76 . Smith MC , Hoeppner TJ . Epileptic encephalopathy of late childhood: Landau \200\223Kleffner syndrome and the syndrome of continuous spikes and waves during slo w-wave sleep . J Clin Neurophysiol 2003 ; 20 ( 6 ): 462 \200\223 72 . 58 . Genton P Guerrini R , Dravet C . The Lennox \200\223Gastaut syndrome . In: Meinardi IH (ed) The Epilepsies. Part II. Handbook of Clinical Neurology , pp. 211 \200\223 22 . Amst erdam : Elsevier , 2000 . 77 . Hughes JR . A review of the relationships between Landau \200\223Kleffner syndrome, el ectrical status epilepticus during sleep, and continuous spike-waves during sleep . Epileps y Behav 2011 ; 20 ( 2 ): 247 \200\223 53 . 59 . Blume WT . Lennox \200\223Gastaut syndrome: potential mechanisms of cognitive regressi on . Ment Retard Dev Disabil Res Rev 2004 ; 10 ( 2 ): 150 \200\223 3 . 78 . Guerrini R , Oguni H . Borderline Dravet syndrome: a useful diagnostic category? Epilepsia 2011 ; 52(Suppl 2) : 10 \200\223 12 . 79 . Hurst DL . Epidemiology of severe myoclonic epilepsy of infancy . 60 . Hoffmann-Riem M , Diener W , Benninger C , Rating D , Unnebrink K , Stephani U , et al . Nonconvulsive status epilepticus \200\224 a possible cause of mental retardation in pat ients with Lennox \200\223Gastaut syndrome . Neuropediatrics 2000 ; 31 ( 4 ): 169 \200\223 74 . Epilepsia 1990 ; 31 : 397 \200\223 400 . 80 . Yakoub M , Dulac O , Jambaque I , Chiron C , Plouin P . Early diagnosis of severe myoc lonic epilepsy in infancy . Brain and Development 1992 ; 14 : 299 \200\223 303 . 61 . Kaminska A , Ickowicz A , Plouin P , Bru MF , Dellatolas G , Dulac O . 81 . Dravet C , Bureau , M , Oguni , H , Fukuyama , Y , Cokar , O . Severe Delineation of cryptogenic Lennox \200\223Gastaut syndrome and myoclonic astatic epilepsy u sing multiple correspondence analysis . Epilepsy Res 1999 ; 36 ( 1 ): 15 \200\223 29 . myoclonic epilepsy in infancy (Dravet syndrome) . In: Roger J , Bureau M , Dravet CH , Gent on P , Tassinari CA , Wolf P (eds) Epileptic CHAPTER 15 epileptic encephalopathies 185 syndrome): recognition and diagnosis in adults . Neurology 2006 ; 67 ( 12 ): 2224 \200\223 6 . syndromes in infancy, childhood and adolescence , pp. 89 \200\223 113 . London, Paris : Jo hn Libbey , 2005 . 101 . Dravet C . Dravet syndrome history . Dev Med Child Neurol 2011 ; 82 . Wolff M , Casse-Perrot C , Dravet C . Severe myoclonic epilepsy of 53(Suppl 2) : 1 \200\223 6 . infants (Dravet syndrome): natural history and neuropsychological \201 ndings . Epilepsia 2006 ; 47(Suppl 2) : 45 \200\223 8 . 102 . Chiron C , Marchand MC , Tran A , Rey E , d \200\231Athis P , Vincent J , et al . Stiripentol in severe myoclonic epilepsy in infancy: a randomized placebo-controlled syndro me-dedicated trial. STICLO study group . Lancet 2000 ; 356 ( 9242 ): 1638 \200\223 42 . 83 . Ragona F , Granata T , Dalla Bernardina B , Offredi F , Darra F , Battaglia D , et al . Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients . Epilepsia 2011 ; 52 ( 2 ): 386 \200\223 92 . 103 . Kassai B , Chiron C , Augier S , Cucherat M , Rey E , Gueyf \201 er F , et al . Seve re myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual pat ient data . Epilepsia 2008 ; 49 ( 2 ): 343 \200\223 8 . 104 . Guerrini R , Dravet C , Gent on P , Belmonte A , Kaminska A , Dulac O . 84 . Singh R , Scheffer IE , Whitehouse W , Harvey AS , Crossland KM , Berkovic SF . Severe myclonic epilepsy of infancy is part of the spectrum of generalized ep ilepsy with febile seizures plus (GEFS + ) . Epilepsia 1999 ; 40 : 175 . Lamotrigine and seizure aggravation in severe myoclonic epilepsy . Epilepsia 1998 ; 39s : 5 08 \200\223 12 . 85 . Claes L , Del-Favero J , Ceulemans B , Lagae L , Van Broeckhoven C , De Jonghe P . De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy . Am J Hum Genet 2001 ; 68 ( 6 ): 1327 \200\223 32 . 105 . Doose H . Myoclonic-astatic epilepsy . Epilepsy Res Suppl 1992 ; 6 : 163 \200\223 8 . 106 . Singh R , Scheffer IE , Crossland K , Berkovic SF . Generalized epilepsy 86 . Mulley JC , Scheffer IE , Petrou S , Dibbens LM , Berkovic SF , Harkin with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome . Ann Neurol 1999 ; 45 ( 1 ): 75 \200\223 81 . LA . SCN1A mutations and epilepsy . Hum Mutat 2005 ; 25 ( 6 ): 535 \200\223 42 . 