99 . Bassan H , Bental Y , Shany E , Berger I , Froom P , Levi L , et al . Neonatal seizure s: dilemmas in workup and management . Pediatr Neurol 2008 ; 38 ( 6 ): 415 \200\223 21 . 115 . Mizrahi EM . Acute and chronic effects of seizures in the developing brain: lessons f rom clinical experience . Epilepsia 1999 ; 40(Suppl 1) : S42 \200\223 50 . 100 . Malingre MM , Van Rooij LG , Rademaker CM , Toet MC , Ververs TF , van KC , et al . D evelopment of an optimal lidocaine infusion strategy for neonatal seizures . Eur J Pediatr 2006 ; 165 ( 9 ): 598 \200\223 604 . 116 . Davis AS , Hintz SR , Van Meurs KP , Li L , Das A , Stoll BJ , et al . Seizures in ex tremely low birth weight infants are associated with adverse outcome . J Pediatr 2010 ; 157 ( 5 ): 720 \200\223 5 . 101 . van den Broek MP , Huitema AD , van Hasselt JG , Groenendaal F , Toet MC , Egberts TC , et al . Lidocaine (lignocaine) dosing regimen based upon a populatio n pharmacokinetic model for preterm and term neonates with seizures . Clin Pharmacokinet 20 11 ; 50 ( 7 ): 461 \200\223 9 . 117 . Guillet R , Kwon J . Seizure recurrence and developmental disabilities 102 . Van Rooij LG , Toet MC , Rademaker KM , Groenendaal F , de Vries LS . Cardiac arrhyth mias in neonates receiving lidocaine as anticonvulsive treatment . Eur J Pediatr 2004 ; 163 ( 11 ): 637 \200\223 41 . after neonatal seizures: outcomes are unrelated to use of phenobarbital prophylaxis . J Chi ld Neurol 2007 ; 22 ( 4 ): 389 \200\223 95 . 118 . Iype M , Prasad M , Nair PM , Geetha S , Kailas L . The newborn with 103 . Silverstein FS , Ferriero DM . Off-label use of antiepileptic drugs for the treatment of neonatal seizures . Pediatr Neurol 2008 Aug ; 39 ( 2 ): 77 \200\223 9 . seizures \200\224 a follow-up study . Indian Pediatr 2008 ; 45 ( 9 ): 749 \200\223 52 . 1 19 . Kwon JM , Guillet R , Shankaran S , Laptook AR , McDonald SA , Ehrenkranz RA , et al . Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyzes of data from the ne onatal research network hypothermia trial . J Child Neurol 2011 ; 26 ( 3 ): 322 \200\223 8 . 104 . Glass HC , Poulin C , Shevell MI . Topiramate for the treatment of neonatal seizures . Pediatr Neurol 2011 ; 44 ( 6 ): 439 \200\223 42 . 105 . Filippi L , la MG , Fiorini P , Poggi C , Cavallaro G , Malvagia S , et al . Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hyp oxic ischemic encephalopathy . Epilepsia 2009 ; 50 ( 11 ): 2355 \200\223 61 . 120 . McBride MC , Laroia N , Guillet R . Electrographic seizures in neonates correlate with poor neurodevelopmental outcome . Neurology 2000 ; 55 ( 4 ): 506 \200\223 1 3 . 106 . Khan O , Chang E , Cipriani C , Wright C , Crisp E , Kirmani B . Use of intravenous l evetiracetam for management of acute seizures in neonates . Pediatr Neurol 2011 ; 44 ( 4 ): 265 \200\223 9 . 121 . Pisani F , Barilli AL , Sisti L , Bevilacqua G , Seri S . Preterm infants with video EEG con \201 rmed seizures: outcome at 30 months of age . Brain Dev 2008 ; 30 ( 1 ): 20 \200\223 30 . 107 . Abend NS , Gutierrez-Colina AM , Monk HM , Dlugos DJ , Clancy RR . Levetiracetam for treatment of neonatal seizures . J Child Neurol 2011 ; 26 ( 4 ): 465 \200\223 70 . 122 . Ronen GM , Buckley D , Penney S , Streiner DL . Long-term prognosis in children with neonatal seizures: a population-based study . Neurology 2007 ; 69 ( 19 ): 181 6 \200\223 22 . 108 . Furwentsches A , Bussmann C , Ramantani G , Ebinger F , Philippi H , Poschl J , et al . Levetiracetam in the treatment of neonatal seizures: a pilot study . Seizure 2010 ; 19 ( 3 ): 185 \200\223 9 . 123 . Yamamoto H , Okumura A , Fukuda M . Epilepsies and epileptic syndromes starting in the neonatal period . Brain Dev 2011 ; 33 ( 3 ): 213 \200\223 20 . 109 . Ramantani G , Ikonomidou C , Walter B , Rating D , Dinger J . 124 . Burgess DL . Neonatal epilepsy syndromes and GEFS + : mechanistic Levetiracetam: safety and ef \201 cacy in neonatal seizures . Eur J Paediatr Neurol 2011 ; 15 ( 1 ): 1 \200\223 7 . considerations . Epilepsia 2005 ; 46 (Suppl 10 ): 51 \200\223 8 . 125 . Ohtahara S , Yamatogi Y . Ohtahara syndrome: with special reference to its developmen tal aspects for differentiating from early myoclonic encephalopathy . Epilepsy Res 2006 ; 7 0 (Suppl 1 ): S58 \200\223 67 . 110 . Kahle KT , Staley KJ . The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism- based treatment strategy fo r neonatal seizures . Neurosurg Focus 2008 ; 25 ( 3 ): E22 . 126 . Ohtahara S , Ishida T , Oka E , Yamatogi Y, Inoue H . On the speci \201 c age-depend ent epileptic syndrome. The early-infantile epileptic encephalopathy with suppression burst . No To Hattatsu 1976 ; 8 : 270 \200\223 80 . 111 . Silverstein FS , Jensen FE , Inder T , Hellstrom-Westas L , Hirtz D , Ferriero DM . Improving the treatment of neonatal seizures: National Institute of Neurologi cal Disorders and Stroke workshop report . J Pediatr 2008 ; 153 ( 1 ): 12 \200\223 15 . 