied topilepsy.

agnetoencephalography and IFEtudies have focused on spike localisation, theirelationship to clinical features, and more recently


ime-frequency analyses of oscillatory rhythms. In anarly MEG study on five patients, the spike ECDs were

ocalised to the same area as lower lip stimulationMinami et al., 1996). Subsequently, a study of sevenases reported spikes with an anterior positivity in theuperior Rolandic (hand motor) region in four patientsnd in the inferior Rolandic (oromotor) region in three


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pike and lower trace, V1, and the virtual sensor electrode fromhe synthetic aperture magnetometer (SAM) image overlaid onhowing the location in the inferior and anterior bank of the cen

atients (Kamada et al., 1998). The spike locationsere related to seizure semiology, with orofacial sei-

ure manifestations in patients with inferior Rolandicpikes and hand manifestations in those with super-or Rolandic spikes. Increased fast wave activity waseported in five patients with neuropsychological defi-its (Kamada et al., 1998). In one case study, unilateralpikes localised to the bilateral operculum (Morikawa,000). Combining EEG/MEG source localisation andMRI of tongue movements localised IEDs to the loweromatosensory cortex with co-located tongue move-ent fMRI activation (van der Meij et al., 2001).

ater studies using whole head MEG localised IEDs 10-0 mm anterior and lateral to the hand somatosensoryortex (with concurrent median nerve stimulation) (Lint al., 2003a). Dipole analysis of bilateral dischargeshowed two ECD sources in homotopic motor areasLin et al., 2003b). A single ECD accounted for most ofhe unilateral spikes in a pre-central location and over8% of spikes were seen simultaneously on EEG andEG, suggesting a stable tangential dipole source. For

ilateral IED, the temporal difference between bilate-al foci was 15-21 ms (Lin et al., 2003a). The same grouporrelated the location of IED sources with sensory res-


onses (Lin et al., 2003b), finding IED sources closero S2 than S1. Further analysis in the time frequencyomain using Morlet Wavelets showed power increase

n the 0.5 to 40-Hz range on the side of the spike (mostrominent in the alpha band) and increase in the rangef 0.5 to 25 Hz on the other homologous area of thether hemisphere (Lin et al., 2006).

awtdtts

SAMg2 algorithm. (C) Flux potential and dipole illustration. (D)e partially inflated 3D render of the structural MRI brain scan,ulcus. (E) The equivalent current dipole.

study using the spatiotemporal multiple signal clas-ification (MUSIC) analysis in five cases found thatsingle dipolar source was sufficient to account for

he spiking activity in two cases, whereas in threeases, complex sources were resolved that started inhe more superior areas (finger/hand) and propaga-ed along the precentral sulcus to the mouth/tonguerea (Huiskamp et al., 2004). Based on a modest, butevertheless larger series, in a study of 15 patients withenign epilepsy of childhood with centro-temporalpikes (BECTS), three main types of spikes accordingo ECD analysis were identified:

superiorly oriented spike MEG dipoles in the oper-ular area;

anteriorly oriented spike dipoles in the Rolandicrea;laterally oriented spike dipoles in the interhemisphe-

ic area (Ishitobi et al., 2005).n perhaps the most detailed descriptive study ofECTS IED to date, using data from 17 patients,ataraia et al. (2008) found spikes on the right inix, left in nine, and bilateral in two. Examination ofsopotential and isofield maps over 250 ms beforend after the maximum negative peak of the spike

265

nd using a PCA (Principal component analysis), asell as spatio-temporal dipole modelling, suggested

hat spikes were generated by a single tangentialipolar source located in the precentral gyrus, with

he positive pole directed frontally and the nega-ive pole directed centro-temporally. The dipole wastable over the entire (500-ms) time window analysed,


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ith no differences in spike location or orientationver time.

correlation between cognitive deficits and spikeocation is described in 20 children with IFE whosecores on language tests decreased in the setting of lefterisylvian spikes, and whose information processingas impaired in the setting of occipital spikes (Wolfft al., 2005). No relationship between spike rate andsychological deficits was found (Wolff et al., 2005).ne publication reports MEG findings in Panayioto-

oulos syndrome (PS) (Kanazawa et al., 2005). Thirteenatients were studied with ECD analysis. Dipoles were

ocalised along the parieto-occipital or calcarine sulcusn 11 of 13 patients and in the Rolandic area in two withtypical PS and Rolandic IEDs (Kanazawa et al., 2005).

few MEG studies have been reported on Landau-leffner syndrome (LKS) or CSWS, typically inonjunction with pre-surgical evaluation for multipleub-pial transection. A study of four children withKS found that the earliest spike activity originated inhe intrasylvian cortex, spreading to contralateral syl-ian cortex over 20 ms in one patient (Paetau et al.,999). Secondary spikes occurred within 10-60 ms inpsilateral perisylvian, temporo-occipital, and parieto-ccipital areas (Paetau et al., 1999). Others have alsoeported more widespread spikes in LKS. In a studyxamining 19 patients, 13 had perisylvian MEG spikes,0 had bilateral, three unilateral spike populations, andour also had non-sylvian spikes in frontal or parietalreas (Sobel et al., 2000). In a larger cohort of 28 patientsith LKS, 80% had bilateral epileptic discharges gene-

ated in the auditory and language-related perisylvianortex, and approximately 20% had a unilateral per-sylvian spike pacemaker that triggered secondaryilateral synchrony (Paetau, 2009). Based on an analysisf MEG alongside FDG positron emission tomography

PET) findings in six children with CSWS, spike-wavenset was shown to correspond to areas of PET hyper-etabolism during wakefulness. This occurred in the

uperior temporal gyrus in LKS and centro-parietalegions in atypical Rolandic epilepsy. Areas of spikeropagation predominantly showed PET hypermeta-olism (De Tiege et al., 2013).

iscussion

he analysis of MEG data described above shows thathe ECD model produces plausible descriptions ofhe spike generators in IFEs, typically with a stable

66

ipolar source. Some but not all studies success-ully attempt to correlate spike source localisationith phenotypic features. MEG is an expensive tech-ology, which does not easily lend itself to longecordings. There are, therefore, many more EEG stu-ies in IFE that are covered elsewhere. Skull resistancend the sensitivity of the EEG to the conductivity

dfstwo(

rofile between the generators and electrodes intro-uce a blurring of the signal not seen in MEG. Untilecently, most EEG studies have been limited to des-riptions of signal semiology rather than descriptionsf generators. A recent cross-sectional study of PS inhich 76 children were followed for over two years

Ohtsu et al., 2003) found that EEG foci frequentlyhift in location, multiply, and propagate diffusely overime, rather than remaining persistently localised tohe occipital region. These changes in foci at theignal level cannot guarantee that there are equivalenthanges in spike generators. It could be, for example,hat the activity of dominant focal generators sub-ides and makes way for other generators to becomerominent.

f a single or fixed number of ECDs are postulated,hen the appropriate fixed single foci will be identified.nder these circumstances the modelling is judged

o be successful if the solutions are plausible and theata fit well. This seems to be the case for Rolandicpikes. However, MUSIC analysis demonstrates thatt least in some cases, a succession of generators isnvolved, even for Rolandic spikes (Huiskamp et al.,004). It might then appear that the results changeepending on which method is used. In reality, eachodel has both limitations and the flexibility to allow

or useful generalisations. For example, by allowingultiple and independent ECD solutions (for data

rom different times, periods, or subjects), the ECDodel can provide a distribution of solutions rather

han a single location, as was modelled in a compari-on of 10 children with PS and 10 with other types ofpilepsy (Yoshinaga et al., 2006).ur view of the relationship between MEG techno-

ogy and epilepsy is slowly changing. Even in the casesn which a single focal generator dominates, the restf the brain cannot be ignored. Discharges need to bexplained not just in terms of changes within a localrea, but as variations within a network (Richardson,012). To operate in this new framework, the ECD muste replaced by models that allow activity in differentrain areas to be identified at different times and thensed to delineate a network. SAM analysis offers dis-

inct advantages while maintaining the computationalimplicity of linear methods (Vrba and Robinson, 2001;obinson et al., 2004). The use of distributed sourcenalysis is slowly gaining ground both for MEG (Grovat al., 2008) and multichannel EEG (Dai et al., 2012)nalysis. It is even beginning to look possible that syn-


rome classification and some common aetiologiesor epilepsy may be derived from source space analy-is and subsequent network descriptions, especially ifhese descriptions allow for dynamically changing net-orks, which have so far been used for the descriptionf network properties evoked by well-defined stimuli

Ioannides et al., 2012).


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anguage impairment and idiopathicocal epilepsies

nne de Saint-Martin and Caroline Seegmuller

hen they described “mid temporal epilepsy” in 1954,ibbs and Gibbs made specific reference to speech

mpairment in those children: “Non ictal speech dis-urbances are commoner in those patients; they may

anifest themselves as attacks of speechlessness orphasia, or as failure to learn to talk” (Gibbs et al., 1954).ince then, a large amount of literature has been publi-hed about the cognitive, and more specifically, verbaleficits observed in “benign” epilepsy with centro-

emporal spikes, or Rolandic epilepsy (BECTS/RE).ifferent mechanisms have been hypothesized about

he interaction between language development andhis age-related epilepsy with a perisylvian epilepto-enic zone.e reviewed the variety of speech and language

mpairments encountered in different types of Rolan-ic epilepsy. Indeed, the clinician may observe tran-ient, acquired speech or language alterations in aty-ical or active forms of Rolandic epilepsy, more prolon-ed impairment of “high-level language” acquisition inypical forms, or, rarely, permanent severe speech dys-raxia associated with atypical forms. We also makeeference to the association of centro-temporal spikesuring sleep and specific language impairment.

ransient acquired speech or language impairmentn atypical or active RE

ome children with atypical Rolandic epilepsy, oractive” Rolandic epilepsy with strong activation ofpike and waves (SW) during sleep, may experienceransient oromotor symptoms, such as perioral myo-lonia (“spike-and-wave symptoms”), or oromotorypotonia with drooling, slurred speech or dys-rthria, mimicking sometimes a “pseudo-opercularyndrome”. These symptoms often fluctuate and mayesolve after sleep EEG normalization (Deonna et al.,993). A longitudinal case study correlated these symp-oms with the amount of bilateral SW during sleep,ith a prominent opercular SW focus (de Saint-Martint al., 1999). Some of these atypical forms may evolveo an epileptic encephalopathy with continuous spikend waves (ECSWS or ESES), and more permanent


ymptoms.he semiology of this acquired motor or expressive

anguage impairment is completely different fromoth the acquired auditory and verbal agnosia and

he receptive aphasia observed in Landau-Kleffner syn-rome, associated with bitemporal continuous SWctivity during sleep. Their mechanism, however, may

aMsrfiR


e similar. The various acquired verbal deficits appearo be directly correlated to the location and the inten-ity of the epileptic focus, during wakefulness andleep, with a strong focal bilateral cortical inhibitionlocated in different language areas). Metabolic brainmaging performed during the active period of the epi-epsy showed a marked focal hypermetabolism within

surrounding wide area of hypometabolism, sugges-ing a “remote inhibition” in distant cortical areasMaquet et al., 1995, De Tiege et al., 2008). Urgent treat-

ent modifications are often necessary to reduce thetrong epileptic activation during sleep, in order toeverse acquired clinical symptoms.

requent “high-level language”mpairment in typical RE

eterogeneous cognitive deficits have been descri-ed since the 1990s in typical Rolandic epilepsy (RE),ffecting both non-verbal cognitive functions (visual,xecutive, fine motor execution, attention, memory,nd speed processing), and verbal functions duringhe active phase of the epilepsy (Weglage et al., 1997;

etz-Lutz et al., 1999). These are associated with a highrequency of learning disorders (10 to 40%) and acade-

ic underachievement (Pinton et al., 2006; Piccinelli etl., 2008; Smith et al., 2015).any studies have focused on oral and written

anguage skills and compared the performances offfected children to those of controls during the activehase, or after remission of the epilepsy. A languageelay is more frequent in atypical RE versus typical

orms. Typical RE children may have mild phonemic,emantic, auditory-verbal or lexical comprehensioneficits revealed by accurate testing. These verbaleficits may impact reading, spelling, and learning,hich are often impaired during the active phase of

he epilepsy (Staden et al., 1998; Carlsson et al., 2000;onjauze et al., 2005; Northcott et al., 2007; Riva et al.,

007). They may also impact verbal knowledge and ver-al reasoning or learning strategies. It is important toecall, however, that other cognitive deficits may inter-ere with language development and literacy learning,ncluding deficits in executive function, short-term andong term verbal memory and attention, as well asariable degrees of hyperactivity, which is also fre-uently encountered in RE children during the activehase of the epilepsy (Chevalier et al., 2000; Metz-Lutz

267

nd Filippini, 2006; Verrotti et al., 2014).ost of these studies are cross-sectional comparative

tudies and may not accurately capture the hete-ogeneity of these children, as some of them mayunction very well, and there is variability regardingndividual cognitive evolution (Deonna et al., 2000;iva et al., 2007). Moreover, in some children, specific


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omorbid language learning disorders, specific lan-uage impairment (SLI), or dyslexia may precede thepilepsy.

olandic epilepsy, language network,nterictal discharges and sleep

he question of the direct consequence of the perisyl-ian epileptic activity on language development, or theresence of an underlying common disorder of brainaturation remains unresolved.roup studies show that a correlation between the

ype of cognitive deficits and the hemispheric locationf the EEG is not self-evident (Nicolai et al., 2006; Riva etl., 2007). A recent comprehensive review performedy Overvliet emphasized the relationship between

he intensity of cognitive deficits and the abun-ance of nocturnal epileptiform discharges (Overvliett al., 2010).vidence from behavioural investigations suggests ansymmetric response to dichotic listening in childrenith Rolandic epilepsy, correlated to the location of thepileptic focus (Metz-Lutz et al., 1999; Bulgheroni etl., 2008). Indeed, some authors hypothesized that thepileptic activity could “remodel” the language net-ork. Small samples of functional imaging data shed

ome light on this hypothesis. fMRI analyses revealedhat language-related activation was less lateralised tohe left hemisphere in anterior brain regions in theE patients, relative to the control group. This findingas consistent with decreased performance in the REroup compared to the control group on the neuro-sychological measure of neuroanatomically anteriorspects of the language axis, namely, sentence produc-ion (Lillywhite et al., 2009).

ore recently, a study demonstrated that the func-ional connectivity between the resting-state networknvolving the Rolandic regions and the left inferiorrontal gyrus (Broca’s area) was reduced in RE. Thisunctional decoupling might be a clue to understandanguage impairment in typical RE and is in line withhe identified neuropsychological profile of anterioranguage dysfunction (Besseling et al., 2013b).ecently, a deficit of declarative memory consolida-

ion in a few RE and ESES patients was documentedUrbain et al., 2011). In children with RE, non-REM sleepnterictal epileptiform discharges (IED) may interfere

68

n the dialogue between the temporal and frontal cor-ex, causing declarative memory deficits. The role ofon-REM sleep interictal discharges acquires a special

mportance, due to their possible alteration of sleepomeostasis (Chevalier et al., 2000; Bolsterli et al., 2011).his could impact academic learning, notably high-

evel language and other cognitive acquisitions, duringhe epilepsy.

oqdspand

peech dyspraxia and Rolandic epilepsy:genetic comorbidity?

n the last few decades, there have been descriptionsf both families and sporadic cases of atypical Rolan-ic epilepsy with co-occurrence of permanent severe

anguage impairment (Scheffer et al., 1995; Kuglert al., 2008). In these families, different phenotypesere observed, from severe speech dyspraxia with

ognitive impairment, to expressive dysphasia or evenore mild language impairments. Some individuals

xperienced a worsening of impairments during thective phase of the epilepsy (Lesca et al., 2013). In013, the results of three large genetic studies wereublished confirming the presence, in some cases,f a mutation in the GRIN2A gene, which encodesn NMDA receptor subunit; the cerebral expressionf this gene is age related (Carvill et al., 2013; Lemket al., 2013b; Lesca et al., 2013). To better understandhe role of this gene, more accurate descriptions ofhe clinical and neurophysiological phenotypes of theatients are being undertaken. Speech dyspraxia haslso been demonstrated among typical children withE, and the genetic locus for speech dyspraxia coin-ides with that for centro-temporal spikes on 11p13Pal et al., 2010).

pecific language impairment and Rolandic spikes

everal authors have reported a higher incidencef nocturnal epileptiform EEG discharges in childrenith specific language impairment (SLI). Duvelleroy-ommet described centro-temporal spike and waves

SW) on sleep EEGs in 24.3% of children with expres-ive SLI, as compared with 5.1% of children in a controlroup (Duvelleroy-Hommet et al., 1995). Several stu-ies have been performed showing between 14% and0% interictal discharges during sleep in children withpecific language impairment (Overvliet et al., 2010).he benefit of antiepileptic drug treatment remainsuestionable, unless an intense sleep SW activation orn acquired regression has been documented (Picardt al., 1998; Billard et al., 2010).

onclusion

ifferent types of speech and language impairmentsre observed in children with BECTS or RE. Somef these deficits are subtle, without any daily conse-


uence; others can be severe and impact literacyevelopment and verbal reasoning. In these children,pecific developmental rehabilitation, and sometimesharmacological adjustments are needed during thective phase of the epilepsy. Regular cognitive scree-ing and environmental information are necessaryuring the follow-up of those children to reduce


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cademic or later social consequences. Differentechanisms undergird speech and language impair-ents, from comorbidities with a probable genetic

ubstrate to direct consequences of the focal per-sylvian epileptiform activity during sleep. Furtheresearch in genetics or on the consequences of dis-upted sleep may enhance our understanding.