87 . Mari ni C , Scheffer IE , Nabbout R , Suls A , De Jonghe P , Zara F , et al . The genetics of Dr avet syndrome . Epilepsia 2011 ; 52(Suppl 2) : 24 \200\223 9 . 88 . Marini C , Scheffer IE , Nabbout R , Mei D , Cox K , Dibbens LM , et al . SCN1A duplications and deletions detect ed in Dravet syndrome: implications for molecular diagnosis . Epilepsia . 2009 ; 50 ( 7 ): 1670 \200\223 8 . 107 . Scheffer IE , Berkovic SF . Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes . Brain 1997 ; 120 : 479 \200\223 90 . 108 . Singh R , Andermann E , Whitehouse WP , Harvey AS , Keene DL , Seni MH , et al . Seve re myoclonic epilepsy of infancy: extended spectrum of GEFS + ? Epilepsia 2001 ; 42 ( 7 ): 837 \200\223 44 . 89 . Sugawara T , Mazaki-Miyazaki E , Fukushima K , Shimomura J , Fujiwara T , Hamano S , e t al . Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy . Neurology 2002 ; 58 ( 7 ): 1122 \200\223 4 . 109 . Mullen SA , Marini C , Suls A , Mei D , Della Giustina E , Buti D , et al . Glucose transporter 1 de \201 ciency as a treatable cause of myoclonic astatic epilepsy . Arch Neurol 2011 ; 68 ( 9 ): 1152 \200\223 5 . 110 . Oguni H , Fukuyama Y , Imaizumi Y , Uehara T . Video-EEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome) . Epilepsia 1992 ; 33 ( 5 ) : 805 \200\223 13 . 90 . Nabbout R , Gennaro E , Dalla Bernardina B , Dulac O , Madia F , Bertini E , et al . Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy . N eurology 2003 ; 60 ( 12 ): 1961 \200\223 7 . 111 . Guerrini R , Arzimanoglou A , Brouwer O . Rationale for treating epilepsy in children . Epileptic Disord 2002 ; 4(Suppl 2) : S9 \200\223 21 . 91 . Wallace RH , Hodgson BL , Grinton BE , Gardiner RM , Robinson R , Rodriguez-Casero V , et al . Sodium channel alpha1-subunit mutations in severe myoclonic ep ilepsy of infancy and infantile spasms . Neurology 2003 ; 61 ( 6 ): 765 \200\223 9 . 112 . Lortie A , Chiron C , Mumford J , Dulac O . The potential for increasing seizure frequency, relapse, and appearance of new seizure types with vigabatrin . Neurology 1993 ; 43 ( 11 Suppl 5 ): S24 \200\223 7 . 92 . Depienne C , Arzimanoglou A , Trouillard O , Fedirko E , Baulac S , Saint-Martin C , e t al . Parental mosaicism can cause recurrent transmission of SCN1A mutations associated wi th severe myoclonic epilepsy of infancy . Hum Mutat 2006 ; 27 ( 4 ): 389 . 113 . Oguni H , Uehara T , Imai K , Osawa M . Atonic epileptic drop attacks associated with generalized spike-and-slow wave complexes: video- polygraphic study in two patients . Epilepsia 1997 ; 38 ( 7 ): 813 \200\223 18 . 114 . Patry G , Lyagoubi S , Tassi nari CA . Subclinical \200\230electrical status epilepticus \200\231 induced by sleep in c hildren . Arch Neurol 1971 ; 24 : 242 \200\223 52 . 93 . Marini C , Mei D , Helen Cross J , Guerrini R . Mosaic SCN1A mutation in familial seve re myoclonic epilepsy of infancy . Epilepsia 2006 ; 47 ( 10 ): 1737 \200\223 40 . 115 . Biraben A , Allain H , Scarabin JM , Schuck S , Edan G . Exacerbation of juvenile myo clonic epilepsy with lamotrigine . Neurology 2000 ; 55 ( 11 ): 1758 . 94 . Marini C , Mei D , Temudo T , Ferrari AR , Buti D , Dravet C , et al . Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities . Epileps ia 2007 ; 48 ( 9 ): 1678 \200\223 85 . 116 . Dulac O , Kaminska A . Use of lamotrigine in Lennox \200\223Gastaut 95 . Meisler MH , Kearney JA . Sodium channel mutations in epilepsy and other neurological disorders . J Clin Invest 2005 ; 115 ( 8 ): 2010 \200\223 17 . 96 . Depienne C , Bouteille r D , Keren B , Cheuret E , Poirier K , Trouillard O , et al . Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females . PLoS Genet 2009 ; 5 ( 2 ): e1000381 . and related epilepsy syndromes . J Child Neurol 1997 ; 12(Suppl 1) : S23 \200\223 8 . 117 . Guerrini R , Parmeggiani , L , Kaminska , A , Dulac , O . Myoclonic astatic epilepsy. In: Roger J , Bureau M , Dravet CH , Genton P , Tassinari CA, Wolf P ( eds) Epile ptic syndromes in infancy, childhood and adolescence ( 3rd edn), pp. 105 \200\223 12 . Lon don and Paris : John Libbey , 2002 . 