127 . Djukic A , Lado FA , Shinnar S , Mosh SL . Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other? Epilepsy R es 2006 ; 70 : 68 \200\223 76 . 112 . Kahle KT , Barnett SM , Sassower KC , Staley KJ . Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na( + )-K( + )-2Cl (-) cotransporter NKCC1 . J Child Neurol 2009 ; 24 ( 5 ): 572 \200\223 6 . 128 . Kato M , Saitoh S , Kamei A , Shiraishi H , Ueda Y , Akasaka M , et al . A longer polyalanine expansion mutation in the ARC gene causes early infantile epileptic en cephalopathy with suppression-burst pattern . (Ohtahara syndrome). Am J Hum Genet 2007 ; 81 : 361 \200\223 6 . 113 . Scher MS , Alvin J , Gaus L , Minnigh B , Painter MJ , et al . Uncoupling of EEG-clin ical neonatal seizures after antiepileptic drug use . Pediatr Neurol 2003 ; 28 : 277 \200 \223 80 . 129 . Coppola G , Plouin P , Chiron C , Robain O , Dulac O . Migrating partial seizures in infancy: a malignant disorder with developmental arrest . Epilepsia 1995 ; 36 : 1017 \200\223 24 . This page intentionally left blank CHAPTER 15 Epileptic Encephalopathies Renzo Guerrini and Carla Marini It is generally acknowledged that proper recognition and ration- ale treatment choices prov ide higher chances of reducing seizure severity and cognitive impairment in epileptic encep halopathies, although this is dif \201 cult to demonstrate unequivocally in relation to di fferent aetiologies. Although vigorous early treatment is often advocated, for most conditi ons there are no established endpoints and drug choices are empirically made. Surgical trea tment can be successful in selected cases. However, only in some surgically treat- able syn dromes early treatment has a de \201 nite effect on long-term prognosis ( 8 ). In many ind ividuals the underlying cause, which often remains unrecognized, probably plays a greater p art than is acknowledged in determining cognitive outcome. It has been recognized for many years that some patients with severe forms of epilepsy expe rience clinical deterioration even when an underlying progressive disease has been ruled ou t. There must therefore be an ongoing process, likely related to epilepsy, which causes a r egress in neurological function. The term \200\230epileptic encephalopathy \200\231 has be en initially used to designate Lennox \200\223Gastaut syndrome ( 1 ) in which cognitive and behavioral deterioration are prominent manifestations and has over the years been better d e \201 ned in its supposed pathophysiological bases as applicable to conditions in which s eizures, the epileptiform abnormalities, or both, contrib- ute to the progressive disturban ce in cerebral function ( 2 ). About 40 % of all epilepsies occurring in the \201 rst 3 years of life \201 t this de \201 nition ( 3 ). However, the epileptic encephalopathies repre- sent more a concept and a n operational category than a syndrome spectrum. Some syndromes such as West syndrome, Drav et syn- drome (severe myoclonic epilepsy), epilepsy with continuous spike and waves during sleep, Landau \200\223Kleffner syndrome, and Lennox \200\223 Gastaut syndrome are always ma nifested as epileptic encephalopa- thies, irrespective from the underlying cause and severi ty of electroencephalogram (EEG) abnormalities. However, even syn- dromes with good outcome , such as benign rolandic epilepsy, may sometimes have a complicated evolution, with learni ng and lan- guage impairment, especially if severe spike and wave discharges appear on the EEG and persist for at least several months ( 4 ). Persistent spike-and-wave related anatom o-speci \201 c cortical dys- function has been blamed for such an ominous evolution ( 5 , 6 ). Other syndromes seem to have almost equal chances of either having a short course and a good outcome or precipitating within the spectrum of an epileptic encephalopathy. For exa mple, myo- clonic-astatic epilepsy might unpredictably evolve as an epileptic encephalopath y or rapidly remit without major consequences on cognitive outcome, irrespective from its i nitial clinical and EEG characteristics ( 7 ). In such cases it is often entirely unclear w hich factors, clinical or EEG, can be blamed for either outcome. Finally, a particular situ ation is represented by epileptic encephalopathies that appear in children with a highly ep ileptogenic, usually devel- opmental, brain lesion, such as, for example, hemimegalencephal y, from which epileptic activity spreading to intact, remote areas interferes with their fu nction and ampli \201 es the clinical conse- quences of the malformation. Infantile spasms and West syndrome Infantile spasms (IS) are typical of the \201 rst year of life, are