o-occurring difficulties in Rolandicpilepsy: a focus upon attention

nna B Smith

n Rolandic epilepsy (RE), seizures and focal interic-al epileptiform discharges are in remission during orefore adolescence. This syndrome is often coupledith deficits in literacy (Croona et al., 1999; Lindgrent al., 2004; Lundberg et al., 2005; Monjauze et al., 2005;apavasiliou et al., 2005; Northcott et al., 2007; Stadent al., 2007; Ay et al., 2009; Clarke et al., 2009; Tedrust al., 2009; Goldberg-Stern et al., 2010; Smith et al.,012), language (Baglietto et al., 2001; Monjauze etl., 2005; Riva et al., 2007; Volkl-Kernstock et al., 2009;errotti et al., 2010), and attention (Giordani et al., 2006;eltour et al., 2007; Kavros et al., 2008a; Cerminarat al., 2010). The disorder is described as benign, butased upon the time course of childhood reading dif-culties (Catts et al., 2002) and attentional impairments

Spira and Fischel, 2005) in other patient populations,europsychological impairments may persist into later

ife. The following account focuses on the difficul-ies that children with RE experience in attention andow they might be linked with co-occurring literacy

mpairments.ttentional processes are complex but can be broadlyivided into approximately two categories. The firstf these entails orienting to and detecting target sti-uli amongst non-targets. Top down processing of

argets is most commonly measured, where a responses required to a predefined target embedded within

stream of non-targets, typically using a continuouserformance task (CPT) or a cancellation task (CT).ther most commonly utilised attention tasks involvecomponent of inhibition. Several tasks are available

o measure subtle differences within executive func-ion (EF), including: the stop task, in which a pre-potent


esponse to “go” must be inhibited in response toare “stop” signals which follow very closely behindhese “go” signals; the stroop task, in which a frequent,ongruent response must be suppressed in favour ofn infrequent, incongruent one; the go/no-go task,n which a pre-potent signal to respond is intersper-ed with infrequent “no-go” signals; and switching or

cad(nrc


hifting tasks, such as the Wisconsin Card Sortingask, in which response rules are periodically chan-ed throughout the task, requiring cognitive flexibilitynd a shift in engagement. Overarching most aspectsf these EFs is the ability to sustain attention over arolonged period (for more details of these tasks seeubia et al. [2007]).systematic review of attention in children with RE

Kavros et al., 2008b) brings together 14 studies ofttention to examine the nature of the problem inhis specific patient population. The majority of stu-ies reviewed used either target detection tasks or

asks of inhibition, such as those outlined above, andound deficits where both of these kinds of tasks weresed. More recent studies of attention in children withE have added to this evidence (Giordani et al., 2006;eltour et al., 2007; Cerminara et al., 2010).ur team has been exploring attention in children with

E and we present here some recent data from our lab.e have access to a large sample of children with RE

nd we have shown firstly that 20% of them have symp-oms of ADHD, which is significantly greater than rateseen in the general population (Hernández-Vega et al.,014). Although it has been pointed out that a distinc-ion should be made between a diagnosis of ADHD andhe presence of attentional impairments (Cerminarat al., 2010), it is clear that one of the hallmarks ofhildren with ADHD is the presence of attentionaleficits and furthermore, neurofunctional abnormali-

ies during tasks of inhibition and attention have beenound in this patient group (Smith et al., 2006, Smith etl., 2008) which correspond with attentional networks,articularly fronto-cingulate regions (Fan et al., 2005).econdly, in a study of the cognitive deficits seen inamilies with children with RE, we were able to confirmhe findings from the systematic review that childrenith RE have deficits in target detection as measuredy the CPT, and also that these deficits are present in

heir siblings unaffected by RE. This latter finding sug-ests that attentional difficulties are not explained byhe presence of the seizures or spikes associated withE. Instead, their presence in siblings unaffected by REay be due to susceptibility factors shared between

ttentional deficits and RE.e also wanted to know whether these attentional

eficits were related to reading difficulties in ourample of 23 children with RE and their siblings.lthough it is now well established that phonologi-al processing is a strong predictor of reading success

269

nd that deficits in this domain explain the readingifficulties experienced by individuals with dyslexia

Snowling, 1995; Carroll and Snowling, 2004), attentio-al processes are likely to have an important role ineading. In typical readers, 10% of the variance asso-iated with reading comprehension was explained by


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ttentional control, and was shown to be as impor-ant as phonological processing in predicting readingConners, 2009). However, the task used to measurettentional control in that study was a complex trackingask involving several automatic, as well as effortful,unctions and, as such, not a pure measure of attention.urther analysis of our data (unpublished) shows thatommission errors on our purer measure of atten-ion (the CPT) correlate significantly with all literacy

easures of the Gray Oral Reading Test, including rea-ing rate (r=0.63; p=0.002), accuracy (r=0.52; p=0.02),uency (r=0.66; p=0.001), and comprehension (r=0.58;=0.006). These correlations suggest that in this albeitmall sample of children with RE and their siblings,ttention accounted for approximately one third of theariance associated with performance. The implicationf these findings is that reading difficulties in childrenith RE may be underpinned by attentional deficits,hich warrants further investigation.

urthermore, given this strong association with atten-ion and reading comprehension, it is possible thatttentional training may have benefits for this patientroup. This has not been extensively explored butvidence exists that attentional training can enhanceeveral aspects of attentional function and behaviourn children with ADHD (Shalev et al., 2007; Beck et al.,010) and furthermore, has been shown to improveiteracy in this patient group (Shalev et al., 2007).n the light of these findings by our own team andthers, a future goal should be to establish a com-rehensive understanding of the neuropsychologicaleficits observed in children with RE with a largeample size. While attentional deficits are clearlyresent, the evidence remains less clear about lite-acy problems and whether attention is as importants phonological processing in predicting these diffi-ulties. If this is the case, this population of childrenith RE may constitute a separate sub-group of poor

eaders.

sychosocial aspects, parental reactionsnd needs in idiopathic focal epilepsies

halia Valeta

ur study aimed to document the psychosocial

70

spects of, parental reactions to, and needs associatedith idiopathic focal epilepsies (IFEs). The psychoso-

ial effects of IFE on parents, their reactions, and needs,ere assessed using a questionnaire that I specificallyesigned for this purpose. Out of 100 parents of chil-ren with epilepsy who completed the questionnaires,2 were parents of children with IFE (Rolandic epilepsy,

Tdmpatl

anayiotopoulos syndrome, and late-onset childhoodccipital epilepsy of Gastaut). The questionnaire hasood internal consistency. Parents of children withFE expressed significant panic, fear, anxiety, shock,error, and thoughts about death. Their sleep and qua-ity of work were affected. The behaviour of half ofhe parents towards their children changed. Most ofhe parents expressed the need for education on epi-epsies and psychological support for the child andhemselves. They also expressed the need to parti-ipate in groups of parents with the same problem.his study is the first to provide detailed evidencehat, despite the fact that IFE has an excellent prog-osis, parental reactions are severe and their needsre significant and unmet. Completing the specificallyesigned questionnaire has given the parents space

o reflect on their experience and express their fee-ings. The results inform physicians and consequentlyelp to improve prevention and treatment outcome.he results of this study indicate that there is a needor family management, education, and psychologicalupport for parents of children with IFE.he psychosocial impact of epilepsy on affectedhildren and their families is manifold with nume-ous and often synergistically interacting medical,sychological, economic, educational, personal, andocial repercussions (Camfield, 2007; Valeta et al.,008; Valeta, 2010). The adjustment and other pro-lems experienced by children with epilepsy and theirarents have always been of concern to clinicians andealthcare providers. Understandably, attention andesearch has been primarily focused on severe epilep-ies because of profound challenges in dealing withrequent and severe seizures, an endless quest foreizure control, and additional physical, social, andsychological problems.ompared to other forms of epilepsy, the burden pla-ed on the parents of children with IFEs, also knowns benign childhood focal epilepsies (Panayiotopoulost al., 2008), has not been emphasized because ofhe comparative ease with which IFEs are medically

anaged and their comparatively better prognoses.evertheless, psychological research over the lastecade (Valeta, 2005, 2011, 2012) has suggested that inhildren with IFE, parental attitudes and reactions areften severe and contrast with the physician’s percep-

ion of these epilepsies as uncomplicated and benignonditions.he purpose of this report is to show evidence that,


espite their excellent prognosis, IFE represent a dra-atic experience for the patients and the parents. The

arents have significant and unmet needs that mayffect the quality of their life, their parental role, andherefore the functioning of their children and the qua-ity of life of the whole family.


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ethods

y personal interest started in 2000, when talkingxtensively to parents of children with IFE; I was tou-hed, impressed, and inspired by their experiences. Iealised that they were concerned about many moressues other than the seizures themselves and thosehat they were able to discuss with their physician.onsequently, I designed a questionnaire in order to:identify the parents’ reactions and needs;identify the parents’ feelings during and after the

eizure;examine the relationship between the parents and

heir children after the event;examine how the event has affected their family;and identify its impact on the child’s health, deve-

opment, and future.he initial questionnaire with the response of 15arents of children with IFE in St. Thomas’ Hospitalas published in 2005 (Valeta, 2005).ubsequently, in 2008, I initiated a study on parentaleactions and needs of children with epilepsy in gene-al. I modified and translated the questionnaire intoreek. The questionnaire, named “Valeta Thalia Ques-

ionnaire for Parents of children with Epilepsy©”1, haseen validated and consists of 34 questions, of which8 are qualitative and 16 quantitative. The question-aire covers the following themes:

parents’ and children’s demographic and clinicalata;parental attitude, reaction and feelings during and

fter the seizures;parental experience to the medical examination;impact of seizures on parent-child relationship;impact of seizures on the family;parental reactions and attitude outside the family;parental reactions and attitude to antiepileptic drugs;parental needs other than medical.

arents were recruited from the clinical practice athe department of Child Neurology, Agia Sophia Chil-ren’s Hospital in Athens. Children with epilepsyere classified according to the ILAE classifications

Berg et al., 2010). Out of 100 parents of childrenith epilepsy who completed the questionnaire, 22ere parents of children with IFE, comprising Rolandic


pilepsy, Panayiotopoulos syndrome, and late-onsethildhood occipital epilepsy of Gastaut.or analysis of the open-ended questions, descriptivetatistics were used (e.g. means, standard deviation,requency, and % cumulative frequency). Data fromhe qualitative questions were processed via content

Researchers who would like to use “Valeta Th. Questionnaireor Parents with Children with Epilepsy©”, please contact theuthor at: [email protected]

dNDarrvecFe


nalysis methods. The parents’ answers (raw data)ere summarised in higher order themes in order

o provide, in a more parsimonious manner, thearticipants’ behaviour, reaction, and feelings, before,uring and after a seizure. Reliability and internalonsistency were 0.73 as measured using Cronbach’slpha, with inter-item correlations of 0.379, and cor-ected item total correlations of 0.355. The participantsere given the opportunity to provide more thanne answer in order to portray their experiences andxpress their feelings.

esults

he responses of the parents of children with IFE to theuestionnaire provide interesting material on socialnd psychological issues. One quarter of parents reac-ed to their children’s seizures in ways that are not

edically recommended, or are potentially harmful,uch as putting a spoon into the child’s mouth, givinghe child a bath, or lifting the child from the floor.o protect their children from social stigma or fromullying at school, parents discussed seizures with

he child involved and the extended family more thanith friends or the child’s school. Half of the parents

aid that their behaviour towards the child had chan-ed. They described becoming overprotective and lessemanding in school performance. Some parent-childelationships became closer and some did not change.he following results from six representative questions

llustrate the parental reactions and feelings duringnd after seizures, the effect that seizures have on eve-yday life and, finally, the parental needs of childrenith IFE. All the percentages are based on the ans-ers/responses of the parents and not on the numberf parents/participants.Feelings of parents during the seizure:egative feelings: fear, panic, terror: 37.5%; bad: 15.6%;

nxiety: 9.4%; insecurity: 28.1%; guilt: 3.1%; thoughtsbout death: 6.3%; calm: 3.1%; denial: 3.1%. For thisuestion, the results were dramatic because the fee-

ings of nearly all the parents during the seizure wereegative.Feelings of parents after the seizure:egative feelings: panic, fear, terror: 34%; anxiety: 31%;isappointment: 31.8%. Positive feelings: joy: 45%.eutral feelings: secure under the doctor’s care: 9.1%.enial was expressed by 9.1%. For this question, panic,

nxiety, and disappointment dominated. Some expe-

271

ienced joy and relief. The high percentage of joy andelief was due to the attack ending and the child reco-ering. During and after the event, we noticed parentsxpressing denial about a problem, which may haveome from extreme fear.igure 3 shows the results for the question: “has thevent influenced you in the following areas?” Figure 4

mailto:[email protected]


2

D.K. Pal, et al.

Yes54.2%

60

50

40

20

10

30

0

50.0%

Fear Sleep

16.7%20.8%

Appetite Work

Figure 3. Results for the question: “has the event influenced youin the following areas?”

Yes

25.0%

16.7%

37.5%40

30

20

10

0

Fy

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Yes75%

No25%

Figure 5. Results for the question: “do you need help other thanmedical?”

54.2%

Psychological Psychological Education on Parents groups

45.8%

66.7%

Yes

45.8%

70

60

50

40

30

20

10

0

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YearsWeeks Months

igure 4. Results for the question: “how long has this lasted?ears, months, weeks”

hows the results for the question: “how long hashis lasted? years, months, weeks?” The event affectedarents mostly in that they were scared, and their sleepnd quality of work was affected (figure 3), mostly foronths, but for some years and others weeks (figure 4).

igure 5 shows the results for the question: “do youeed help other than medical?” Figure 6 shows theesults for the question: “do you need help in any ofhe following areas?”he parents need help other than medical attentionfigure 5), more specifically, education on epilepsies,sychological support for the child, parental supportnd advocacy groups, and psychological support forhemselves (figure 6).

72

iscussion

his is the first study to provide quantitative andualitative evidence that IFE has a dramatic impactn parents, with multiple emotional, psychological,

Itp–tsp

support forthe child

support forthe parents

epilepsies with the sameproblem

igure 6. Results for the question: “do you need help in any ofhe following areas?”

ocial, and medical ramifications. As the results of thistudy show, this impact is much more severe than oneould expect from a benign and self-limited condition.nmet negative feelings of panic, fear, and thoughts

bout death, as mentioned in the results section, mayffect the parents’ reactions and attitude and conse-uently their parental role, the functioning of theirhildren, and the quality of life of the whole family.hus, it is crucial that parents are given sufficient timend opportunity to discuss their concerns with specia-ists.suggest that health care professionals working withhildren who have IFE consider the following:Parents should be given general information about


FE and training to remain calm and confident aboutheir children’s condition. Demonstrations of first aidractices for seizures are necessary.

Educating parents about epilepsies and differentypes of seizure will help to alleviate the social stigmaurrounding these conditions, which parents oftenass on to their children.


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Parents who have watched their child during aeizure need specific information and psychologicalupport to overcome anxiety, fear, panic, and otheregative feelings, as detailed in the results of my study.his should be properly addressed from the time ofrst diagnosis, in order to improve the quality of life of

he child and family.Anxiety and fear may result in overprotection, which

nterferes with parent/child separation and indepen-ence. Psychological support will help parents andatients, with coping techniques to manage stress,nger, anxiety or self-esteem. It can moderate paren-al perceptions of the child’s illness and the maritaltrain related to the child’s rearing, thus contribute toffective parenting.hope that the results of my study will assist the patientnd parents, inform the physician, and, consequently,elp to improve the treatment outcome.

ecent progress in the genetics ofidiopathic” childhood focal epilepsies

aetan Lesca, Gabrielle Rudolf, Pierre Szepetowski

o-called “idiopathic”, focal epilepsies of child-ood are age-related epilepsy syndromes that mainlyccur during critical developmental periods. Benignhildhood epilepsy with centro-temporal spikes, orolandic epilepsy (BECTS/RE), is the most frequent

orm of childhood idiopathic focal epilepsies (IFEs).ogether with the Landau-Kleffner syndrome (alsonown as “acquired” epilepsy-aphasia) and theyndrome of continuous spike-and-waves duringlow-wave sleep, RE exists on a single and continuouspilepsy-aphasia spectrum of childhood epilepticisorders with associated speech and language defi-its. The pathophysiology has long been attributed tocomplex interplay between brain development andaturation processes on the one hand and suscepti-

ility genes on the other. Studies based on variableombinations of molecular cytogenetics, Sanger andext-generation DNA sequencing tools, and functio-al assays have led to the identification and validationf simple genetic mutations that can directly causearious types of childhood IFEs with variable degree ofeverity. The recent identification of GRIN2A defectsn the epilepsy-aphasia spectrum represents a first


tep and makes significant progress in understandingnderlying pathophysiological mechanisms.hile the relationships between RE and various

omorbid conditions (e.g. migraine, cognitive andehavioural issues, or reading impairment) haveecently been increasingly recognised, the associationith transient or permanent speech and/or language

edoRmtr


mpairment has actually long been reported, includinghe identification of the genetic syndrome of RE witherbal dyspraxia (Scheffer et al., 1995; Kugler et al.,008). The continuous spike-and-waves during slow-ave sleep syndrome (CSWS) and the Landau-Kleffner

yndrome (LKS), also known as “acquired” epilepticphasia, are two closely related epileptic encepha-opathies (EEs) that represent more severe and lessrequent forms of the IFE continuum. Indeed, each ofhese syndromes is now considered a different clinicalxpression of the same pathological spectrum (Rudolft al., 2009), which share the association of typically

nfrequent seizures with paroxysmal EEG dischargesctivated during drowsiness and sleep, and with morer less severe neuropsychological deficits.

more modern view that takes into account theecent advances in determining the genetic origin ofarious types of epilepsies has recently challengedhe classic distinction between idiopathic and symp-omatic epilepsies (Berg et al., 2010). For instance, itas unexpectedly demonstrated that EEs of various

ypes, such as Dravet or Ohtahara syndromes, canave simple, monogenic causes (Depienne et al., 2012;pi4K Consortium et al., 2013); conversely, epilepsiesf genetic origin (formerly considered as idiopathic)an be associated with comorbid neurological condi-ions (e.g. migraine, behavioural or cognitive issues)r with structural lesions (e.g. cortical dysplasia). In

he IFE, the possible existence of behavioural andognitive issues, for instance, inherently challengedhe use of the “idiopathic” term. It had long beenssumed that in contrast to generalised epilepsies,ost focal epilepsies are caused by lesions, infec-

ions, tumours, etc., and are under hardly any geneticnfluence. Twin studies and familial concurrences thenndicated that focal epilepsies can also be sustainedy genetic factors (Ryan, 1995). As an example, theapping and the subsequent identification of the

rst “idiopathic epilepsy” gene (CHRNA4) encodingnicotinic acetylcholine receptor subunit was obtai-ed in autosomal dominant nocturnal frontal lobepilepsy (ADNFLE) (Steinlein et al., 1995; Berkovic etl., 2006). Since then, several genes responsible forhis and for other types of focal epilepsies have beendentified.amilial aggregation has long been recognised in RENeubauer et al., 1998). Relatives of RE patients display

higher risk of epilepsy (notably RE, LKS or CSWS)han control individuals (De Tiege et al., 2006; Vearst al., 2012; Dimassi et al., 2014). Most RE, however,

273

oes not show simple inheritance. In recent years,ne susceptibility gene for centro-temporal spikes inE, ELP4, was proposed (Strug et al., 2009) and rareutations that might influence RE were identified in

he paralogous RBFOX1 and RBFOX3 neuronal splicingegulators (Lal et al., 2013a).