usually resistant to conventional antiepileptic drugs and are associated with developmental delay, or deterioration. Interictal EEG is often \200\230hypsarrhythmic \200\231, with high voltage (up to 500 V) slow waves, irregularly interspersed with spik es and sharp waves giving the EEG the appearance of a chaotic disorganization of electrogen esis. During slow sleep, bursts of more synchronous, polyspikes and waves often appear. In West syndrome spasms, hypsarrhythmia, and cognitive deterioration occur together. However, IS may also occur without the typical EEG features of West syndrome, espe- cially in severe brain lesions, such as tuberous sclerosis or lissen- cephaly ( 9 ). Disappearance of socia l smile, loss of visual attention, or autistic withdrawal are often reported by the parents with the onset of spasms. However, developmental delay may predate the onset of spasms in up to 70 % of children ( 10 ). A cumulative incidence of 2.9 per 10,000 live births and an age- speci \201 c prevalence o f 2.0 per 10,000 in 10-year-old children were observed in the US ( 11 ). Epileptic spasms c an persist or, rarely, appear in older children. IS are manifested as clusters of increasing-plateau -decreasing- intensity brisk (0.5 \200 \2232.0 s) \202 exions or extensions of the neck, with abduction or adduction of the uppe r limbs and upward eye devia- tion that are repeated many times per day. After a series, th e child is usually exhausted. Asymmetric spasms are often associated with a lateralized bra in lesion (12), although unilateral lesions might oxford textbook of epilepsy and epileptic seizures 178 cause symmetric spasms. Lateralized motor phenomena, including lateral or upward eye deviat ion and eyebrow contraction, and abduction of one shoulder, may sometimes constitute the en tire series of spasms or initiate a series which will eventually develop into bilateral man ifestations. Such lateralized manifestations are usually accompanied by asymmetric ictal EE G changes. Other sei- zure types can coexist. (progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy) ( 30 ). Cases e xist outside Finland. Other genetic dis- orders are more rare and may be of recessive ( 31 , 32 ) or of unde- termined nature ( 33 ). IS and West syndrome have also been associated w ith various mitochondrial disorders, inherited disor- ders of metabolism, chromosomal abnor malities, and copy number variations (Table 15. 1 ). Duration of spasms is variable, depending both on treatment and on their tendency to remit or evolve into other seizure types. Rapid spontaneous remission is rare. In about 50 % of c hildren, spasms disappear before the age of 3 years and in 90 % before the age of 5 years ( 13 ). Misdiagnosis of colic, startles, Moro response, or shoulder shrugs is still frequent . Prognosis of infantile spasms and West syndrome depends more on etiology than on treatment. Unfavorable prognostic factors include symptomaticity, early onset (before 3 months), and pre- existing seizures other than spasms, an asymmetric EEG, and relapse after initial resp onse to treatment ( 10 ). Adequate resolu- tion requires the cessation of clinical spasms a nd normalization of EEG ( 34 ). Good prognostic indicators include no obvious aetiol- ogy, normal brain magnetic resonance imaging (MRI) ( 35 ) typical hypsarrhythmia, rapid response to treatment, and no regression after onset of spasms or its short duration ( 36 ). Overal l, about 80 % of patients have residual cognitive or behavioral impairment, but only one-th ird of cryptogenic cases do ( 36 ). About 50 % of children will subsequently exhibit other epilepsy types. The initial diagnostic efforts directed at the causes of spasms may have immediate practica l implications as symptomatic and cryp- togenic spasms carry a different prognostic outlook and, in relation to speci \201 c aetiologies, may determine different therapeutic options . However, the terms symptomatic and cryptogenic have not been used uniformly. Most investi gators de \201 ne as symptomatic those cases in which an aetiological factor can be clearl y identi \201 ed. Others link symptomaticity to either or both abnormal development prior to the onset of spasms and clinical or imaging evidence of a brain lesion, with brain malfo rmations and perinatal hypoxic-ischaemic encephalopathy being the most frequent causes. Cry ptogenic spasms are those for which no cause can be identi \201 ed, or develop- ment was n ormal before clinical onset. The term cryptogenic does not necessarily mean that no lesion is present; therefore, a differ- ence of nature between cryptogenic and symptomatic cases i s not clearly established. A few cases that are not included in the sympto- matic group, de spite increasingly accurate investigations, may belong to an \200\230idiopathic \200\231 g roup ( 14 , 15 ). Infantile spasms must be differentiated from rarer, earlier-onset conditions with ominous p rognosis, such as the early infantile epi- leptic encephalopathy and the early myoclonic en cephalopathy. Vigabatrin (GVG) and adrenocorticotropic hormone (ACTH) have proven effective in a few cont rolled trials, but uncertainties remain regarding the best treatment. In three comparative studies, GVG was slightly less effective than, or as effective as ACTH ( 37 \200\22339 ), b ut possibly better tolerated ( 37 ). Two randomized trials reported a 78 % responder rate ( 40 ), and a higher effectiveness of high doses (100 \200\223148 mg/kg per day) ( 41 ). Par ticular ef \201 cacy has been shown in children with tuberous sclerosis ( 42 ). Response t o 100 mg/kg per day occurs within a few days. Some clinician consid- ers GVG the \201 rst -line drug, despite the risk of visual \201 eld constric- tion ( 43 ). This side effect a ppears in 30 \200\22350 % of patients having received a substantial drug load, but is not a scertainable in small children. According to the Vigabatrin Pediatric Advisory Group (2000) responders should receive GVG for no more than 6 months and non-responders should be switc hed to ACTH within 3 weeks. Transient MRI hyperintensities of globus pallidi, thalami, dent ate nuclei, and cerebral peduncles have been described in infants treated with GVG for infa ntile spasms ( 44 , 45 ). The meaning of these \201 ndings and how their report would aff ect treatment choices is still unclear. The United Kingdom IS Study (UKISS) comparing hormo nal treatment against GVG showed that tetracosactide (syn- thetic ACTH) or prednisolone con trolled spasms better than did vigabatrin initially, but not at 12 \200\22314 months of age ( 46 ). On 24-month follow-up cognitive outcome was better for the hormo- nal group. It is used in daily doses from 20 to 40 IU. An individual- ized regimen permits to keep dose-rel ated side effects such as hypertension, brain shrinking, adrenal hypo-responsiveness, and c ardiac hypertrophy to a minimum ( 47 ). Infections are an omi- nous complication of ACTH tr eatment and are responsible for most deaths ( 48 ). A 4 \200\2236-week duration of ACTH cou rse is advisa- ble. Spasms may respond within days but behavioral improve- ment needs sever al weeks. Relapse rate is 30%. A second cycle of ACTH is recommended in cases of relapse af ter an initial good response. High-dose oral prednisolone has been suggested as an alternat ive to ACTH, providing an equivalent ef \201 cacy, with reduced side effects and considera bly lower cost (49). In a recent review of A family history of IS is found in about 4 % of the cases ( 16 ). Familial cases are probab ly the expression of several genetic disor- ders, some of which are well characterized, inc luding leucodystro- phy ( 17 ), tuberous sclerosis ( 18 ), X-linked lissencephaly and band heterotopia ( 19 ), X-linked mental retardation and IS due to muta- tions of the ARX gene ( 20 , 21 ). Boys with X-linked IS due to ARX mutations usually have severe developmental de lay and may have microcephaly. Onset of spasms is early and hypsarrhythmia is fre- quent ( 22 , 23 ). A syndrome of early-onset IS, and severe quadriple- gic dyskinesia, in which spa sms tend to remit but episodes of status dystonicus complicate the course, has been associa ted with expan- sions in the \201 rst polyalanine tract of the ARX gene ( 21 ). A syndrome with microcephaly and early-onset intractable sei- zures, including spasms with or without hypsarrhythmia, has been associated with mutations or deletions of the X-linked gene CDKL5 ( 24 \200\22326 ). The syndrome is much more frequent in females. Infants with C DKL5 -related early epileptic encephalopathy can present in the \201 rst year of life wit h an unusual electroclinical pattern of pro- longed generalized tonic \200\223clonic seizur es ( 27 ). Patients harboring deletions of chromosome 7q11.23 including the MAGI2 gene, inv olved in regulation of traf \201 cking, distribution, or function of the glutamate recepto rs, have infantile spasms ( 28 ). Mutations in STXBP1 gene associated with Ohtahara syndrom e can also cause infantile spasms ( 29 ). A possibly recessive syndrome of early onset IS, often preceded and followed by other types of seizures, associated with hypsar- rhythmia, facial dysmorphisms, optic atrophy, and per ipheral oedema, has been reported from Finland as PEHO syndrome CHAPTER 15 epileptic encephalopathies 179 Table 15.1 West syndrome and Lennox \200\223Gastaut syndromes: aetiologies the literature the US Consensus report has suggested that a short course of high-dose ACTH (150 units/m 2 /day in two divided doses for 2 weeks followed by a 2-week taper) and VGB 10 0 -150 mg/kg/ day demonstrated the best evidence for ef \201 cacy and a safe adverse event pro \201 le (50). Pyridoxine is a preferred agent in Japan but its use is not supported b y controlled studies (51). Video-EEG moni- toring is often necessary to show that the spasm s have truly disap- peared (50, 52). Type of etiology Speci \201 c etiology Syndrome Malformations of cortical development \227\206 Focal cortical dysplasia \227\206 Tuberous sclerosis TSC1, TSC2 genes \227\206 Lissencephaly LIS1, DCX, ARX, TUBA1A \227\206 Subcortical band heterotopia DCX, LIS1 \227 \206 Bilateral perisylvian polymicrogyria \227\206 Bilateral frontoparietal polymicrogyria WS WS-LGS WS-LGS WS-LGS WS WS WS-LGS WS WS IS IS IS Surgical treatment should be considered early when drug resist- ance is faced and focal epi leptogenesis is shown. About 60 % of operated children become seizure free; the best result s are obtained when operating on small lesions ( 53 ). However, most children have large mu ltilobar cortical dysplasia needing extensive resec- tions, with limited cognitive improvem ent ( 8 ). GPR56 \227\206 Diffuse polymicrogyria TUBB2B \227\206 Hemimegalencephaly \227\206 Neurocutaneo us disorders \227\206 Aicardi syndrome \227\206 Schizencephaly \227\206 Periventricular heterotopia/ microcephaly ARFGEF2 There is some evidence for use of the ketogenic diet in resistant spasms ( 49 , 54 ). WS \227\206 Holoprosencephaly SIX3, SHH, Lennox \200\223Gastaut syndrome Lennox \200\223Gastaut syndrome is characterized by intract able brief tonic and atonic seizures, atypical absences, and a generalized interictal EEG p attern of spike and slow wave discharges. It accounts for 2.9 % of all childhood epilepsy ( 55 ). Incidence peaks between 3 \200\2235 years of age. Cognitive and psychiatric impairme nt is frequent. About 30 % of cases occur de novo in previously healthy children. However, multiple aetiologies are observed in the remaining cases with neuronal migration disorders and hypoxic brain damage being the most frequent causes. About 40 % of children have previ- ous IS ( 10 ). Persistence of seizures in adulthood is frequent. TGIF, ZIC2, PTCH1, GLI2 WS Pre-, peri-, or postnatal damage \227\206 Hypoxic ischaemic sequelae \227\206 Haemorrhagic \227\206 Fetal infections \227\206 Postnatal infection (encephalitis and WS WS WS-LGS meningitis) WS-LGS WS WS \227\206 Trauma \227\206 Cardiac surgery with hypothermia Chromosomal abnormalities and copy number variations \227\206 15q11.2 \200\223q13.1 duplication \227\206 4p- (Wolf \200\223Hirshhorn syndrome) \227\206 invdup15 \227\206 Angelman syndrome \227\206 Down syndrome \227\206 Miller \200\223Dieker syndrome \227\206 del1p36 \227\206 del 7q11.23 \200\223q21.1 ( MAGI2) \227\206 Pallister \200\223Killian syndrome: mosaic LGS LGS LGS WS WS-LGS WS-LGS WS WS The term Lennox \200\223Gastaut syndrome, which was adopted by the International League Aga inst Epilepsy in 1989 ( 56 ), is still used loosely to designate children with multiple typ es of intractable seizures, which include drop attacks. Cognitive impairment is often present before seizure onset but the proportion of mentally r etarded patients increases, reaching up to 75 \200\22395 % at 5 years from onset ( 57 ). Co gnitive slowing is a con- stant element of the syndrome even in de novo cases. 12p(i[12p]) IS Inborn errors of metabolism \227\206 Menkes disease \227\206 Phenylketonuria \227\206 Mitochondrial disease (NARP) \227\206 Complex 1 de \201 ciency \227\206 Hypoglycaemia \227\206 PEHO syndrome \227 \206 Non-ketotic hyperglycaemia \227\206 Other organic acid disorders \227\206 Pyridoxine dependency \227\206 Biotinidase dependency \227\206 Congenital disorders of glycosylatio n WS WS WS IS WS WS WS WS IS WS WS About 80 % of patients continue to have seizures later in life, with symptomatic origin and early onset having the poorest outcome ( 10 ). The core seizure types of the syndrome, inc luding tonic, atonic seizures, atypical absences, and non-convulsive status are not always present at onset nor are interictal slow spike and wave discharges. Some authors consider f ast (10 Hz) rhythms associated with tonic seizures or with minimal manifestations (such as a brief apnoea or upward eye deviation), especially during non-REM sleep, an essential diag nostic criterion ( 58 ). Vascular malformations Sturge \200\223Weber syndrome WS-LGS Tonic seizures, with a \200\230sustained increase in muscle contraction lasting a few seco nds to minutes \200\231 are the most characteristic type ( 59 ). Tonic seizures may be mani fested as sudden drop attacks. During sleep, tonic seizures are usually manifested as full- blown stiffening of the whole body with abduction and elevation of the limbs. Atypical abse nces are dif \201 cult to identify due to their