2

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.K. Pal, et al.

n contrast to RE, the genetic influence in LKS andSWS has long remained controversial (Landau andleffner, 1957; De Tiege et al., 2006; Rudolf et al., 2009)nd a role for autoimmunity was even hypothesizedConnolly et al., 1999; Nieuwenhuis and Nicolai, 2006).ecent advances in molecular cytogenetics and next-eneration DNA sequencing have dramatically helped

n addressing this issue. Consistent with the exis-ence of genomic defects (copy number variations)hat may have possible pathophysiological influence inumerous human disorders including the epilepsies

Helbig et al., 2009; Mefford et al., 2010), the scree-ing of a series of 61 patients with LKS or CSWS led

o an overall picture with highly heterogeneous geno-ic architecture (Lesca et al., 2012). A large number

f potentially pathogenic alterations corresponded toenomic regions or genes (e.g. encoding cell adhe-ion proteins) that were either associated with thepectrum of autism disorders, or involved in speechr language impairment. This was of interest given

he well-known association of LKS and CSWS spec-rum with autistic-like manifestations (e.g. regression,isturbance of social interactions, perseveration) and

anguage disorders. Particularly, the detection of seve-al de novo genomic alterations in sporadic casesointed to the possible role of several genes (Lescat al., 2012), including the NMDA glutamate receptorubunit gene GRIN2A, in LKS and CSWS.ince then, the crucial and direct causal role of deovo or inherited GRIN2A mutations of various types

microdeletions, splice-site, nonsense, and missenseutations) in LKS, CSWS, and RE with verbal dys-

raxia, has been demonstrated in three parallel studiesCarvill et al., 2013; Lemke et al., 2013b; Lesca et al.,013). It appears that up to 20% of disorders in this spec-rum can be caused by simple defects in a single gene.n even more recent genomic study was performedt the milder end of the LKS/CSWS/RE spectrum; in aeries of 47 patients with RE, one GRIN2A microdele-ion and two 16p11.2 microduplications encompassinghe PRRT2 gene were identified (Dimassi et al., 2014).RRT2 was recently shown to be involved in a wideange of paroxysmal neurological disorders, includingnfantile convulsions, paroxysmal dyskinesia (mostlyinesigenic), or hemiplegic migraine, which wereariably associated (Cloarec et al., 2012; Lee et al., 2012).nterestingly, a p.Asn327Ser partial gain-of-lycosylation mutation in the Sushi repeat-containingRPX2 protein had been reported previously in a

74

arge family with RE, verbal dyspraxia, and intellec-ual disability (Roll et al., 2006). The SRPX2 gene isranscriptionally down-regulated by the so-calledspeech gene”, FOXP2 (Roll et al., 2010), mutationsn which can cause verbal dyspraxia (Lai et al., 2001).ince then, it was shown that the p.Asn327Ser SRPX2ominant-negative mutation co-segregated with a

nrecveM

.Ala716Thr GLUN2A (the protein product of theRIN2A gene) missense mutation in most affectedembers of the same family (Lesca et al., 2013).

.Asn327Ser was also detected in a few so-calledontrol individuals according to the Exome Varianterver database (Piton et al., 2013). On the one hand,hose findings clearly challenged the direct causalole of this SRPX2 mutation. On the other hand, theat Srpx2 knock-down in utero was shown to haveramatic consequences on neuronal migration in theeveloping rat cerebral cortex, and led to postnatalpileptiform activity that could be prevented earlyn by maternal administration of tubacin (Salmi etl., 2013). Also, it was recently demonstrated thatrpx2 influences synaptogenesis and vocalization inhe mouse. Overall, SRPX2 mutation might well be

strong genetic risk factor for neurodevelopmentalisorders, including RE with verbal dyspraxia; in fact,splice site SRPX2 mutation was reported in one

atient with autism (Lim et al., 2013). As GRIN2Autations unambiguously cause disorders of the

pilepsy-aphasia spectrum, whether and how theRPX2 and GRIN2A products and related molecularetworks would interfere with each other at theolecular and at the cellular levels at specific deve-

opmental stages emerges as an important questionhat surely deserves future investigations. Togetherith the future identification of other genetic andon-genetic factors involved in the spectrum of IFE,nd of epilepsy-aphasia in particular, this will help innderstanding the pathophysiology of this fascinatingroup of disorders situated at the crossroads ofpileptic, cognitive, behavioural, and speech and

anguage disorders.

opy number variationsn the idiopathic focal epilepsies

ngo Helbig, Dennis Lal, Hiltrud Muhle,ernd A Neubauer

opy number variations (CNVs) are duplications oreletions of chromosomal segments. While structuralenomic variation on a larger scale has been knowno be the cause of rare genetic disorders for a longime, the abundance of variation on a submicroscopiccale came as a surprise to the field of genetic research.p to 10% of the human genome is considered copy-


umber variable, i.e. deletions or duplications in theseegions can be observed in healthy individuals (Itsarat al., 2009). In addition, an increasing number ofopy number variations are associated with neurode-elopmental disorders, including the idiopathic focalpilepsies (IFEs) (Helbig et al., 2009; de Kovel et al., 2010;efford et al., 2010; Reutlinger et al., 2010). Amongst


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he various microdeletions and microduplications,ariations in the GRIN2A gene are strongly associa-ed with electrical status epilepticus during slow-waveleep (ESES), atypical benign partial epilepsy (ABPE),nd Landau-Kleffner syndrome (LKS) (Reutlinger et al.,010; Carvill et al., 2013; Lemke et al., 2013b; Lesca etl., 2013). To some extent, deletions encompassing theRIN2A gene are also observed in less severe IFEs, i.e.

ypical Rolandic epilepsy. In this review, we summarisehe current approaches regarding structural genomicariants, their relevance to neurodevelopmental disor-ers, and their role in the IFEs.

opy number variations in the human genome

opy number variations in the human genome fallnto two big classes: recurrent copy number variantsue to the underlying genomic architecture and non-ecurrent deletion or duplication events (Itsara etl., 2009). Recurrent structural genomic variants fre-uently arise due to the intricate architecture of theuman genome, a complicated meshwork of dele-

ions, duplications, and more complex rearrangementsue to the recent evolutionary history of the species

Mefford and Eichler, 2009). These structural genomiceatures generate default breakpoints in the humanenome through segmental duplications, particularmall regions of the genome with a high degreef similarity (“microhomology”) (Zhang et al., 2009).uring meiosis, a process referred to as non-allelicomologous recombination (NAHR) may result in theeletion or duplication of the interspersed genomicaterial (Shaw and Lupski, 2004). Depending on the

ize and gene composition of the interspersed region,eletions or duplications may result in neurodevelop-ental disorders. These genomic hotspots, includingicrodeletions at 1q21.1, 15q13.3, 16p13.11, 16p11.2

nd 15q11.2, are amongst the most frequent eventsound in neurodevelopmental disorders (Girirajan etl., 2010; Cooper et al., 2011). Homogeneous pheno-ypes due to deletions or duplications in genomicotspots, such as Angelman syndrome, are referred

o as genomic disorders (Lupski, 1998). Other rareeletion and duplication events encompass particularandidate genes, but are non-recurrent with differentenomic breakpoints in each patient; deletions asso-iated with human epilepsies include the 1q44 deletionnd variations of the SHANK3, NRXN1, and RBFOX1enes (Caliebe et al., 2010; Han et al., 2013; Lal et al.,


013a; Lal et al., 2013b; Moller et al., 2013).

egrees of pathogenicity

y 2014, structural genomic variations were assessedn a routine clinical basis in tens of thousands ofatients with intellectual disability and autism or

fltrcgtm


atients with syndromic features (Girirajan et al., 2010;ooper et al., 2011). Also, large control datasets arevailable that allow researchers to assess possible fin-ings against the normal variation in copy numbers innaffected individuals. Given these unique and largeatasets, it was possible to identify pathogenic struc-

ural genomic variants beyond the classic genomicisorders. Large datasets made it possible to identifytructural genomic variants with variable penetrancend phenotypic heterogeneity, including the micro-eletions 15q11.2, 15q13.3, and 16p13.11, and CNVs

hat were identified through a “genome first” strategyMefford et al., 2008; Girirajan et al., 2010), linkingntirely unrelated phenotypes through commonenetic findings that are absent in controls. The latterpplies to the 1q21.1 microdeletion, which has alsoeen identified in patients with IFEs (Mefford et al.,010).

ssessing pathogenicity

he high frequency of unique structural genomicariation in the human genome poses a difficulty whenrying to assess the pathogenic role of a deletion oruplication identified in an individual patient (Conradt al., 2010). Even though cohort data suggest thatroups of patients with neurodevelopmental disor-ers or various epilepsies have a significantly higher

requency of structural genomic variants than unaffec-ed controls (Cooper et al., 2011; Helbig et al., 2013),he interpretation at the level of a single CNV mighte difficult. In fact, most structural genomic variants

dentified in a given individual are likely to be transmit-ed from parents. This confounds the interpretation ofhe pathogenicity unless additional information can beaken into account. Accordingly, guidelines have beenuggested for the interpretation of CNVs in patientsith neurodevelopmental disorders (Miller et al., 2010;efford et al., 2011). For example, CNVs may be clas-

ified as pathogenic, likely pathogenic, or of unknownignificance. Pathogenic CNVs are de novo deletionsr deletions involving known epilepsy genes. Likelyathogenic CNVs are de novo duplications or anyNVs larger than 1 Mb of unknown inheritance. Allther CNVs that have not been previously observed

n controls and encompass genes are considered toe of unknown significance. This classification already

mplies that the interpretation of copy number varia-ions in a clinical context is conservative, given the

275

ood of unique and individual deletions and duplica-ions in the human genome (Conrad et al., 2010). Withespect to the genetic architecture of human disease,opy number variations were the first example of rareenetic variants, foreshadowing many of the issues inhe interpretation of rare genetic variants from current

assive parallel sequencing studies.


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.K. Pal, et al.

NVs in the idiopathic focal epilepsies

n the following, we aim to provide a list of bonade CNV findings in IFEs, including the full spectrumf Rolandic epilepsy, atypical benign partial epilepsy,andau-Kleffner syndrome, and electrical status epi-epticus during slow-wave sleep. We have selectedtructural genomic variants reported in the literatureased on the following criteria:a particular structural genomic variation or candidate

ene encompassed by a structural genomic varia-ion that has been observed at least twice in patientsith IFE;or a particular CNV that has been observed at least

nce in a patient with IFE and additionally in patientsith other neurodevelopmental disorders.e have deliberately excluded structural genomic

ariants from this list that were only found once, ashey constitute variants of unknown significance, thenterpretation of which is difficult. This list of structu-al genomic variants includes various microdeletionst genomic hotspots and two candidate genes affectedy non-recurrent exonic deletions.

enomic hotspots in idiopathic focal epilepsies

tructural genomic variations at genomic hotspotsere the first recurrent genetic risk factors identi-ed for a common epilepsy syndrome, particularly

diopathic or genetic generalised epilepsy (IGE/GGE)Dibbens et al., 2009; Helbig et al., 2009; de Kovelt al., 2010). Among the various hotspot deletions, theicrodeletion at 15q13.3 assumes the most prominent

ole. The copy number variation can be found in up to% of patients with IGE/GGE, but is virtually absent inontrol cohorts. Other structural genomic variationshat are prominent in IGE/GGE are the microdeletions5q11.2 and 16p13.11 (de Kovel et al., 2010). Theseariants, however, represent moderate risk factors andre also identified in a significant subset of unaffectedndividuals. Other CNVs, including the microdeletionst 1q21.1, 16p11.2 and 22q11.2, and microduplica-ions at 16p11.2, were identified in single patientsde Kovel et al., 2010; Mefford et al., 2010; Meffordt al., 2011; Dimassi et al., 2013). Microdeletions at2q11.2 (Di George region) show some associationith juvenile myoclonic epilepsy (Lemke et al., 2009;elbig et al., 2013).ith respect to the IFEs, individual patients have

76

een described with microdeletions at 1q21.1, 16p12.1,6p13.11, and 15q13.3 (Mefford et al., 2010; Kevelamt al., 2012; Lesca et al., 2013). Given the known lin-age of the 15q13.3 region to the EEG phenotype ofentro-temporal spikes (Neubauer et al., 1998), theack of 15q13.3 microdeletions in IFE compared tohe relative abundance in generalised epilepsies is

tltGttL

stounding. However, this observation is congruentith the observed absence of 15q13.3 microdeletions

n temporal lobe epilepsy (Heinzen et al., 2010). Thisuggests a novel phenotypic boundary that delineates5q13.3 microdeletion-related phenotypes, such asGE/GGE, autism, and intellectual disability, from otherpilepsy phenotypes, particularly the non-lesionalocal epilepsies. A single patient with ESES/CSWSas been described to carry a 15q13.3 microdeletion

Kevelam et al., 2012), which has so far not been repor-ed in less severe phenotypes.

andidate genes affected by non-canonical CNVs

RIN2Ahe GRIN2A gene has emerged as the major candi-ate gene for the IFEs. Reutlinger et al., first observed

he association between GRIN2A and ESES/CSWS inhree patients with larger, overlapping microdeletionsReutlinger et al., 2010). The GRIN2A gene emerged ashe only gene in the overlapping region in all threeatients. Subsequently, further deletions and muta-

ions were identified in GRIN2A, suggesting that thisene mutation is present in up to one third of patientsith IFEs (Reutlinger et al., 2010; Carvill et al., 2013;

emke et al., 2013b; Lesca et al., 2013). While the rolef GRIN2A variation is not entirely clear in phenotypest the more benign end of the IFE spectrum, the rolen epilepsy-aphasia phenotypes, including ESES/CSWSnd LKS, is uncontested. In fact, GRIN2A is one of theew genes implicated in human epilepsy that is foundn a significant proportion of patients with a givenhenotype, a role that is only paralleled by the impor-

ance of SCN1A mutations in Dravet syndrome (Hiroset al., 2013).he GRIN2A gene encodes the NR2A subunit of theMDA receptor, one of the main glutamate recep-

ors in the central nervous system. At first glance, thenvolvement of GRIN2A in human epilepsy appearsaradoxical, given that a gene dosage effect with redu-ed expression of the GRIN2A gene would reducexcitation rather than increase it. However, given thenown interactions between NMDA receptor subu-its, it can be speculated that the lack of GRIN2A isompensated by other subunits, such as the NR2Bubunit, encoded by the GRIN2B gene. In particular,he NR2B subunit has different kinetics that might


hese subunits are regulated dynamically during deve-opment, providing a template that may account forhe age-dependence of IFE phenotypes. The role ofRIN2B in human epilepsy is further corroborated by

he recent identification of activating GRIN2B muta-ions in infantile spasms (Epi4K Consortium, 2013;emke et al., 2013a).