gradual onset and termination. Myoclonic s eizures occur in a minority of patients. Between 50 \200\22375 % of patients exhibit non-co nvulsive status, manifested as subcontinuous atypical absences with \202 uctuating respon siveness that may sometimes be interspersed with recurring brief tonic seizures ( 57 ). Non -convulsive status has been associated with worse cognitive outcome ( 60 ). Generalized ton ic \200\223clonic sei- zures or focal seizures may be present in a minority of patients. Brain tumors All brain tumors WS Monogenic: non- malformative \200\224 non-metabolic \227\206 ARX \227\206 CDKL5 \227\206 STPBX1 WS No identi \201 able causes About 40 % positive family history of epilepsy WS-LGS Aetiologies are cumulatively intended for West syndrome, the infantile spasms an epilep- ti c spasms and Lennox \200\223Gastaut syndrome. The column legend indicates the prominent syn drome presentation. For example, girls with Aicardi syndrome exhibit infantile spasms, rath er than West syndrome. However this distinction may not always be feasible. IS, infantile s pasms; LGS, Lennox \200\223Gastaut syndrome; WS, West syndrome. oxford textbook of epilepsy and epileptic seizures 180 initial symptom in 60 % of children, but are absent altogether in 25 % . They have variable severity but remit before adulthood. EEG abnormalities predominate in the temporoparietal regions, bilater- ally, or on either side ( 70 ). EEG discharges interfere with auditory- e voked responses ( 71 ), suggesting epilepsy-related dysfunction of auditory processing. Ons et before age 5 years and persistent EEG anomalies over the language areas forecast a sever e evolution. Although prognosis of aphasia is overall unpredictable, recovery without conse quences is exceptional ( 72 ). No etiology has been identi \201 ed, although rare lesional cases have been reported. The classic EEG feature of Lennox \200\223Gastaut syndrome is the slow spike and wave patte rn, often repeated in bilaterally synchronous complexes at 1 \200\2232 Hz. Generalized burs ts of \200\230polyspikes \200\231 or fast rhythms ( > 10 Hz), also called generalized paro xysmal fast activity, are recorded during slow sleep. They occur as an interictal mani- fes tation or are accompanied by a grading range of clinical mani- festations. Sleep EEG record ings may be necessary to elicit their presence. Drop-attacks are also observed in other epilepsy syndromes typi- cal of childhood. In parti cular, children with myoclonic-astatic epilepsy, making differential diagnosis dif \201 cu lt ( 61 ). Dif \201 cult problems of differential diagnosis are sometimes posed by epileps y with continuous spike and waves during sleep ( 62 ) and the atypical benign rolandic epil epsy ( 63 ). Children with this syndrome spec- trum present with atypical and atonic absenc es that may cause repeated falls. Treatment ef \201 cacy has been empirically investigated. Large doses of ACTH or steroids for prolonged periods ( > 3 months) have a de \201 nite effect on EEG and language ( 73 ). Scattered reports indicate that benzodiazepines, VPA, ESM, and immunoglobulins may be usef ul. It has been suggested that surgical treatment with multiple subpial transections is fol lowed by longlasting improvement in selected cases ( 74 ). However, the merit of this appro ach remains highly uncertain. Language therapy is indicated and alternatives to oral langua ge should be offered to the most severely impaired children. Lennox \200\223Gastaut syndrome can appear in the absence of any obvious or suspected etiol ogy (cryptogenic), in otherwise healthy children or be symptomatic. Etiology of Lennox \200 \223Gastaut syn- drome is extremely heterogeneous (Table 15. 1 ). Familial cases of Lennox \200\223Gastaut syndrome have been associated with familial bilateral frontoparietal polymi crogyria due to GPR56 gene muta- tions ( 64 ) and with familial pachygyria associated with DCX gene mutations ( 65 ). In many cases, brain imaging is normal and no etiology is found. The multiple causes that can be related to the syndrome can in \202 uence prognosis or, s ometimes, therapeutic strategies. In epilepsy with continuous spike and wave discharges during slow sleep (or electrical stat us epilepticus during slow sleep), cog- nitive decline is associated with continuous sleep- related EEG discharges, persisting for months to years. The syndrome appears in previously healthy or in delayed children. Brain lesions, espe- cially polymicrogyria ( 62 ) and poren cephaly ( 75 ) are found in 30 \200\22350 % of patients. Onset is insidious. Seizures start at 3 \200\2235 years as nocturnal and focal attacks and share similarities to those observ ed in rolandic epilepsy. After a few months, continuous spike and waves during slow sleep a nd atypical or atonic absences appear. There is marked decrease in intelligence quotient sc ores with attention de \201 cit and hyperactivity, sometimes with language disturbances an d autistic features. Long-term course of epilepsy is favorable, but cognitive impairment pe rsists in most children. Earlier onset and long duration of typical sleep-related EEG abnor - malities are major risk factors for a poor prognosis ( 76 ). The benign atypical partial epilepsy syndrome ( 63 ) bears a close relation to continuous spike and waves during slow w ave sleep. Drug treat- ment is the same as in Landau \200\223Kleffner syndrome as many aspe cts of these syndromes truly overlap ( 77 ). The optimum treatment for Lennox \200\223Gastaut syndrome remains uncertain. Broad-spectrum drugs should be preferred ( 66 ). Only a few controlled studies are available, usually des igned to evaluate ef \201 cacy of one drug on one or two types of seizures and no study is available investigating early overall effect of a given drug on the syndrome evolution. Ra ndomized clinical trials in Lennox \200\223Gastaut syndrome have been performed for lamotri gine (LTG), topiramate (TPM), felbamate, ru \201 namide, thyrotropin-releasing hormone (TR H) analog, and cinromide ( 57 ). A Cochrane review ( 67 ) sug- gested that although no stud y to date has shown any one drug to be highly ef \201 cacious, ru \201 namide, LTG, TPM a nd felbamate might be helpful as add-on therapy. However, there is no guidance on how to co mbine these drugs and many researchers combine them with valproate (VPA), ethosuximide (ESM ), or benzodiazepines, espe- cially clobazam where available. However, treatment approaches are complicated by the potential of polytherapies for adverse events and seizure aggravati on ( 10 ). It has been suggested that vagus nerve stimulation and the ketogenic diet can be useful in some cases ( 68 ). Corpus callosotomy might reduce seizures with drop attacks, w ith better results when performed at a younger age ( 69 ). Dravet syndrome (severe myoclonic epilepsy in infancy) Dravet syndrome (DS), otherwise know n as severe myoclonic epi- lepsy of infancy (SMEI) is an increasingly recognized epileptic encephalopathy where the clinical diagnosis can be genetically con- \201 rmed in around 8 0 % of patients. The syndrome spectrum includes conditions with variable severity, all appe aring in otherwise normal infants ( 81 ), spanning from the classical phenotype to \200 \230borderline SMEI \200\231 (SMEB) in which patients share most but not all the charac- te ristic clinical features ( 78 ). Landau \200\223Kleffner syndrome and epilepsy with continuous spike and waves during slow w ave sleep In Landau \200\223Kleffner and continuous spike and waves during slow wave sleep syndromes, frequent or persistent discharges, with or without accompanying seizures, cause impairment of cortical func- tions. These two syndromes, which may on occasion partially ov er- lap, are non-convulsive age- related epileptic encephalopathies. Since its \201 rst descriptions DS has been increasingly recognized worldwide; yet it rem ains a rare disorder with an incidence proba- bly less than 1 per 40,000 ( 79 ). The preval ence of Dravet syndrome in children with seizure onset in the \201 rst year of life varie s between 3 \200\2238 % ( 80 , 81 ). The initial manifestations are generalized or unilat- eral clonic (hemiclonic with alternating side) seizures, typically triggered by fever. Thes e seizures are often prolonged, tend to recur in clusters, and may evolve into status epile pticus. Vaccinations or Landau \200\223Kleffner syndrome is a rare, severely disabling disorder, with an insidious, or sudden, loss of language understanding (audi- tory agnosia), followed by progressive lo ss of verbal expression ( 70 ). Age at onset is between 3 \200\2237 years. Focal seizures r epresent the CHAPTER 15 epileptic encephalopathies 181 hot water immersion can precipitate seizures through increase in body temperature. Neuroradiological studies are unrevealing in most patients ( 98 ). In an extensive postmort em neuropathological study of three adult cases, no histological signature of the condition was identi \201 ed ( 99 ). At onset children are often regarded as having febrile seizure s, only their frequent repetition, often with unilateral features, makes one suspect Dravet syndrome or GEFS + . Between ages 1 \200\2234 years other seizure types appear, including myoclonic, atypical ab sences, focal, and, exceptionally, tonic sei- zures. Myoclonic jerks can be massive and inv olve the whole body leading to falling or be barely visible, exhibiting a multifocal distri - bution. They are often precipitated by photic stimulation. Myoclonic jerks are inconstant ly accompanied by time-locked par- oxysmal EEG