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DGA2esca and collaborators described recurrent deletionsffecting the MDGA2 gene (Lesca et al., 2012), codingor the MAM domain-containing glycosylphosphatidy-inositol anchor protein 2. This protein represents aell adhesion molecule, which is known to bind neu-oligin 2, and regulates the development of inhibitoryynapses (Lee et al., 2013). While the MDGA2 pro-ein represents an interesting candidate protein, thenterpretation of the genetic data demonstrates theomplexity and difficulty in interpreting the pathoge-ic role of microdeletions against the river of rare,ut benign variants. While larger deletions involving

he MDGA2 gene are absent in control populations,maller deletions affecting only parts of the gene haveeen reported in control databases. While it is unclearhether these smaller deletions are real findings ver-

us false positive database entries, this observationalls into question the pathogenic nature of MDGA2eletions. However, even though the rate of false posi-

ive findings in CNV databases is decreasing, somearlier studies using bacterial artificial chromosomeBAC) arrays have overestimated the size of CNVsn control populations. This may “mask” true patho-enic variants as has been observed previously forhe 1q21.1 microdeletion (Sharp, 2009). Taken toge-her, the study by Lesca and collaborators implies

DGA2 deletions as a rare cause of ESES/CSWS, buthe identification of further patients may help disperseemaining doubts.

onclusion

he role of structural genomic variants came as a sur-rise to the field of epilepsy genetics and varioustudies suggest an attributable risk of up to 5% forarger deletions. Current bona fide structural geno-

ic variants implicated in IFE include various genomicotspot deletions, as well as microdeletions spanning

he GRIN2A and MDGA2 gene. With current, large-cale studies underway, the number of candidate CNVsor IFE and the proportion of patients with explanatoryndings is likely to increase in the near future.

he genetics of centro-temporalharp waves

aura Addis, Lisa J. Strug, Deb K. Pal


olandic epilepsy (RE) or benign epilepsy with centro-emporal spikes (BECTS) is a common childhoodeurodevelopmental disorder that is part of a pheno-

ypic spectrum of idiopathic (genetic) focal epilepsiesIFEs). This spectrum encompasses RE, atypical benign

n2wslmr


artial epilepsy (ABPE), Landau-Kleffner syndromeLKS), and the most severe: epileptic encephalopathyith continuous spike-and-waves during slow-wave

leep (CSWS) (Gobbi et al., 2006). All RE patients exhibithe defining electroencephalographic (EEG) abnorma-ity of centro-temporal sharp waves (CTS), which canlso be seen in other IFEs.he onset of focal seizures in RE is frequently preceded

n early childhood by various developmental deficits,ncluding speech dyspraxia and impairments in lan-uage and literacy, and attention (Kavros et al., 2008a;mith et al., 2012; Hernández-Vega et al., 2015; Smith etl., 2015). These neuropsychological deficits, as well asigraine, also cluster in families of RE patients who do

ot have epilepsy themselves (Clarke et al., 2006; Strugt al., 2012; Addis et al., 2013). Both the seizures andhe CTS spontaneously remit at adolescence, althoughhe prognosis for the other neurodevelopmental pro-lems is less favourable.TS is common (2-4%) in typically developing chil-ren of both genders (Eeg-Olofsson et al., 1971), but

s also observed with increased frequency in otherevelopmental disorders, such as attention deficityperactivity disorder (ADHD) (Holtmann et al., 2003;oltmann et al., 2006), specific language impairment

SLI) (Overvliet et al., 2010), and autism (Ballaban-il and Tuchman, 2000). This suggests that CTS isot specific to epilepsy, but may be a marker of, orontributory factor to, more widespread neurodeve-opmental abnormalities (Doose et al., 1996).he common or typical form of RE appears to have

complex genetic inheritance. The genetic basiss, however, predominantly unknown, despite recentdvances including identification of a low frequency ofutations (5% of cases) in the post-synaptic glutamate

eceptor subunit GRIN2A (Carvill et al., 2013; Lemket al., 2013b; Lesca et al., 2013); a cell growth regulator

n the mTOR pathway, DEPDC5 (Lal et al., 2014); as wells potential new candidate genes, RBFOX1 and RBFOX3Lal et al., 2013a).egregation analysis of the CTS trait in RE familieslearly demonstrates autosomal dominant inheritanceBali et al., 2007). However, prior to these studies,he genetic basis of the disorder was debated dueo differing criteria for case selection, preferenceor densely affected pedigrees, and EEG measure-

ent and other confounders such as age of subjects,hich may have increased genetic heterogeneity (Balit al., 2007). In a candidate gene study of neuro-

277

al nicotinic acetylcholine receptor (AChR) genes in2 families multiplex for RE and two for ABPE, CTSas found to link to 15q14 with a multipoint LOD

core of 3.56 (Neubauer et al., 1998). However, thisocus has never been replicated, and updated geno-

ic maps realign this region to 15q13.33, a hotspot forecurrent CNVs.


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igure 7. A plot of the association evidence for CTS in the chroepresent HapMap CEU linkage disequilibrium r2 with the most s

ost proximal red circle.

genome-wide linkage study for CTS in singly ascer-ained RE families identified strongly linked markersn a region of chromosome 11p13 with a maximumeterogeneity LOD of 4.3 (Strug et al., 2009). Both Euro-ean and non-European ancestry families contributedroportionally to the LOD score at this locus. Forty-

our single nucleotide polymorphisms (SNPs) wereyped across the linked region over six genes; DCDC5,CDC1, DPH4, IMMP1L, ELP4, and PAX6, and significantvidence of association was found with three intro-ic SNPs in the gene ELP4. This association with theame alleles and direction of effect was replicated insecond independent sample within this study. Thearkers rs986527 in intron 5 and rs964112 in intron 9

f ELP4 provided the strongest association evidence inhe joint analysis (p=0.0002; figure 7).

78

nterestingly, a subsequent study has shown a pleio-ropic effect of the 11p13 locus on speech dyspraxiand CTS in families singly ascertained on the basisf RE. Evidence for linkage to this locus increasedubstantially to HLOD 7.5 from 4.3 at D11S914, theame marker linked for CTS alone (Pal et al., 2010).s speech dyspraxia precedes the appearance of CTS

(sdeicc

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me 11p13 region (NCBI build 36, LocusZoom viewer). Colourscant SNPs, rs964112 as the purple diamond, and rs986527 as the

y approximately four years, and siblings can havepeech dyspraxia but no CTS, it is unlikely that CTS isausal for the speech problems, although the sponta-eous EEG discharges could potentially exacerbate thepeech impairment. The comparison of variants in ELP4n siblings without RE themselves, but who have CTSr verbal dyspraxia, may potentially uncover if variants

n ELP4 that associate with CTS are also associated witherbal dyspraxia.o far, the linkage and association results implicateariants in the ELP4-PAX6 region, and both genes makettractive candidates. ELP4 is one of six subunits ofhe Elongator complex, an incompletely characterisedrotein located with different functionality in both theucleus (transcript elongation and gene expression)nd cytoplasm (exocytosis and tRNA modification)


Otero et al., 1999; Svejstrup, 2007). There is increa-ing evidence that Elongator is involved in severalifferent neurological disorders (reviewed in Nguyent al. [2009]). It is believed to play an important role

n the transcription of genes that regulate the actinytoskeleton and cell migration. Mutations in ELP1ause familial dysautonomia (Slaugenhaupt et al.,


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001), a neurodevelopmental autonomic neuropathyhat also includes EEG abnormalities and seizures,Niedermeyer et al., 1967), while ELP3 variants aressociated with motor neuron disease (Simpsont al., 2009). Sequencing of the coding and promo-er regions of ELP4 in RE cases failed to identify any

utations or enrichment of polymorphisms, indica-ing that the effector may lie in the non-coding regionsf this gene. Due to a drop off in linkage disequili-rium, it is less likely that the causal variants reside in

he coding regions of neighbouring genes PAX6 andMMP1L (Strug et al., 2009). Interestingly, the intronicegions between exons 9 and 12 of ELP4 are large andltraconserved. These regions contain long-range cisegulatory enhancers for downstream PAX6, which areissue- or developmental stage-specific in their expres-ion (McBride et al., 2011).AX6 is a transcription factor crucial for normal deve-opment of the eyes, spinal cord, several areas of therain, and other organs (Griffin et al., 2002). Dele-

ions of PAX6 with WT1 cause Wilms tumour, aniridia,enital anomalies, and intellectual disability (WAGRyndrome). A rare case of duplication of PAX6 andhe last two exons/introns of ELP4 has been reportedith fronto-temporal neonatal seizures, developmen-

al delay, microcephaly, and minor ocular findingsAradhya et al., 2011), indicating PAX6 rearrangementsr mutations could also be responsible for neuronalyperexcitability. PAX6 has recently been proposeds the foremost transcription factor governing gluta-atergic neuronal differentiation. Overexpression of

ax6 during rat brain development induced dysregula-ed glutamatergic neuronal differentiation, increasedxpression of glutamate transporters, and reducedeizure thresholds and autistic-like behaviour, whichas reversed on treatment with a glutamate recep-

or antagonist (Kim et al., 2014). Therefore, functionalvidence, from the dysregulation of PAX6 and its linkia the glutamatergic neurotransmission system withRIN2A, makes it a prime candidate for involvement

n CTS.uture work on the ELP4-PAX6 locus will need tonvolve deep sequencing of all variation across theegion, including non-coding regions, in both casesnd controls, in order to identify alleles that are morerequent and potentially increase the risk for CTS.dditional work will identify which gene is implicated

n CTS and by what mechanism. If identified variantsall within known enhancer or promoter regions for


xample, then functional work can ascertain theirffects on gene expression in model systems. Sub-tantiating a gene in this region as a risk locus forTS is another step towards understanding the com-lex genetic model of RE. Although CTS is common

n children (Eeg-Olofsson et al., 1971), only 10% withTS manifest clinical seizures, indicating there must be

2

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dditional genetic factors acting in combination withusceptibility variants in this region to cause eitherhe classic focal seizures of RE, or the other commonomorbidities.

upplementary data.ummary didactic slides are available on theww.epilepticdisorders.com website.

cknowledgements and disclosures.The work of A. Ioannides was partially funded by the

uropean Commission under the Seventh Framework Pro-ramme (FP7/2007-2013) with grant ARMOR, agreement number87720.K. Hamandi has received funding from the Waterloo Founda-

ion for BECTS Imaging Research and is supported by Cardiff andale University Health Board and the National Institute for Healthnd Social Care Research, Welsh Government.

The work on Recent progress in the genetics of “idiopa-hic” childhood focal epilepsies by G. Lesca, G. Rudolf and. Szepetowski was supported by ANR (Agence Nationale dea Recherche) grant “EPILAND” (ANR-2010-BLAon “N-1405 01)

ith EuroBiomed label, National PHRC grant 2010 N 03-08, byhe European Union Seventh Framework Programme FP7/2007-013 under the project DESIRE (grant agreement n602531),nd INSERM (Institut National de la Santé et de la Rechercheédicale).The work on The genetics of centro-temporal sharp waves by

. Addis, LJ Strug and DK Pal was supported by the National Ins-itutes of Health (NS04750), the European Research Commissionhrough Marie Curie Award, and the Waterloo Foundation.ll authors have no conflicts of interest to disclose.hen financial support for related studies was received this is

isclosed at the Acknowledgments section.

eferences

ddis L, Chiang T, Clarke T, et al. Evidence for linkage ofigraine in Rolandic epilepsy to known 1q23 FHM2 and novel

7q22 genetic loci. Genes Brain Behav 2013; 13(3): 333-40.

icardi J. Atypical semiology of Rolandic epilepsy in someelated syndromes. Epileptic Disord 2000; 2(1): S5-9.

icardi J, Chevrie JJ. Atypical benign partial epilepsy of child-ood. Dev Med Child Neurol 1982; 24(3): 281-92.

mbrosetto G, Tassinari CA. Antiepileptic drug treatment ofenign childhood epilepsy with Rolandic spikes: is it neces-ary? Epilepsia 1990; 31(6): 802-5.

radhya S, Smaoui N, Marble M, Lacassie Y. De novo duplica-ion 11p13 involving the PAX6 gene in a patient with neonataleizures, hypotonia, microcephaly, developmental disabi-ity and minor ocular manifestations. Am J Med Genet A

279

011; 155A(2): 442-4.

vanzini G, Manganotti P, Meletti S, et al. The sys-em epilepsies: a pathophysiological hypothesis. Epilepsia012; 53(5): 771-8.

y Y, Gokben S, Serdaroglu G, et al. Neuropsychologicmpairment in children with Rolandic epilepsy. Ped Neurol009; 41(5): 359-63.

http://www.ncbi.nlm.nih.gov/pubmed?term=Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci

http://www.ncbi.nlm.nih.gov/pubmed?term=Atypical semiology of Rolandic epilepsy in some related syndromes

http://www.ncbi.nlm.nih.gov/pubmed?term=Atypical benign partial epilepsy of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Antiepileptic drug treatment of benign childhood epilepsy with Rolandic spikes: is it necessary?

http://www.ncbi.nlm.nih.gov/pubmed?term=De novo duplication 11p13 involving the PAX6 gene in a patient with neonatal seizures, hypotonia, microcephaly, developmental disability and minor ocular manifestations

http://www.ncbi.nlm.nih.gov/pubmed?term=The system epilepsies: a pathophysiological hypothesis

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychologic impairment in children with Rolandic epilepsy


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yrig

ht ©

201

6 Jo

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ibbe

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urot

ext.

Tél

écha

rgé

par

un u

tilis

ateu

r an

onym

e le

23/

11/2

016.

.K. Pal, et al.

aglietto MG, Battaglia FM, Nobili L, et al. Neuropsychologi-al disorders related to interictal epileptic discharges duringleep in benign epilepsy of childhood with centrotempo-al or Rolandic spikes. Dev Med Child Neurol 2001; 43(06):07-12.

ali B, Kull L, Strug L, et al. Autosomal dominant inheritancef centrotemporal sharp waves in Rolandic epilepsy families.pilepsia 2007; 48(12): 2266-72.

allaban-Gil K, Tuchman R. Epilepsy and epileptiform EEG:ssociation with autism and language disorders. Ment Retardev Disabil Res Rev 2000; 6(4): 300-8.

eaumanoir A, Nahory A. Benign partial epilepsies: 11 casesf frontal partial epilepsy with favorable prognosis. Rev Elec-

roencephalogr Neurophysiol Clin 1983; 13(3): 207-11.

eaussart M. Benign epilepsy of children with Rolandiccentro-temporal) paroxysmal foci: a clinical entity. Study of21 cases. Epilepsia 1972; 13: 795-811.

eck SJ, Hanson CA, Puffenberger SS, Benninger KL, Bennin-er WB. A controlled trial of working memory training forhildren and adolescents with ADHD. J Clin Child Adolescsychol 2010; 39(6): 825-36.

erg AT, Berkovic SF, Brodie MJ, et al. Revised terminologynd concepts for organization of seizures and epilepsies:eport of the ILAE Commission on Classification and Termi-ology, 2005-2009. Epilepsia 2010; 51(4): 676-85.

erkovic SF, Mulley JC, Scheffer IE, Petrou S. Human epi-epsies: interaction of genetic and acquired factors. Trends

eurosci 2006; 29(7): 391-7.

esseling RM, Jansen JF, Overvliet GM, et al. Reduced struc-ural connectivity between sensorimotor and language areasn Rolandic epilepsy. PLoS One 2013a; 8(12): e83568.

esseling RM, Jansen JF, Overvliet GM, et al. Reduced func-ional integration of the sensorimotor and language networkn Rolandic epilepsy. Neuroimage Clin 2013b; 2: 239-46.

illard C, Hassairi I, Delteil F. Specific language impair-ent and electroencephalogram: which recommendations

n clinical practice? A cohort of 24 children. Arch Pediatr010; 17(4): 350-8.

olsterli BK, Schmitt B, Bast T, et al. Impaired slow waveleep downscaling in encephalopathy with status epilep-icus during sleep (ESES). Clin Neurophysiol 2011; 122(9):779-87.

raakman HM, Vaessen MJ, Hofman PA, et al. Cognitive andehavioral complications of frontal lobe epilepsy in children:review of the literature. Epilepsia 2011; 52(5): 849-56.

ulgheroni S, Franceschetti S, Vago C, et al. Verbal dichoticistening performance and its relationship with EEG featuresn benign childhood epilepsy with centrotemporal spikes.pilepsy Res 2008; 79(1): 31-8.

80

aliebe A, Kroes HY, van der Smagt JJ, et al. Four patientsith speech delay, seizures and variable corpus callosum thi-

kness sharing a 0.440 Mb deletion in region 1q44 containinghe HNRPU gene. Eur J Med Genet 2010; 53(4): 179-85.

amfield PR. Problems for people with epilepsy beyond sei-ures. Epilepsia 2007; 48(S9): 1-2.

CiP

Ct2

apovilla G, Beccaria F, Montagnini A. ‘Benign focal epilepsyn infancy with vertex spikes and waves during sleep’. Deli-eation of the syndrome and recalling as ’benign infantile

ocal epilepsy with midline spikes and waves during sleep’BIMSE). Brain Dev 2006; 28(2): 85-91.

apovilla G, Berg AT, Cross JH, et al. Conceptual dichoto-ies in classifying epilepsies: Partial versus generalized and

diopathic versus symptomatic (April 18-20, 2008, Monreale,taly). Epilepsia 2009a, Ahead of print.

apovilla G, Striano P, Beccaria F. Changes in Panayiotopou-os syndrome over time. Epilepsia 2009b; 50(S5): 45-8.

apovilla G, Beccaria F, Bianchi A, et al. Ictal EEG pat-erns in epilepsy with centro-temporal spikes. Brain Dev011; 33(4): 301-9.

apovilla G, Moshe SL, Wolf P, Avanzini G. Epilepticncephalopathy as models of system epilepsy. Epilepsia013; 54(S8): 34-7.

araballo R, Fontana E, Michelizza B, et al. Carbamazepina,ssenze atipiche, crisi atoniche e stato di PO continua delonno (POCS). Bolletina della lega italiana contro l’epilessia989; 66/67: 379-81.

araballo RH, Cersosimo RO, Espeche A, Fejerman N. Benignamilial and non-familial infantile seizures: a study of 64atients. Epileptic Disord 2003; 5(1): 45-9.

araballo R, Cersosimo R, Capovilla G, Fejerman N. Benignocal seizures of adolescence. In: Fejerman N, Caraballo R.enign focal epilepsies in infancy, childhood and adoles-ence. Montrouge: John Libbey, 2007a: 243-51.

araballo R, Cersosimo R, Fejerman N. Panayiotopoulosyndrome: a prospective study of 192 patients. Epilepsia007b; 48(6): 1054-61.

araballo R, Cersosimo R, Fejerman N. Symptomatic focalpilepsies imitating atypical evolutions of idiopathic focalpilepsies in childhood. In: Fejerman N, Caraballo R. Benignocal epilepsies in infancy, childhood and adolescence. Mon-rouge: John Libbey, 2007c; 221-39.

araballo RH, Cersosimo RO, Fejerman N. Childhood occi-ital epilepsy of Gastaut: a study of 33 patients. Epilepsia008; 49(2): 288-97.

araballo RH, Cersosimo R, De los Santos C. Levetiracetam-nduced seizure aggravation associated with continuouspikes and waves during slow sleep in children with refrac-ory epilepsies. Epileptic Disord 2010; 12(2): 146-50.

araballo RH, Aldao Mdel R, Cachia P. Benign childhood sei-ure susceptibility syndrome: three case reports. Epilepticisord 2011; 13(2): 133-9.

arlsson G, Igelbrink-Schulze N, Neubauer BA, Stephani. Neuropsychological long-term outcome of Rolandic EEG

raits. Epileptic Disord 2000; 2(S1): S63-6.


arroll JM, Snowling MJ. Language and phonological skillsn children at high risk of reading difficulties. J Child Psycholsychiatry 2004; 45(3): 631-40.

arvill GL, Regan BM, Yendle SC, et al. GRIN2A muta-ions cause epilepsy-aphasia spectrum disorders. Nat Genet013; 45(9): 1073-6.