activity. Atypical absence seizures are pres ent in 40 \200\22390 % of patients ( 81 ) and can be associated with a prominent myoclonic component. Ictal EEG shows 2.5 \200\2233 Hz generalized spike and wave discharges. About 40 % of patients experience non-convulsive status epilepticus or \200\230obtundation status \200\231 charac- terized by \202 uctuating unresponsiveness, with erratic myoclonic jerks . These episodes may last days and be particularly insidious. Ictal EEG shows diffuse slow waves intermingled with focal of dif- fuse spikes. More than 50 % of patients have focal se izures. Convulsive seizures tend to be present throughout as generalized clonic or tonic cl onic seizures, unilateral seizures with alternating side ( 81 ). Interictal EEG, normal at onset, subsequently shows gen- eralized or multifocal paroxysmal activity. About 25 % of ch ildren are photosensitive and may indulge in self-stimulation. Seizures persist into adulthood but are less frequent, rarely pro- longed and are usually c on \201 ned to sleep ( 99 , 100 ). Mortality rates are at around 16 % ( 101 ), mainly as a result of sudden death or seizure-related accidents. VPA, benzodiazepines, TPM, and levetiracetam have demon- strated some ef \201 cacy. Stirip entol, an inhibitor of the P450 cyto- chrome, was effective in combination with clobazam in two class I trials ( 102 , 103 ). Stiripentol acts by increasing the concentration of norc lobazam, an active metabolite of clobazam. Phenytoin (PHT), carbamazepine (CBZ), and LTG ca n worsen seizures and must be avoided ( 81 , 104 ). Myoclonic-astatic (or myoclonic-atonic) epilepsy Myoclonic-astatic epilepsy is a generalize d epilepsy syndrome with multiple seizure types, including myoclonic-astatic, absences, and tonic-clonic and eventually tonic seizures. Seizure onset is between 18 \200\22360 months and most children have normal developmental skills until then ( 7 ). The nosological limits of the disorders are dif \201 cult to determine and its course has variable severity, man ifesting as an epileptic encephalopathy only in some cases. In a hospital popula- tion of c hildren presenting their \201 rst seizure between age 1 and 10 years it was estimated tha t myoclonic-astatic epilepsy represented 2.2 % ( 61 ). Sex ratio has been de \201 ned as 2 .7 \200\2233:1 in favor of males ( 61 , 105 ). Early developmental skills and behavior are usually normal. Around the second year of life, developmental slowing or stagnation becomes obvious in most patients ( 82 , 83 ). Behavior al distur- bances with hyperactivity and autistic traits are frequently reported. The frequ ency of convulsive seizures seems to correlate with the severity of developmental delay ( 8 2 ). An earlier onset of absence and myoclonic seizures carries a higher risk of severe cog nitive impairment ( 83 ). A family history of epilepsy is often found. Affected relatives most often exhibit epilepsy phenotypes consistent with the gener- alized epilepsy with febrile seizure plus (GEFS + ) spectrum ( 84 ). Dravet syndrome has been associated with an overwhelmingly high number of SCN1A mutations ( 85 , 86 ) (see Chapter 2). The fre- quency of detectable mutations is aro und 70 \200\22380 % ( 87 ). Duplications and ampli \201 cations involving SCN1A are additi onal, rare, molecular mechanisms ( 88 ). Most mutations are de novo , but familial SCN1A mu tations also occur ( 85 , 89-91 ). Somatic mosaic mutations have been reported in some pati ents and should be con- sidered when estimating the recurrence ( 92 , 93 ). Genetic factors seem to play a major role. A family history of epilepsy was present in 32 % of children described by Doose (1992) ( 105 ) and in 15 % in the series from Kaminska et a l. (1999) ( 61 ). Ten patients out of 88 belonging to families with the GEFS + com- plex ha d myoclonic-astatic epilepsy ( 106-108 ). In two large series, 5 % of children with myoclon ic-astatic epilepsy had mutations of the SLC2A1 gene ( 109 ), causing glucose transporter-1 (GLUT-1) de \201 ciency. Diagnosing GLUT-1 de \201 ciency, with chronic hypoglyc- orrhac hia, has important therapeutic implications as this condi- tion can be successfully treated with the ketogenic diet. Some general genotype \200\223phenotype correlations have been sug- gested: truncating, non sense, frame shift mutations, and partial or whole gene deletions are correlated with a cla ssical Dravet syn- drome phenotype and appear to have a signi \201 cant correlation with a n earlier age of seizures onset ( 94 ). The severity of the phenotypes is also correlated w ith SCN1A missense mutations falling into the pore forming region of the sodium channel whi le missense changes associated to the GEFS + spectrum are nearly always localized out- side the pore forming region ( 95 ).