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Autosomal dominant inheritance of centrotemporal sharp waves in Rolandic epilepsy families

http://www.ncbi.nlm.nih.gov/pubmed?term=Epilepsy and epileptiform EEG: association with autism and language disorders

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign partial epilepsies: 11 cases of frontal partial epilepsy with favorable prognosis

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign epilepsy of children with Rolandic (centro-temporal) paroxysmal foci: a clinical entity. Study of 221 cases

http://www.ncbi.nlm.nih.gov/pubmed?term=A controlled trial of working memory training for children and adolescents with ADHD

http://www.ncbi.nlm.nih.gov/pubmed?term=Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009

http://www.ncbi.nlm.nih.gov/pubmed?term=Human epilepsies: interaction of genetic and acquired factors

http://www.ncbi.nlm.nih.gov/pubmed?term=Reduced structural connectivity between sensorimotor and language areas in Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Reduced functional integration of the sensorimotor and language network in Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Specific language impairment and electroencephalogram: which recommendations in clinical practice? A cohort of 24 children

http://www.ncbi.nlm.nih.gov/pubmed?term=Impaired slow wave sleep downscaling in encephalopathy with status epilepticus during sleep (ESES)

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognitive and behavioral complications of frontal lobe epilepsy in children: a review of the literature

http://www.ncbi.nlm.nih.gov/pubmed?term=Verbal dichotic listening performance and its relationship with EEG features in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene

http://www.ncbi.nlm.nih.gov/pubmed?term=Problems for people with epilepsy beyond seizures

http://www.ncbi.nlm.nih.gov/pubmed?term='Benign focal epilepsy in infancy with vertex spikes and waves during sleep'. Delineation of the syndrome and recalling as 'benign infantile focal epilepsy with midline spikes and waves during sleep' (BIMSE)

http://www.ncbi.nlm.nih.gov/pubmed?term=Conceptual dichotomies in classifying epilepsies: Partial versus generalized and idiopathic versus symptomatic (April 18-20, 2008, Monreale, Italy)

http://www.ncbi.nlm.nih.gov/pubmed?term=Changes in Panayiotopoulos syndrome over time

http://www.ncbi.nlm.nih.gov/pubmed?term=Ictal EEG patterns in epilepsy with centro-temporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Epileptic encephalopathy as models of system epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Carbamazepina, assenze atipiche, crisi atoniche e stato di PO continua del sonno (POCS)

http://www.ncbi.nlm.nih.gov/pubmed?term=Bolletina della lega italiana contro l'epilessia

http://www.ncbi.nlm.nih.gov/pubmed?term=Panayiotopoulos syndrome: a prospective study of 192 patients

http://www.ncbi.nlm.nih.gov/pubmed?term=Childhood occipital epilepsy of Gastaut: a study of 33 patients

http://www.ncbi.nlm.nih.gov/pubmed?term=Levetiracetam-induced seizure aggravation associated with continuous spikes and waves during slow sleep in children with refractory epilepsies

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign childhood seizure susceptibility syndrome: three case reports

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological long-term outcome of Rolandic EEG traits

http://www.ncbi.nlm.nih.gov/pubmed?term=Language and phonological skills in children at high risk of reading difficulties

http://www.ncbi.nlm.nih.gov/pubmed?term=GRIN2A mutations cause epilepsy-aphasia spectrum disorders


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atania S, Cross H, de Sousa C, Boyd S. Paradoxic reaction toamotrigine in a child with benign focal epilepsy of childhood

ith centrotemporal spikes. Epilepsia 1999; 40(11): 1657-60.

atts HW, Fey ME, Tomblin JB, Zhang X. A longitudinalnvestigation of reading outcomes in children with languagempairments. J Speech Lang Hear Res 2002; 45(6): 1142.

erminara C, D’Agati E, Lange KW, et al. Benign childhoodpilepsy with centrotemporal spikes and the multicom-onent model of attention: A matched control study. EpilepsyBehav 2010; 19(1): 69-77.

hevalier H, Metz-Lutz MN, Segalowitz SJ. Impulsivity andontrol of inhibition in Benign Focal Childhood EpilepsyBFCE). Brain Cogn 2000; 43(1-3): 86-90.

larke T, Bali B, Carvalho J, et al. Speech and language disor-ers aggregate in Rolandic epilepsy families. Neuropediatrics006; 37(S1): 60.

larke T, Baskurt Z, Strug LJ, Pal DK. Evidence of shared gene-ic risk factors for migraine and Rolandic epilepsy. Epilepsia009; 50(11): 2428-33.

loarec R, Bruneau N, Rudolf G, et al. PRRT2 links infantileonvulsions and paroxysmal dyskinesia with migraine. Neu-ology 2012; 79(21): 2097-103.

ole AJ, Andermann F, Taylor L, et al. The Landau-Kleffneryndrome of acquired epileptic aphasia: unusual clinicalutcome, surgical experience, and absence of encephalitis.eurology 1988; 38(1): 31-8.

onners FA. Attentional control and the simple view of rea-ing. Reading and Writing 2009; 22: 591-613.

onnolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S,euel RK. Serum autoantibodies to brain in Landau-Kleffner

ariant, autism, and other neurologic disorders. J Pediatr999; 134(5): 607-13.

onrad DF, Pinto D, Redon R, et al. Origins and functio-al impact of copy number variation in the human genome.ature 2010; 464(7289): 704-12.

ooper GM, Coe BP, Girirajan S, et al. A copy numberariation morbidity map of developmental delay. Nat Genet011; 43(9): 838-46.

ovanis A, Lada C, Skiadas K. Children with Rolandic spikesnd ictal vomiting: Rolandic epilepsy or Panayiotopoulos syn-rome? Epileptic Disord 2003; 5(3): 139-43.

roona C, Kihlgren M, Lundberg S, Eeg-Olofsson O, Eeg-lofsson KE. Neuropsychological findings in children with

enign childhood epilepsy with centrotemporal spikes. Deved Child Neurol 1999; 41(12): 813-8.

ai Y, Zhang W, Dickens DL, He B. Source connectivitynalysis from MEG and its application to epilepsy sourceocalization. Brain Topogr 2012; 25(2): 157-66.


atta A, Sinclair DB. Benign epilepsy of childhood witholandic spikes: typical and atypical variants. Pediatr Neurol007; 36(3): 141-5.

e Kovel CG, Trucks H, Helbig I, et al. Recurrent micro-eletions at 15q11.2 and 16p13.11 predispose to idiopathiceneralized epilepsies. Brain 2010; 133(1): 23-32.

DadE

Dfe


e Marco P, Tassinari CA. Extreme somatosensory evo-ed potential (ESEP): an EEG sign forecasting the possibleccurrence of seizures in children. Epilepsia 1981; 22(5):69-75.

e Saint-Martin A, Petiau C, Massa R, et al. Idiopathic Rolandicpilepsy with interictal facial myoclonia and oromotor defi-it: a longitudinal EEG and PET study. Epilepsia 1999; 40(5):14-20.

e Tiege X, Goldman S, Verheulpen D, Aeby A, Poznanski, Van Bogaert P. Coexistence of idiopathic Rolandic epi-

epsy and CSWS in two families. Epilepsia 2006; 47(10):723-7.

e Tiege X, Ligot N, Goldman S, Poznanski N, de Saint Martin, Van Bogaert P. Metabolic evidence for remote inhibition

n epilepsies with continuous spike-waves during sleep. Neu-oimage 2008; 40(2): 802-10.

e Tiege X, Trotta N, Op de Beeck M, et al. Neurophysiologi-al activity underlying altered brain metabolism in epilepticncephalopathies with CSWS. Epilepsy Res 2013; 105(3):16-25.

eltour L, Quaglino V, Barathon M, De Broca A, Berquin. Clinical evaluation of attentional processes in childrenith benign childhood epilepsy with centrotemporal spikes

BCECTS). Epileptic Disorders 2007; 9(4): 424-31.

eonna T. Annotation: cognitive and behavioural correlatesf epileptic activity in children. J Child Psychol Psychiatry993; 34(5): 611-20.

eonna T, Roulet-Perez E. Early-onset acquired epilepticphasia (Landau-Kleffner syndrome, LKS) and regressiveutistic disorders with epileptic EEG abnormalities: the conti-uing debate. Brain Dev 2010; 32(9): 746-52.

eonna TW, Roulet E, Fontan D, Marcoz JP. Speech andromotor deficits of epileptic origin in benign partial epi-

epsy of childhood with Rolandic spikes (BPERS). Relationshipo the acquired aphasia-epilepsy syndrome. Neuropediatrics993; 24(2): 83-7.

eonna T, Zesiger P, Davidoff V, Maeder M, Mayor C, Roulet. Benign partial epilepsy of childhood: a longitudinal neuro-sychological and EEG study of cognitive function. Dev Medhild Neurol 2000; 42(9): 595-603.

epienne C, Gourfinkel-An I, Baulac S. Genes in infantilepileptic encephalopathies. In: Noebels J, Avoli M, RogawskiA, Olsen RW, Delgado-Escueta AV. Jasper’s basic mecha-

ism of the epilepsies. Bethesda (MD): National Center foriotechnology Information, 2012: 1-19.

ibbens LM, Mullen S, Helbig I, et al. Familial and sporadic5q13.3 microdeletions in idiopathic generalized epilepsy:recedent for disorders with complex inheritance. Hum Molenet 2009; 18(19): 3626-31.

281

imassi S, Labalme A, Lesca G, et al. A subset of genomiclterations detected in Rolandic epilepsies contains candi-ate or known epilepsy genes including GRIN2A and PRRT2.pilepsia 2013; 55(2): 370-8.

oose H, Neubauer B, Carlsson G. Children with benignocal sharp waves in the EEG-developmental disorders andpilepsy. Neuropediatrics 1996; 27(5): 227-41.

http://www.ncbi.nlm.nih.gov/pubmed?term=Paradoxic reaction to lamotrigine in a child with benign focal epilepsy of childhood with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=A longitudinal investigation of reading outcomes in children with language impairments

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign childhood epilepsy with centrotemporal spikes and the multicomponent model of attention: A matched control study

http://www.ncbi.nlm.nih.gov/pubmed?term=Impulsivity and control of inhibition in Benign Focal Childhood Epilepsy (BFCE)

http://www.ncbi.nlm.nih.gov/pubmed?term=Speech and language disorders aggregate in Rolandic epilepsy families

http://www.ncbi.nlm.nih.gov/pubmed?term=Evidence of shared genetic risk factors for migraine and Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine

http://www.ncbi.nlm.nih.gov/pubmed?term=The Landau-Kleffner syndrome of acquired epileptic aphasia: unusual clinical outcome, surgical experience, and absence of encephalitis

http://www.ncbi.nlm.nih.gov/pubmed?term=Attentional control and the simple view of reading

http://www.ncbi.nlm.nih.gov/pubmed?term=Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders

http://www.ncbi.nlm.nih.gov/pubmed?term=Origins and functional impact of copy number variation in the human genome

http://www.ncbi.nlm.nih.gov/pubmed?term=A copy number variation morbidity map of developmental delay

http://www.ncbi.nlm.nih.gov/pubmed?term=Children with Rolandic spikes and ictal vomiting: Rolandic epilepsy or Panayiotopoulos syndrome?

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological findings in children with benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Source connectivity analysis from MEG and its application to epilepsy source localization

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign epilepsy of childhood with Rolandic spikes: typical and atypical variants

http://www.ncbi.nlm.nih.gov/pubmed?term=Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

http://www.ncbi.nlm.nih.gov/pubmed?term=Extreme somatosensory evoked potential (ESEP): an EEG sign forecasting the possible occurrence of seizures in children

http://www.ncbi.nlm.nih.gov/pubmed?term=Idiopathic Rolandic epilepsy with interictal facial myoclonia and oromotor deficit: a longitudinal EEG and PET study

http://www.ncbi.nlm.nih.gov/pubmed?term=Coexistence of idiopathic Rolandic epilepsy and CSWS in two families

http://www.ncbi.nlm.nih.gov/pubmed?term=Metabolic evidence for remote inhibition in epilepsies with continuous spike-waves during sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=Neurophysiological activity underlying altered brain metabolism in epileptic encephalopathies with CSWS

http://www.ncbi.nlm.nih.gov/pubmed?term=Clinical evaluation of attentional processes in children with benign childhood epilepsy with centrotemporal spikes (BCECTS)

http://www.ncbi.nlm.nih.gov/pubmed?term=Annotation: cognitive and behavioural correlates of epileptic activity in children

http://www.ncbi.nlm.nih.gov/pubmed?term=Early-onset acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and regressive autistic disorders with epileptic EEG abnormalities: the continuing debate

http://www.ncbi.nlm.nih.gov/pubmed?term=Speech and oromotor deficits of epileptic origin in benign partial epilepsy of childhood with Rolandic spikes (BPERS). Relationship to the acquired aphasia-epilepsy syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign partial epilepsy of childhood: a longitudinal neuropsychological and EEG study of cognitive function

http://www.ncbi.nlm.nih.gov/pubmed?term=Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance

http://www.ncbi.nlm.nih.gov/pubmed?term=A subset of genomic alterations detected in Rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2

http://www.ncbi.nlm.nih.gov/pubmed?term=Children with benign focal sharp waves in the EEG-developmental disorders and epilepsy


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Cop

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Tél

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tilis

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onym

e le

23/

11/2

016.

.K. Pal, et al.

uvelleroy-Hommet C, Billard C, Lucas B, et al. Sleep EEG andevelopmental dysphasia: lack of a consistent relationshipith paroxysmal EEG activity during sleep. Neuropediatrics

995; 26(1): 14-8.

eg-Olofsson O, Petersen I, Sellden U. The development ofhe electroencephalogram in normal children from the agef 1 through 15 years. Paroxysmal activity. Neuropadiatrie971; 2(4): 375-404.

ngel F Jr. Report of the ILAE classification core group. Epi-epsia 2006; 47(9): 1558-68.

pi4K Consortium, Epilepsy Phenome/Genome Project, AllenS, et al. De novo mutations in epileptic encephalopathies.ature 2013; 501(7466): 217-21.

an J, McCandliss BD, Fossella J, Flombaum IJ, PosnerI. The activation of attentional networks. Neuroimage

005; 26(3): 471-9.

ejerman N. Atypical evolutions of benign partial epilepsiesn children. Int Pediatr 1996; 11(6): 351-6.

ejerman N. Benign childhood epilepsy with centrotempo-al spikes. In : Engel J, Pedley TA. Epilepsy. A comprehensiveextbook. Philadelphia: Lippincott, Williams & Wilkins, 2008:369-78.

ejerman N, Di Blasi AM. Status epilepticus of benign par-ial epilepsies in children: report of two cases. Epilepsia987; 28(4): 351-5.

ejerman N, Tenembaum S, Medina MT, Caraballo R, SopranoM. Continuous spike-waves during slow-wave sleep andwake in a case of childhood epilepsy with occipitalaroxysms: clinical correlations. Epilepsia 1991; 32(S1): 16.

ejerman N, Caraballo R, Tenembaum SN. Atypical evolutionsf benign localization-related epilepsies in children: are theyredictable? Epilepsia 2000; 41(4): 380-90.

ejerman N, Caraballo R, Dalla Bernardina B. Atypical evolu-ions of benign focal epilepsies in childhood. In : Fejerman, Caraballo R. Benign focal epilepsies in infancy, child-ood and adolescence. Montrouge: John Libbey, 2007a:79-200

ejerman N, Caraballo R, Dalla Bernardina B. Benign child-ood epilepsy with centrotemporal spikes. In : Fejerman N,araballo R. Benign focal epilepsies jn infancy, childhood anddolescence. Montrouge: John Libbey 2007b: 77-113.

ejerman N, Caraballo R, Cersosimo R, Ferraro SM, Galic-hio S, Amartino H. Sulthiame add-on therapy in childrenith focal epilepsies associated with encephalopathy rela-

ed to electrical status epilepticus during slow sleep (ESES).pilepsia 2012; 53(7): 1156-61.

ilippini M, Arzimanoglou A, Gobbi G. Neuropsycholo-ical approaches to epileptic encephalopathies. Epilepsia

82

013; 54(S8): 38-44.

aggero R, Pistorio A, Pignatelli S, et al. Early classification ofhildhood focal idiopathic epilepsies: is it possible at the firsteizure? Eur J Paediatr Neurol 2014; 18(3): 376-80.

astaut H. A new type of epilepsy: benign partial epilepsy ofhildhood with occipital spike-waves. Clin Electroencepha-ogr 1982; 13(1): 13-22.

2

Gas

Hcp

ibbs EL, Gillen HW, Gibbs FA. Disappearance and migra-ion of epileptic foci in childhood. Am J Dis Child 1954; 88(5):96-603.

iordani B, Caveney AF, Laughrin D, et al. Cognition andehavior in children with benign epilepsy with centro-

emporal spikes (BECTS). Epilepsy Research 2006; 70(1):9-94.

irirajan S, Rosenfeld JA, Cooper GM, et al. A recurrent6p12.1 microdeletion supports a two-hit model for severeevelopmental delay. Nat Genet 2010; 42(3): 203-9.

obbi G, Boni A, Filippini M. The spectrum of idiopa-hic Rolandic epilepsy syndromes and idiopathic occipitalpilepsies: from the benign to the disabling. Epilepsia006; 47(2): 62-6.

oldberg-Stern H, Gonen OM, Sadeh M, Kivity S, Shuper, Inbar D. Neuropsychological aspects of benign childhoodpilepsy with centrotemporal spikes. Seizure 2010; 19(1): 12-6.

oodman JH, Stewart M, Drislane FW. Autonomic distur-ances. In: Engel J, Pedley TA. Epilepsy. A comprehensive

extbook. Philadelphia: Lippincott, Williams & Wilkins, 2008:999-2005.

regory DL, Wong PK. Clinical relevance of a dipole field inolandic spikes. Epilepsia 1992; 33(1): 36-44.

riffin C, Kleinjan DA, Doe B, van Heyningen V. New 3’lements control Pax6 expression in the developing pre-ectum, neural retina and olfactory region. Mech Dev 2002;12(1-2): 89-100.

rova C, Daunizeau J, Kobayashi E, et al. Concordanceetween distributed EEG source localization and simulta-eous EEG-fMRI studies of epileptic spikes. Neuroimage008; 39(2): 755-64.

uerrini R, Dravet C, Genton P, et al. Idiopathic photosensi-ive occipital lobe epilepsy. Epilepsia 1995; 36(9): 883-91.

uerrini R, Bonanni P, Parmeggiani L, Belmonte A. Adoles-ent onset of idiopathic photosensitive occipital epilepsyfter remission of benign Rolandic epilepsy. Epilepsia997; 38(7): 777-81.

uerrini R, Genton P, Bureau M, et al. Multilobar polymi-rogyria, intractable drop attack seizures, and sleep-relatedlectrical status epilepticus. Neurology 1998; 51(2): 504-12.

uerrini R, Bonanni P, Nardocci N, et al. Autosomal reces-ive Rolandic epilepsy with paroxysmal exercise-inducedystonia and writer’s cramp: delineation of the syndromend gene mapping to chromosome 16p12-11.2. Ann Neurol999; 45: 344-52.

uerrini R, Parmeggiani A, Berta E. Occipital lobe seizures. In :xbury JM, Polkey CE, Duchowny MS. Intractable focal epi-

epsy: medical and surgical treatment. London: WB Saunders,


000: 77-88.

uzzetta F, Battaglia D, Veredice C, et al. Early thalamic injuryssociated with epilepsy and continuous spike-wave duringlow sleep. Epilepsia 2005; 46(6): 889-900.

an K, Holder Jr. JL, Schaaf CP, et al. SHANK3 overexpressionauses manic-like behaviour with unique pharmacogeneticroperties. Nature 2013; 503(7474): 72-7.

http://www.ncbi.nlm.nih.gov/pubmed?term=Sleep EEG and developmental dysphasia: lack of a consistent relationship with paroxysmal EEG activity during sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=The development of the electroencephalogram in normal children from the age of 1 through 15 years. Paroxysmal activity

http://www.ncbi.nlm.nih.gov/pubmed?term=Report of the ILAE classification core group

http://www.ncbi.nlm.nih.gov/pubmed?term=De novo mutations in epileptic encephalopathies

http://www.ncbi.nlm.nih.gov/pubmed?term=The activation of attentional networks

http://www.ncbi.nlm.nih.gov/pubmed?term=Atypical evolutions of benign partial epilepsies in children

http://www.ncbi.nlm.nih.gov/pubmed?term=Status epilepticus of benign partial epilepsies in children: report of two cases

http://www.ncbi.nlm.nih.gov/pubmed?term=Continuous spike-waves during slow-wave sleep and awake in a case of childhood epilepsy with occipital paroxysms: clinical correlations

http://www.ncbi.nlm.nih.gov/pubmed?term=Atypical evolutions of benign localization-related epilepsies in children: are they predictable?

http://www.ncbi.nlm.nih.gov/pubmed?term=Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES)

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological approaches to epileptic encephalopathies

http://www.ncbi.nlm.nih.gov/pubmed?term=Early classification of childhood focal idiopathic epilepsies: is it possible at the first seizure?

http://www.ncbi.nlm.nih.gov/pubmed?term=A new type of epilepsy: benign partial epilepsy of childhood with occipital spike-waves

http://www.ncbi.nlm.nih.gov/pubmed?term=Disappearance and migration of epileptic foci in childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognition and behavior in children with benign epilepsy with centrotemporal spikes (BECTS)

http://www.ncbi.nlm.nih.gov/pubmed?term=A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

http://www.ncbi.nlm.nih.gov/pubmed?term=The spectrum of idiopathic Rolandic epilepsy syndromes and idiopathic occipital epilepsies: from the benign to the disabling

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Clinical relevance of a dipole field in Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=New 3' elements control Pax6 expression in the developing pretectum, neural retina and olfactory region

http://www.ncbi.nlm.nih.gov/pubmed?term=Concordance between distributed EEG source localization and simultaneous EEG-fMRI studies of epileptic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Idiopathic photosensitive occipital lobe epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Adolescent onset of idiopathic photosensitive occipital epilepsy after remission of benign Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Multilobar polymicrogyria, intractable drop attack seizures, and sleep-related electrical status epilepticus

http://www.ncbi.nlm.nih.gov/pubmed?term=Autosomal recessive Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2

http://www.ncbi.nlm.nih.gov/pubmed?term=Early thalamic injury associated with epilepsy and continuous spike-wave during slow sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties


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Cop

yrig

ht ©

201

6 Jo

hn L

ibbe

y E

urot

ext.

Tél

écha

rgé

par

un u

tilis

ateu

r an

onym

e le

23/

11/2

016.

einzen EL, Radtke RA, Urban TJ, et al. Rare deletionst 16p13.11 predispose to a diverse spectrum of spo-adic epilepsy syndromes. Am J Hum Genet 2010; 86(5):07-18.

elbig I, Mefford HC, Sharp AJ, et al. 15q13.3 microdeletionsncrease risk of idiopathic generalized epilepsy. Nat Genet009; 41(2): 160-2.

elbig I, Hartmann C, Mefford HC. Clarifying the role of the2q11.2 microdeletion in juvenile myoclonic epilepsy. Epi-epsy Behav 2013; 29(3): 589-90.

elbig I, Swinkels ME, Aten E, et al. Structural genomic varia-ion in childhood epilepsies with complex phenotypes. Eur Jum Genet 2014; 22(7): 896-901.

ernández-Vega Y, Smith A, Cockerill H, et al. The epidemio-ogy of comorbidities in Rolandic epilepsy. Epilepsia 2014,ubmitted.

ernández-Vega Y, Smith AB, Cockerill H, et al. Risk factorsor reading disability in Rolandic Epilepsy. Epilepsy & Beha-ior 2015; 53: 174-9.

irose S, Scheffer IE, Marini C, et al. SCN1A testingor epilepsy: application in clinical practice. Epilepsia013; 54(5): 946-52.

oltmann M, Becker K, Kentner-Figura B, Schmidt MH.ncreased frequency of Rolandic spikes in ADHD children.pilepsia 2003; 44(9): 1241-4.

oltmann M, Matei A, Hellmann U, Becker K, Poustka F,chmidt MH. Rolandic spikes increase impulsivity in ADHDa neuropsychological pilot study. Brain Dev 2006; 28(10):

33-40.

uiskamp G, van Der Meij W, van Huffelen A, van Nieu-enhuizen O. High resolution spatio-temporal EEG-MEG

nalysis of Rolandic spikes. J Clin Neurophysiol 2004; 21(2):4-95.

oannides AA, Dimitriadis SI, Saridis GA, et al. Source spacenalysis of event-related dynamic reorganization of brain net-orks. Comput Math Methods Med 2012: 452503.

shitobi MN, Nakasato K, Yamamoto K, Iinuma K. Opercularo interhemispheric source distribution of benign Rolandicpikes of childhood. Neuroimage 2005; 25(2): 417-23.

tsara AG, Cooper M, Baker C, et al. Population analysis ofarge copy number variants and hotspots of human geneticisease. Am J Hum Genet 2009; 84(2): 148-61.

amada KM, Moller M, Saguer M, et al. Localization ana-ysis of neuronal activities in benign Rolandic epilepsysing magnetoencephalography. J Neurol Sci 1998; 154(2):64-72.

anazawa O, Tohyama J, Akasaka N, Kamimura T. A magne-oencephalographic study of patients with Panayiotopoulosyndrome. Epilepsia 2005; 46(7): 1106-13.


avros PM, Clarke T, Strug LJ, Halperin JM, Dorta NJ, PalK. Attention impairment in Rolandic epilepsy: systematic

eview. Epilepsia 2008a; 49: 1570-80.

avros PM, Clarke T, Strug LJ, Halperin JM, Dorta NJ, PalK. Attentional Impairment in Rolandic epilepsy: systematic

eview. Epilepsia 2008b; 49: 1-11.

LBg

LJwt


evelam SH, Jansen FE, Binsbergen Ev FE, et al. Copy num-er variations in patients with electrical status epilepticus inleep. J Child Neurol 2012; 27(2): 178-82.

im KC, Lee DK, Go HS, et al. Pax6-dependent corticallutamatergic neuronal differentiation regulates autism-likeehavior in prenatally valproic Acid-exposed rat offspring.ol Neurobiol 2014; 49(1): 512-28.

obayashi K, Watanabe Y, Inoue T, Oka M, Yoshinaga H,htsuka Y. Scalp-recorded high-frequency oscillations in

hildhood sleep-induced electrical status epilepticus. Epilep-ia 2010; 51(10): 2190-4.

obayashi K, Yoshinaga H, Toda Y, Inoue T, Oka M, Ohtsuka. High-frequency oscillations in idiopathic partial epilepsyf childhood. Epilepsia 2011; 52(10): 1812-9.

outroumanidis M. Panayiotopoulos syndrome: an impor-ant electroclinical example of benign childhood systempilepsy. Epilepsia 2007; 48(6): 1044-53.

ramer U, Zelnik N, Lerman-Sagie T, Shahar E. Benignhildhood epilepsy with centrotemporal spikes: clinical cha-acteristics and identification of patients at risk for multipleeizures. J Child Neurol 2002; 17: 17-9.

ugler SL, Bali B, Lieberman P, et al. An autosomal dominantenetically heterogeneous variant of Rolandic epilepsy andpeech disorder. Epilepsia 2008; 49(6): 1086-90.

ai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP.forkhead-domain gene is mutated in a severe speech and

anguage disorder. Nature 2001; 413(6855): 519-23.

al D, Reinthaler EM, Altmuller J, et al. RBFOX1 and RBFOX3utations in Rolandic epilepsy. PLoS One 2013a; 8(9): e73323.

al D, Trucks H, Moller RS, et al. Rare exonic deletions ofhe RBFOX1 gene increase risk of idiopathic generalized epi-epsy. Epilepsia 2013b; 54(2): 265-71.

al D, Reinthaler EM, Schubert J, et al. DEPDC5 muta-ions in genetic focal epilepsies of childhood. Ann Neurol014; 75(5): 788-92.

andau WM, Kleffner FR. Syndrome of acquired aphasia withonvulsive disorder in children. Neurology 1957; 7: 523-30.

eal A, Dias A, Vieira JP, Secca M, Jordao C. The BOLD effect ofnterictal spike activity in childhood occipital lobe epilepsy.pilepsia 2006; 47(9): 1536-42.

ee HY, Huang Y, Bruneau N, et al. Mutations in the geneRRT2 cause paroxysmal kinesigenic dyskinesia with infantileonvulsions. Cell Rep 2012; 1(1): 2-12.

ee K, Kim Y, Lee SJ, et al. MDGAs interact selectivelyith neuroligin-2 but not other neuroligins to regulate

nhibitory synapse development. Proc Natl Acad Sci USA013; 110(1): 336-41.

283

egarda S, Jayakar P, Duchowny M, Alvarez L, Resnick T.enign Rolandic epilepsy: high central and low central sub-roups. Epilepsia 1994; 35(6): 1125-9.

emke JR, Beck-Wodl S, Zankl A, Riegel M, Kramer G, Dorn T.uvenile myoclonic epilepsy with photosensitivity in a femaleith Velocardiofacial syndrome (del(22)(q11. 2))-causal rela-

ionship or coincidence? Seizure 2009; 18(9): 660-3.

http://www.ncbi.nlm.nih.gov/pubmed?term=Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes

http://www.ncbi.nlm.nih.gov/pubmed?term=15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Clarifying the role of the 22q11.2 microdeletion in juvenile myoclonic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Structural genomic variation in childhood epilepsies with complex phenotypes

http://www.ncbi.nlm.nih.gov/pubmed?term=The epidemiology of comorbidities in Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Risk factors for reading disability in Rolandic Epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=SCN1A testing for epilepsy: application in clinical practice

http://www.ncbi.nlm.nih.gov/pubmed?term=Increased frequency of Rolandic spikes in ADHD children

http://www.ncbi.nlm.nih.gov/pubmed?term=Rolandic spikes increase impulsivity in ADHD - a neuropsychological pilot study

http://www.ncbi.nlm.nih.gov/pubmed?term=High resolution spatio-temporal EEG-MEG analysis of Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Source space analysis of event-related dynamic reorganization of brain networks

http://www.ncbi.nlm.nih.gov/pubmed?term=Opercular to interhemispheric source distribution of benign Rolandic spikes of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Population analysis of large copy number variants and hotspots of human genetic disease

http://www.ncbi.nlm.nih.gov/pubmed?term=Localization analysis of neuronal activities in benign Rolandic epilepsy using magnetoencephalography

http://www.ncbi.nlm.nih.gov/pubmed?term=A magnetoencephalographic study of patients with Panayiotopoulos syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Attention impairment in Rolandic epilepsy: systematic review

http://www.ncbi.nlm.nih.gov/pubmed?term=Attentional Impairment in Rolandic epilepsy: systematic review

http://www.ncbi.nlm.nih.gov/pubmed?term=Copy number variations in patients with electrical status epilepticus in sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic Acid-exposed rat offspring

http://www.ncbi.nlm.nih.gov/pubmed?term=Scalp-recorded high-frequency oscillations in childhood sleep-induced electrical status epilepticus

http://www.ncbi.nlm.nih.gov/pubmed?term=High-frequency oscillations in idiopathic partial epilepsy of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Panayiotopoulos syndrome: an important electroclinical example of benign childhood system epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign childhood epilepsy with centrotemporal spikes: clinical characteristics and identification of patients at risk for multiple seizures

http://www.ncbi.nlm.nih.gov/pubmed?term=An autosomal dominant genetically heterogeneous variant of Rolandic epilepsy and speech disorder

http://www.ncbi.nlm.nih.gov/pubmed?term=A forkhead-domain gene is mutated in a severe speech and language disorder

http://www.ncbi.nlm.nih.gov/pubmed?term=RBFOX1 and RBFOX3 mutations in Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=DEPDC5 mutations in genetic focal epilepsies of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Syndrome of acquired aphasia with convulsive disorder in children

http://www.ncbi.nlm.nih.gov/pubmed?term=The BOLD effect of interictal spike activity in childhood occipital lobe epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions

http://www.ncbi.nlm.nih.gov/pubmed?term=MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign Rolandic epilepsy: high central and low central subgroups

http://www.ncbi.nlm.nih.gov/pubmed?term=Juvenile myoclonic epilepsy with photosensitivity in a female with Velocardiofacial syndrome (del(22)(q11. 2))-causal relationship or coincidence?


2

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yrig

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6 Jo

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ext.

Tél

écha

rgé

par

un u

tilis

ateu

r an

onym

e le

23/

11/2

016.

.K. Pal, et al.

emke JR, Hendrickx R, Geider K, et al. GRIN2B mutations inest syndrome and intellectual disability with focal epilepsy.

nn Neurol 2013a; 75(1): 147-54.

emke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2Aause idiopathic focal epilepsy with Rolandic spikes. Natenet 2013b; 45(9): 1067-72.

esca G, Rudolf G, Labalme A, et al. Epileptic encephalopa-hies of the Landau-Kleffner and continuous spike and wavesuring slow-wave sleep types: genomic dissection makes the

ink with autism. Epilepsia 2012; 53(9): 1526-38.

esca G, Rudolf G, Bruneau N, et al. GRIN2A mutations incquired epileptic aphasia and related childhood focal epi-epsies and encephalopathies with speech and languageysfunction. Nat Genet 2013; 45(9): 1061-6.

illywhite LM, Saling MM, Harvey AS, et al. Neuropsy-hological and functional MRI studies provide convergingvidence of anterior language dysfunction in BECTS. Epilep-ia 2009; 50(10): 2276-84.

im ET, Raychaudhuri S, Sanders SJ, et al. Rare complete kno-kouts in humans: population distribution and significantole in autism spectrum disorders. Neuron 2013; 77(2): 235-42.

in YY, Chang KP, Hsieh JC, et al. Magnetoencephalogra-hic analysis of bilaterally synchronous discharges in benignolandic epilepsy of childhood. Seizure 2003a; 12(7): 448655.

in YY, Shih YH, Chang KP, et al. MEG localization of Rolandicpikes with respect to SI and SII cortices in benign Rolandicpilepsy. Neuroimage 2003b; 20(4): 2051-61.

in YY, Hsiao FJ, Chang KP, Wu ZA, Ho LT. Bilateral oscillationsor lateralized spikes in benign Rolandic epilepsy. Epilepsyes 2006; 69(1): 45-52.

indgren A, Kihlgren M, Melin L, Croona C, Lundberg S, Eeg-lofsson O. Development of cognitive functions in childrenith Rolandic epilepsy. Epilepsy & Behav 2004; 5(6): 903-10.

oiseau P, Beaussart M. The seizures of benign childhoodpilepsy with Rolandic paroxysmal discharges. Epilepsia973; 14: 381-9.

undberg S, Frylmark A, Eeg-Olofsson O. Children witholandic epilepsy have abnormalities of oromotor andichotic listening performance. Dev Med Child Neurol005; 47(9): 603-8.

upski JR. Genomic disorders: structural features of theenome can lead to DNA rearrangements and human diseaseraits. Trends Genet 1998; 14(10): 417-22.

aquet P, Hirsch E, Metz-Lutz MN, et al. Regional cerebrallucose metabolism in children with deterioration of oner more cognitive functions and continuous spike-and-waveischarges during sleep. Brain 1995; 118(6): 1497-520.

84

cBride DJ, Buckle A, Heyningen V, Kleinjan DA. DNa-eI hypersensitivity and ultraconservation reveal novel,nterdependent long-range enhancers at the complex Pax6is-regulatory region. PLoS One 2011; 6(12): e28616.

efford HC, Eichler EE. Duplication hotspots, rare geno-ic disorders, and common disease. Curr Opin Genet Dev

009; 19(3): 196-204.

ip

Nnwn2

efford HC, Sharp AJ, Baker C, et al. Recurrent rear-angements of chromosome 1q21.1 and variable pediatrichenotypes. N Engl J Med 2008; 359(16): 1685-99.

efford HC, Muhle H, Ostertag P, et al. Genome-wide copyumber variation in epilepsy: novel susceptibility loci in

diopathic generalized and focal epilepsies. PLoS Genet010; 6(5): e1000962.

efford HC, Yendle SC, Hsu C, et al. Rare copy numberariants are an important cause of epileptic encephalopa-hies. Ann Neurol 2011; 70(6): 974-85.

etz-Lutz MN, Filippini M. Neuropsychological findings inolandic epilepsy and Landau-Kleffner syndrome. Epilepsia006; 47(2): 71-5.

etz-Lutz MN, Kleitz C, de Saint Martin A, Massa R, Hirsch, Marescaux C. Cognitive development in benign focal epi-epsies of childhood. Dev Neurosci 1999; 21(3-5): 182-90.

iller DT, Adam MP, Aradhya S, et al. Consensus statement:hromosomal microarray is a first-tier clinical diagnostic testor individuals with developmental disabilities or congenitalnomalies. Am J Hum Genet 2010; 86(5): 749-64.

inami T, Gondo K, Yamamoto T, Yanai S, Tasaki K, Ueda K.agnetoencephalographic analysis of Rolandic discharges in

enign childhood epilepsy. Ann Neurol 1996; 39(3): 326-34.

oller RS, Weber YGLLKlitten, Weber, et al. Exon-disruptingeletions of NRXN1 in idiopathic generalized epilepsy. Epi-

epsia 2013; 54(2): 256-64.

onjauze C, Tuller L, Hommet C, Barthez MA, Khomsi A. Lan-uage in benign childhood epilepsy with centro-temporalpikes abbreviated form: Rolandic epilepsy and language.rain & Language 2005; 92(3): 300-8.

ontenegro MA, Guerreiro MM. Electrical status epilep-icus of sleep in association with topiramate. Epilepsia002; 43(11): 1436-40.

orikawa T. Rolandic discharges in benign childhood epi-epsy with centrotemporal spikes, and in other forms ofartial epilepsies. Epileptic Disord 2000; 2(1): S23-8.

eubauer BA, Fiedler B, Himmelein B, et al. Centrotemporalpikes in families with Rolandic epilepsy: linkage to chromo-ome 15q14. Neurology 1998; 51(6): 1608-12.

guyen L, Humbert S, Saudou F, Chariot A. Elongator - anmerging role in neurological disorders. Trends Mol Med009; 16(1): 1-6.

icolai J, Aldenkamp AP, Arends J, Weber JW, Vles JSH.ognitive and behavioral effects of nocturnal epileptiformischarges in children with benign childhood epilepsy withentrotemporal spikes. Epilepsy & Behav 2006; 8: 56-70.

iedermeyer E, McKusick VA, Brunt P, Mahloudji M. The EEG


n familial dysautonomia (Riley-Day syndrome). Electroence-halogr Clin Neurophysiol 1967; 22(5): 473-5.

ieuwenhuis L, Nicolai J. The pathophysiological mecha-isms of cognitive and behavioral disturbances in childrenith Landau-Kleffner syndrome or epilepsy with conti-uous spike-and-waves during slow-wave sleep. Seizure006; 15(4): 249-58.

http://www.ncbi.nlm.nih.gov/pubmed?term=GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Mutations in GRIN2A cause idiopathic focal epilepsy with Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism

http://www.ncbi.nlm.nih.gov/pubmed?term=GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological and functional MRI studies provide converging evidence of anterior language dysfunction in BECTS

http://www.ncbi.nlm.nih.gov/pubmed?term=Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders

http://www.ncbi.nlm.nih.gov/pubmed?term=Magnetoencephalographic analysis of bilaterally synchronous discharges in benign Rolandic epilepsy of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=MEG localization of Rolandic spikes with respect to SI and SII cortices in benign Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Bilateral oscillations for lateralized spikes in benign Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Development of cognitive functions in children with Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=The seizures of benign childhood epilepsy with Rolandic paroxysmal discharges

http://www.ncbi.nlm.nih.gov/pubmed?term=Children with Rolandic epilepsy have abnormalities of oromotor and dichotic listening performance

http://www.ncbi.nlm.nih.gov/pubmed?term=Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits

http://www.ncbi.nlm.nih.gov/pubmed?term=Regional cerebral glucose metabolism in children with deterioration of one or more cognitive functions and continuous spike-and-wave discharges during sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=DNaseI hypersensitivity and ultraconservation reveal novel, interdependent long-range enhancers at the complex Pax6 cis-regulatory region

http://www.ncbi.nlm.nih.gov/pubmed?term=Duplication hotspots, rare genomic disorders, and common disease

http://www.ncbi.nlm.nih.gov/pubmed?term=Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies

http://www.ncbi.nlm.nih.gov/pubmed?term=Rare copy number variants are an important cause of epileptic encephalopathies

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological findings in Rolandic epilepsy and Landau-Kleffner syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognitive development in benign focal epilepsies of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies

http://www.ncbi.nlm.nih.gov/pubmed?term=Magnetoencephalographic analysis of Rolandic discharges in benign childhood epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Language in benign childhood epilepsy with centro-temporal spikes abbreviated form: Rolandic epilepsy and language

http://www.ncbi.nlm.nih.gov/pubmed?term=Electrical status epilepticus of sleep in association with topiramate

http://www.ncbi.nlm.nih.gov/pubmed?term=Rolandic discharges in benign childhood epilepsy with centrotemporal spikes, and in other forms of partial epilepsies

http://www.ncbi.nlm.nih.gov/pubmed?term=Centrotemporal spikes in families with Rolandic epilepsy: linkage to chromosome 15q14

http://www.ncbi.nlm.nih.gov/pubmed?term=Elongator - an emerging role in neurological disorders

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognitive and behavioral effects of nocturnal epileptiform discharges in children with benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=The EEG in familial dysautonomia (Riley-Day syndrome)

http://www.ncbi.nlm.nih.gov/pubmed?term=The pathophysiological mechanisms of cognitive and behavioral disturbances in children with Landau-Kleffner syndrome or epilepsy with continuous spike-and-waves during slow-wave sleep


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onym

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23/

11/2

016.

orthcott E, Connolly AM, Berroya A, et al. Memory andhonological awareness in children with Benign Rolandicpilepsy compared to a matched control group. Epilepsy Res007; 75(1): 57-62.

htsu M, Oguni H, Hayashi K, Funatsuka M, Imai K, Osawa M.EG in children with early-onset benign occipital seizure sus-eptibility syndrome: Panayiotopoulos syndrome. Epilepsia003; 44(3): 435-42.

ser N, Hubacher M, Specht K, Datta AN, Weber P, PennerK. Default mode network alterations during language taskerformance in children with benign epilepsy with centro-

emporal spikes (BECTS). Epilepsy Behav 2014; 33: 12-7.

tero G, Fellows J, Li Y, et al. Elongator, a multisubunitomponent of a novel RNA polymerase II holoenzyme forranscriptional elongation. Mol Cell 1999; 3(1): 109-18.

vervliet GM, Besseling RM, Vles JS, et al. Nocturnal epi-eptiform EEG discharges, nocturnal epileptic seizures, andanguage impairments in children: review of the literature.pilepsy Behav 2010; 19(4): 550-8.

aetau R. Magnetoencephalography in Landau-Kleffner syn-rome. Epilepsia 2009; 50 Suppl 7: 51-4.

aetau R, Granstrom ML, Blomstedt G, Jousmaki V, Korkman, Liukkonen E. Magnetoencephalography in presurgical

valuation of children with the Landau-Kleffner syndrome.pilepsia 1999; 40(3): 326-35.

al DK, Li W, Clarke T, Lieberman P, Strug LJ. Pleiotropicffects of the 11p13 locus on developmental verbal dyspraxiand EEG centrotemporal sharp waves. Genes Brain Behav010; 9(8): 1004-12.

anayiotopoulos CP. Benign nocturnal childhood occipi-al epilepsy: a new syndrome with nocturnal seizures,onic deviation of the eyes, and vomiting. J Child Neurol989; 4(1): 43-9.

anayiotopoulos CP. Occipital seizures and epilepsies in chil-ren. In : Anderman F, Beaumanoir A, Mira L, Tassinari CA.enign childhood epilepsy with occipital paroxysms. London:

ohn Libbey, 1993: 151-64.

anayiotopoulos CP. The birth and evolution of theoncept of Panayiotopoulos syndrome. Epilepsia 2007; 48(6):041-3.

anayiotopoulos CP, Michael M, Sanders S, Valeta T, Koutrou-anidis M. Benign childhood focal epilepsies: assessment

f established and newly recognized syndromes. Brain008; 131(9): 2264-86.

apavasiliou A, Mattheou D, Bazigou H, Kotsalis C, Paraske-oulakos E. Written language skills in children with benignhildhood epilepsy with centrotemporal spikes. Epilepsy &ehav 2005; 6(1): 50-8.


ataraia E, Feucht M, Lindinger G, Aull-Watschinger S, Baum-artner C. Combined electroencephalography and magne-oencephalography of interictal spikes in benign Rolandicpilepsy of childhood. Clin Neurophysiol 2008; 119(3): 635-41.

atry G, Lyagoubi S, Tassinari CA. Subclinical electrical statuspilepticus induced by sleep in children: a clinical and EEGtudy of six cases. Arch Neurol 1971; 24: 242-52.

Lf

R1

SrS


icard A, Cheliout Heraut F, Bouskraoui M, Lemoine M, Lacert, Delattre J. Sleep EEG and developmental dysphasia. Deved Child Neurol 1998; 40(9): 595-9.

iccinelli P, Borgatti R, Aldini A, et al. Academic performancen children with Rolandic epilepsy. Dev Med Child Neurol008; 50(5): 353-6.

inton F, Ducot B, Motte J, et al. Cognitive functions in chil-ren with benign childhood epilepsy with centrotemporalpikes (BECTS). Epileptic Disord 2006; 8(1): 11-23.

iton A, Redin C, Mandel JL. XLID-causing mutations andssociated genes challenged in light of data from large-scaleuman exome sequencing. Am J Hum Genet 2013; 93(2):68-83.

orciatti V, Bonanni P, Fiorentini A, Guerrini R. Lack of corticalontrast gain control in human photosensitive epilepsy. Nateurosci 2000; 3(3): 259-63.

rats JM, Garaizar C, Garcia-Neto ML, Madoz P. Antiepilepticrugs and atypical evolution of idiopathic partial epilepsy.ediatric Neurology 1998; 18: 402-6.

eutlinger C, IHelbig I, Gawelczyk B, et al. Deletions in6p13 including GRIN2A in patients with intellectual disabi-ity, various dysmorphic features, and seizure disorders of theolandic region. Epilepsia 2010; 51(9): 1870-3.

ichardson MP. Large scale brain models of epilepsy: dyna-ics meets connectomics. J Neurol Neurosurg Psychiatry

012; 83(12): 1238-48.

iva D, Vago C, Franceschetti S, et al. Intellectual and lan-uage findings and their relationship to EEG characteristics

n benign childhood epilepsy with centrotemporal spikes.pilepsy & Behav 2007; 10(2): 278-85.

obinson SE, Nagarajan SS, Mantle M, Gibbons V, Kirsch H.ocalization of interictal spikes using SAM(g2) and dipole fit.eurol Clin Neurophysiol 2004; 2004: 74.

oll P, Rudolf G, Pereira S, et al. SRPX2 mutations in disor-ers of language cortex and cognition. Hum Mol Genet006; 15(7): 1195-207.

oll P, Vernes SC, Bruneau N, et al. Molecular networksmplicated in speech-related disorders: FOXP2 regulates theRPX2/uPAR complex. Hum Mol Genet 2010; 19(24): 4848-60.

oulet-Perez E, Deonna T, Despland PA. Prolonged inter-ittent drooling and oromotor dyspraxia in benign

hildhood epilepsy with centrotemporal spikes. Epilepsia989; 30(5): 564-8.

ubia K, Smith A, Taylor E. Performance of children withDHD on a test battery of impulsiveness. Child Neuropsy-hology 2007; 13(3): 276-304.

udolf G, Valenti MP, Hirsch E, Szepetowski P. From Rolan-ic epilepsy to continuous spike-and-waves during sleep andandau-Kleffner syndromes: insights into possible genetic

285

actors. Epilepsia 2009; 50(7): 25-8.

yan SG. Partial epilepsy: chinks in the armour. Nat Genet995; 10(1): 4-6.

almi M, Bruneau N, Cillario J, et al. Tubacin prevents neu-onal migration defects and epileptic activity caused by ratrpx2 silencing in utero. Brain 2013; 136(8): 2457-73.

http://www.ncbi.nlm.nih.gov/pubmed?term=Memory and phonological awareness in children with Benign Rolandic Epilepsy compared to a matched control group

http://www.ncbi.nlm.nih.gov/pubmed?term=EEG in children with early-onset benign occipital seizure susceptibility syndrome: Panayiotopoulos syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Default mode network alterations during language task performance in children with benign epilepsy with centrotemporal spikes (BECTS)

http://www.ncbi.nlm.nih.gov/pubmed?term=Elongator, a multisubunit component of a novel RNA polymerase II holoenzyme for transcriptional elongation

http://www.ncbi.nlm.nih.gov/pubmed?term=Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature

http://www.ncbi.nlm.nih.gov/pubmed?term=Magnetoencephalography in Landau-Kleffner syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Magnetoencephalography in presurgical evaluation of children with the Landau-Kleffner syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Pleiotropic effects of the 11p13 locus on developmental verbal dyspraxia and EEG centrotemporal sharp waves

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign nocturnal childhood occipital epilepsy: a new syndrome with nocturnal seizures, tonic deviation of the eyes, and vomiting

http://www.ncbi.nlm.nih.gov/pubmed?term=The birth and evolution of the concept of Panayiotopoulos syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign childhood focal epilepsies: assessment of established and newly recognized syndromes

http://www.ncbi.nlm.nih.gov/pubmed?term=Written language skills in children with benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Combined electroencephalography and magnetoencephalography of interictal spikes in benign Rolandic epilepsy of childhood

http://www.ncbi.nlm.nih.gov/pubmed?term=Subclinical electrical status epilepticus induced by sleep in children: a clinical and EEG study of six cases

http://www.ncbi.nlm.nih.gov/pubmed?term=Sleep EEG and developmental dysphasia

http://www.ncbi.nlm.nih.gov/pubmed?term=Academic performance in children with Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognitive functions in children with benign childhood epilepsy with centrotemporal spikes (BECTS)

http://www.ncbi.nlm.nih.gov/pubmed?term=XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing

http://www.ncbi.nlm.nih.gov/pubmed?term=Lack of cortical contrast gain control in human photosensitive epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Antiepileptic drugs and atypical evolution of idiopathic partial epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the Rolandic region

http://www.ncbi.nlm.nih.gov/pubmed?term=Large scale brain models of epilepsy: dynamics meets connectomics

http://www.ncbi.nlm.nih.gov/pubmed?term=Intellectual and language findings and their relationship to EEG characteristics in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Localization of interictal spikes using SAM(g2) and dipole fit

http://www.ncbi.nlm.nih.gov/pubmed?term=SRPX2 mutations in disorders of language cortex and cognition

http://www.ncbi.nlm.nih.gov/pubmed?term=Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex

http://www.ncbi.nlm.nih.gov/pubmed?term=Prolonged intermittent drooling and oromotor dyspraxia in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Performance of children with ADHD on a test battery of impulsiveness

http://www.ncbi.nlm.nih.gov/pubmed?term=From Rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors

http://www.ncbi.nlm.nih.gov/pubmed?term=Partial epilepsy: chinks in the armour

http://www.ncbi.nlm.nih.gov/pubmed?term=Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero


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6 Jo

hn L

ibbe

y E

urot

ext.

Tél

écha

rgé

par

un u

tilis

ateu

r an

onym

e le

23/

11/2

016.

.K. Pal, et al.

altik S, Uluduz D, Cokar O, Demirbilek V, Dervent A.clinical and EEG study on idiopathic partial epilepsies

ith evolution into ESES spectrum disorders. Epilepsia005; 46(4): 524-33.

cheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Ber-ovic SF. Autosomal dominant Rolandic epilepsy and speechyspraxia: a new syndrome with anticipation. Ann Neurol995; 38(4): 633-42.

halev L, Tsal Y, Mevorach C. Computerized Progressivettentional Training (CPAT) Program: effective direct inter-ention for children with ADHD. Child Neuropsychology007; 13(4): 382-8.

harp AJ. Emerging themes and new challenges in defininghe role of structural variation in human disease. Hum Mutat009; 30(2): 135-44.

haw CJ, Lupski JR. Implications of human genome architec-ure for rearrangement-based disorders: the genomic basisf disease. Hum Mol Genet 2004; 13(1): R57-64.

hields WD, Saslow E. Myoclonic, atonic, and absence sei-ures following institution of carbamazepine therapy inhildren. Neurology 1983; 33(11): 1487-9.

impson CL, Lemmens R, Miskiewicz K, et al. Variants of thelongator protein 3 (ELP3) gene are associated with motoreuron degeneration. Hum Mol Genet 2009; 18(3): 472-81.

iniatchkin M, Capovilla G. Functional neuroimaging in epi-eptic encephalopathies. Epilepsia 2013; 54(8): 27-33.

iniatchkin M, Groening K, Moehring J, et al. Neuronal net-orks in children with continuous spikes and waves during

low sleep. Brain 2010; 133(9): 2798-813.

laugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specificxpression of a splicing mutation in the IKBKAP gene causesamilial dysautonomia. Am J Hum Genet 2001; 68(3): 598-605.

mith A, Taylor E, Brammer M, Toone B, Rubia K. Taskpecific hypoactivation in prefrontal and temporoparietalrain regions during motor inhibition and task switching inedication-naïve children and adolescents with ADHD. Am

Psychiatry 2006; 163: 1044-51.

mith AB, Taylor E, Brammer M, Halari R, Rubia K. Reducedctivation in right lateral prefrontal cortex and anterior cin-ulate cortex in medication-naïve adolescents with Attentioneficit Hyperactivity Disorder during time discrimination. Jhild Psychol Psychiatry 2008; 49(9): 977685.

mith A, Kavros PM, Clarke T, Dorta N, Tremont G, Pal DK.neurocognitive endophenotype associated with Rolandic

pilepsy. Epilepsia 2012; 53(4): 705-11.

mith AB, Bajojo O, Pal DK. A meta-analysis of literacy andanguage in children with Rolandic Epilepsy. Dev Med Child

eurol 2015; 57(11): 1019-26.

86

nowling MJ. Phonological processing and developmentalyslexia. J Res Read 1995; 18(2): 132-8.

obel DF, Aung M, Otsubo H, Smith MC. Magnetoence-halography in children with Landau-Kleffner syndromend acquired epileptic aphasia. AJNR Am J Neuroradiol000; 21(2): 301-7.

o3

VcdB

pecchio N, Trivisano M, Di Ciommo V, et al. Panayioto-oulos syndrome: a clinical, EEG, and neuropsychologicaltudy of 93 consecutive patients. Epilepsia 2010; 51(10):098-107.

pira EG, Fischel JE. The impact of preschool inattention,yperactivity, and impulsivity on social and academic deve-

opment: a review. J Child Psychol Psychiatry 2005; 46(7):55-73.

taden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Languageysfunction in children with Rolandic epilepsy. Neuropedia-

rics 1998; 29(5): 242-8.

taden U, Isaacs E, Boyd S, Brandl U, Neville B. Language dys-unction in children with Rolandic epilepsy. Neuropediatrics007; 29(05): 242-8.

teinlein OK, Mulley JC, Propping P, et al. A missense muta-ion in the neuronal nicotinic receptor alpha 4 subunit isssociated with autosomal dominant nocturnal frontal lobepilepsy. Nature Genetics 1995; 11: 201-3.

triano P, Capovilla G. Epileptic encephalopathy with conti-uous spikes and waves during sleep. Curr Neurol Neurosciep 2013; 13(7): 360.

trug LJ, Clarke T, Chiang T, et al. Centrotemporal sharp waveEG trait in Rolandic epilepsy maps to Elongator Protein Com-lex 4 (ELP4). Eur J Hum Genet 2009; 17: 1171-81.

trug LJ, Addis L, Chiang T, et al. The genetics of readingisability in an often excluded sample: novel loci sugges-

ed for reading disability in Rolandic epilepsy. PLoS One012; 7(7): e40696.

vejstrup JQ. Elongator complex: how many roles does itlay? Curr Opin Cell Biol 2007; 19(3): 331-6.

assinari CA, Rubboli G, Volpi L, et al. Encephalopathy withlectrical status epilepticus during slow sleep or ESES syn-rome including the acquired aphasia. Clin Neurophysiol000; 111(2): S94-102.

assinari CA, Rubboli G, Volpi L. Electrical status epilepticusuring slow sleep (ESES or CSWS) including acquired epilep-

ic aphasia (Landau-Kleffner syndrome). In: Roger J, Bureau, Dravet C. Epileptic syndromes in infancy, childhood and

dolescence. Montrouge: John Libbey Eurotext Ltd, 2005:95-314.

aylor JG, Ioannides AA, Muller-Gartner HW. Mathematicalnalysis of lead field expansions. IEEE Trans Med Imaging999; 18(2): 151-63.

edrus GM, Fonseca LC, Melo E, Ximenes VL. Educationalroblems related to quantitative EEG changes in benign child-ood epilepsy with centrotemporal spikes. Epilepsy & Behav009; 15(4): 48690.

rbain C, Di Vincenzo T, Peigneux P, Van Bogaert P. Is sleep-elated consolidation impaired in focal idiopathic epilepsies


f childhood? A pilot study. Epilepsy Behav 2011; 22(2):80-4.

aleta T. Parental attitude, reaction and education in benignhildhood focal seizures. In: The epilepsies: seizures, syn-romes and management. Panayiotopoulos CP. Oxford:ladon Medical Publishing, 2005: 258-61.

http://www.ncbi.nlm.nih.gov/pubmed?term=A clinical and EEG study on idiopathic partial epilepsies with evolution into ESES spectrum disorders

http://www.ncbi.nlm.nih.gov/pubmed?term=Autosomal dominant Rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation

http://www.ncbi.nlm.nih.gov/pubmed?term=Computerized Progressive Attentional Training (CPAT) Program: effective direct intervention for children with ADHD

http://www.ncbi.nlm.nih.gov/pubmed?term=Emerging themes and new challenges in defining the role of structural variation in human disease

http://www.ncbi.nlm.nih.gov/pubmed?term=Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease

http://www.ncbi.nlm.nih.gov/pubmed?term=Myoclonic, atonic, and absence seizures following institution of carbamazepine therapy in children

http://www.ncbi.nlm.nih.gov/pubmed?term=Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

http://www.ncbi.nlm.nih.gov/pubmed?term=Functional neuroimaging in epileptic encephalopathies

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuronal networks in children with continuous spikes and waves during slow sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia

http://www.ncbi.nlm.nih.gov/pubmed?term=Task specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-nave children and adolescents with ADHD

http://www.ncbi.nlm.nih.gov/pubmed?term=Reduced activation in right lateral prefrontal cortex and anterior cingulate cortex in medication-nave adolescents with Attention Deficit Hyperactivity Disorder during time discrimination

http://www.ncbi.nlm.nih.gov/pubmed?term=A neurocognitive endophenotype associated with Rolandic Epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=A meta-analysis of literacy and language in children with Rolandic Epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Phonological processing and developmental dyslexia

http://www.ncbi.nlm.nih.gov/pubmed?term=Magnetoencephalography in children with Landau-Kleffner syndrome and acquired epileptic aphasia

http://www.ncbi.nlm.nih.gov/pubmed?term=Panayiotopoulos syndrome: a clinical, EEG, and neuropsychological study of 93 consecutive patients

http://www.ncbi.nlm.nih.gov/pubmed?term=The impact of preschool inattention, hyperactivity, and impulsivity on social and academic development: a review

http://www.ncbi.nlm.nih.gov/pubmed?term=Language dysfunction in children with Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Language dysfunction in children with Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=A missense mutation in the neuronal nicotinic receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Epileptic encephalopathy with continuous spikes and waves during sleep

http://www.ncbi.nlm.nih.gov/pubmed?term=Centrotemporal sharp wave EEG trait in Rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4)

http://www.ncbi.nlm.nih.gov/pubmed?term=The genetics of reading disability in an often excluded sample: novel loci suggested for reading disability in Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Elongator complex: how many roles does it play?

http://www.ncbi.nlm.nih.gov/pubmed?term=Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia

http://www.ncbi.nlm.nih.gov/pubmed?term=Mathematical analysis of lead field expansions

http://www.ncbi.nlm.nih.gov/pubmed?term=Educational problems related to quantitative EEG changes in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Is sleep-related consolidation impaired in focal idiopathic epilepsies of childhood? A pilot study


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Cop

yrig

ht ©

201

6 Jo

hn L

ibbe

y E

urot

ext.

Tél

écha

rgé

par

un u

tilis

ateu

r an

onym

e le

23/

11/2

016.

aleta T. Psychosocial impact of epilepsy in children andamily. In: Panayiotopoulos CP. Atlas of epilepsies. London:pringer, 2010: 1371-3.

aleta T. Parental reactions and needs in benign childhoodocal seizures. Epilepsia 2011; 52(S6): 122-3.

aleta T. Parental reactions in benign childhood focal sei-ures. Epilepsia 2012; 53(S5): 222-3.

aleta T, Sogawa Y, Moshe SL. Impact of focal sei-ures on patients and family. In: PanayiotopoulosP, Benbadis S, Sisodiya S. Focal epilepsies: seizures,

yndromes and management. Oxford: Medicinae,008: 5.

an Bogaert P. Epileptic encephalopathy with continuouspike-waves during slow-wave sleep including Landau-leffner syndrome. Handbook Clin Neurol 2013; 111:35-40.

an der Meij W, Van Huffelen AC, Wieneke GH,illemse J. Sequential EEG mapping may differen-

iate epileptic from non-epileptic Rolandic spikes.lectroencephalogr Clin Neurophysiol 1992; 82(6):08-14.

an der Meij W, Wieneke GH, van Huffelen AC. Dipoleource analysis of Rolandic spikes in benign Rolandic epi-epsy and other clinical syndromes. Brain Topogr 1993; 5(3):03-13.

an der Meij W, Huiskamp GJ, Rutten GJ, Wieneke GH,an Huffelen AC, van Nieuwenhuizen O. The existence ofwo sources in Rolandic epilepsy: confirmation with highesolution EEG, MEG and fMRI. Brain Topogr 2001; 13(4):75-82.

ears DF, Tsai MH, Sadleir G, et al. Clinical genetic studiesn benign childhood epilepsy with centrotemporal spikes.pilepsia 2012; 53(2): 319-24.

eggiotti P, Beccaria F, Guerrini R, Capovilla G, Lanzi. Continuous spike-and-wave activity during slow-wave

leep: syndrome or EEG pattern? Epilepsia 1999; 40(11):593-601.

eggiotti P, Pera MC, Teutonico F, Brazzo D, Balottin U, Tas-inari CA. Therapy of encephalopathy with status epilepticusuring sleep (ESES/CSWS syndrome): an update. Epilepticisord 2012; 14(1): 1-11.


errotti A, Latini G, Trotta D, et al. Typical and atypical Rolan-ic epilepsy in childhood: a follow-up study. Pediatr Neurol002; 26(1): 26-9.

errotti A, D’Egidio C, Agostinelli S, Parisi P, Chiarelli F,oppola G. Cognitive and linguistic abnormalities in benignhildhood epilepsy with centrotemporal spikes. Acta Paedia-rica 2010; 100(5): 768-72.

YcaD

Zm2


errotti A, Filippini M, Matricardi S, Agostinelli MF, Gobbi. Memory impairment and benign epilepsy with centro-

emporal spike (BECTS): a growing suspicion. Brain Cogn014; 84(1): 123-31.

olkl-Kernstock S, Bauch-Prater S, Ponocny-Seliger E, Feucht. Speech and school performance in children with benign

artial epilepsy with centro-temporal spikes (BCECTS). Sei-ure 2009; 18(5): 320-6.

rba J, Robinson SE. Signal processing in magnetoencepha-ography. Methods 2001; 25(2): 249-71.

eglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsy-hological, intellectual, and behavioral findings in patientsith centrotemporal spikes with and without seizures. Deve-

opmental Medicine and Child Neurology 1997; 39(10): 646-51.

olf P. Basic principles of the ILAE syndrome classification.pilepsy Res 2006; 70(1): S20-6.

olff M, Weiskopf N, Serra E, Preissl H, Birbaumer N,raegeloh-Mann. N. Benign partial epilepsy in childhood:elective cognitive deficits are related to the location ofocal spikes determined by combined EEG/MEG. Epilepsia005; 46(10): 1661-7.

ong PK. Stability of source estimates in Rolandic spikes.rain Topogr 1989; 2(1-2): 31-6.

oshinaga H, Amano R, Oka E, Ohtahara S. Dipole tracing inhildhood epilepsy with special reference to Rolandic epi-epsy. Brain Topogr 1992; 4(3): 193-9.

oshinaga H, Koutroumanidis M, Shirasawa A, Kikumoto K,htsuka Y, Oka E. Dipole analysis in panayiotopoulos syn-

rome. Brain Dev 2005; 27(1): 46-52.

oshinaga H, Koutroumanidis M, Kobayashi K, et al. EEGipole characteristics in Panayiotopoulos syndrome. Epilep-ia 2006; 47(4): 781-7.

oshinaga H, Kobayashi K, Akiyama T, Shibata T, Endoh F,htsuka Y. Clinical implications of preceding positive spikes

n patients with benign partial epilepsy and febrile seizures.rain Dev 2013; 35(4): 299-306.

oshinaga H, Kobayashi K, Shibata T, Inoue T, Oka M, Akiyama. Manifestation of both emetic seizures and sylvian seizures

n the same patients with benign partial epilepsy. Brain Dev015; 37(1): 13-7.

ou SJ, Kim DS, Ko TS. Benign childhood epilepsy with

287

entro-temporal spikes (BCECTS): early onset of seizures isssociated with poorer response to initial treatment. Epilepticisord 2006; 8(4): 285-8.

hang F, Carvalho CM, Lupski JR. Complex human chro-osomal and genomic rearrangements. Trends Genet

009; 25(7): 298-307.

http://www.ncbi.nlm.nih.gov/pubmed?term=Parental reactions and needs in benign childhood focal seizures

http://www.ncbi.nlm.nih.gov/pubmed?term=Parental reactions in benign childhood focal seizures

http://www.ncbi.nlm.nih.gov/pubmed?term=Epileptic encephalopathy with continuous spike-waves during slow-wave sleep including Landau-Kleffner syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Sequential EEG mapping may differentiate epileptic from non-epileptic Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Dipole source analysis of Rolandic spikes in benign Rolandic epilepsy and other clinical syndromes

http://www.ncbi.nlm.nih.gov/pubmed?term=The existence of two sources in Rolandic epilepsy: confirmation with high resolution EEG, MEG and fMRI

http://www.ncbi.nlm.nih.gov/pubmed?term=Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Continuous spike-and-wave activity during slow-wave sleep: syndrome or EEG pattern?

http://www.ncbi.nlm.nih.gov/pubmed?term=Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update

http://www.ncbi.nlm.nih.gov/pubmed?term=Typical and atypical Rolandic epilepsy in childhood: a follow-up study

http://www.ncbi.nlm.nih.gov/pubmed?term=Cognitive and linguistic abnormalities in benign childhood epilepsy with centrotemporal spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Memory impairment and benign epilepsy with centrotemporal spike (BECTS): a growing suspicion

http://www.ncbi.nlm.nih.gov/pubmed?term=Speech and school performance in children with benign partial epilepsy with centro-temporal spikes (BCECTS)

http://www.ncbi.nlm.nih.gov/pubmed?term=Signal processing in magnetoencephalography

http://www.ncbi.nlm.nih.gov/pubmed?term=Neuropsychological, intellectual, and behavioral findings in patients with centrotemporal spikes with and without seizures

http://www.ncbi.nlm.nih.gov/pubmed?term=Basic principles of the ILAE syndrome classification

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign partial epilepsy in childhood: selective cognitive deficits are related to the location of focal spikes determined by combined EEG/MEG

http://www.ncbi.nlm.nih.gov/pubmed?term=Stability of source estimates in Rolandic spikes

http://www.ncbi.nlm.nih.gov/pubmed?term=Dipole tracing in childhood epilepsy with special reference to Rolandic epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Dipole analysis in panayiotopoulos syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=EEG dipole characteristics in Panayiotopoulos syndrome

http://www.ncbi.nlm.nih.gov/pubmed?term=Clinical implications of preceding positive spikes in patients with benign partial epilepsy and febrile seizures

http://www.ncbi.nlm.nih.gov/pubmed?term=Manifestation of both emetic seizures and sylvian seizures in the same patients with benign partial epilepsy

http://www.ncbi.nlm.nih.gov/pubmed?term=Benign childhood epilepsy with centro-temporal spikes (BCECTS): early onset of seizures is associated with poorer response to initial treatment

http://www.ncbi.nlm.nih.gov/pubmed?term=Complex human chromosomal and genomic rearrangements



D.K. Pal, et al.

TEST YOURSELFEDUCATION

(1) What are the epilepsies in the idiopathic focal epilepsy group and what is the evidence that they are relatedor form part of a spectrum or continuum? What other clinical overlaps exist?

(2) Name two advanced electrophysiological techniques and discuss their contribution to understandingidiopathic focal epilepsies.

(3) What neurodevelopmental complications and comorbidities occur in Rolandic epilepsy?

Note: Reading the manuscript provides an answer to all questions. Correct answers may be accessed on thewebsite, www.epilepticdisorders.com, under the section “The EpiCentre”.

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D:JLEissueEPD1818(3)ArticlesMNT JLE JOURNAL EPD 0839 … · 2018. 4. 3. · Journal Identiﬁcation = EPD Article Identiﬁcation = 0839 Date: August 17, 2016 Time: 2:18pm 254 Epileptic