118 . Nordli D , DeVivo DC . Inherited metabolic disor ders . In: Engel J , 97 . Marini C , Mei D , Parmeggiani L , Norci V , Calado E , Ferrari A , et al . Protocadherin 19 mutations in girls with infantile-onset epilepsy . Neurology 2010 ; 75 ( 7 ): 646 \200\223 53 . Pedley TA (eds) Epilepsy: A Comprehensive Textbook ( 2nd edn), pp. 2603 \200\223 19 . Phil adelphia, PA : Wolters Klower , 2008 : 98 . Striano P , Mancardi MM , Biancheri R , Madia F , Gennaro E , 119 . Pellock J , Nordli DR , Dulac O . Drug treatment in children . In: Paravidino R , et al . Brain MRI \201 ndings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations . Epilepsia 2007 ; 48 ( 6 ): 1092 \200\223 96 . Engel J , Pedley PT (eds) Epilepsy: A Comprehensive Textbook ( 2nd edn), pp, 1249 \200\223 57 . Philadelphia, PA : Wolters Klower , 2008 . 120 . Guerrini R , Pollock J . Epileptic e ncephalopathies . In: Stefan H, Theodore WH (eds) Epilepsy. Handbook of Clinical Neurology . London : Elsevier , in press . 99. Catarino CB , Liu JY , Liagkouras I , Gibbons VS , Labrum RW , Ellis R , et al . Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neu ropathology . Brain 2011 ; 134 (Pt 10 ): 2982 \200\223 3010 . 121 . Paladin F , Chiron C , Dulac O , Plouin P , Ponsot G . Electroencephalographic aspects of hemimegalencephaly . Dev Med Child Neurol 1989 ; 31 ( 3 ): 377 \200\223 83 . 100 . Jansen FE , Sadleir LG , Harkin LA , Vadlamudi L , McMahon JM , Mulley JC , et al . Severe myoclonic epilepsy of infancy (Dravet This page intentionally left blank CHAPTER 16 Principles of Treatment of Epilepsy in Children and Adolescents Renzo Guerrini General considerations The bases for classifying epilepsy syndromes and treatment options o f most syndromes of childhood and adolescence have been dealed with, in part, in Chapters 7 and 15. This chapter will be mainly devoted to principles of treatment in young patients w ith different types of epilepsy, excluding the epileptic encephalopathies and early childho od syndromes dealed with in these other chapters. Advances in clinical pharmacology, a bett er understanding of the molecular mechanisms involved in epileptogenesis, and a more precis e diagnosis of the speci \201 c aetiologies and of epilepsy syn- dromes, have allowed more rational treatment choices. Childhood- onset epilepsies encompass all known seizure types: focal seizures, epileptic spasms, typical and atypical absences, myoclonic, tonic, atonic, clonic, and tonic \200\223clonic seizures. Epilepsies starting in ado- lescence will manif est with focal, myoclonic, generalized tonic \200\223 clonic seizures (GTCSs) or, rarely, a bsence seizures. Atonic or tonic seizures very rarely start in adolescence. A syndrome-spec i \201 c response to treatment has been demonstrated to occur in a few of these conditions , including responsiveness to drugs or drug- induced seizure aggravation ( 1 ). In a few in stances speci \201 city relates to the etiology of epilepsy, not just its electroclinical pat- tern of presentation, but this is unusual. An example is infantile spasm secondary to tuberous sclerosis which shows the best response to vigabatrin treatment ( 2 ). Carbamazepi ne is highly effective in nocturnal frontal lobe epilepsy ( 3 ). children only if they appear promising in adults, with considerable delay. When to start treatment The decision to start treating a child with epilepsy should ideally be tailored to the individual patient. Some seizure types, such as absences, spasms, or to nic seizures, are always frequent and once their presence is ascertained, treatment should be started. Analogously, the etiology of epilepsy should be taken into account, as some epi leptogenic conditions, especially cortical dysplasia, are associated with a very high seizu re recurrence risk and very low chances of prolonged remission. Some conditions appear to b e scarcely in \202 uenced by AED treatment and this can be the case for both some \200 \230benign \200\231 epilepsies and some \200\230severe encephalopathies \200\231. Ambroset to and Tassinari ( 4 ) showed no clear difference in the total number of seizures suffered by children with rolandic epi- lepsy, either treated or not. Treatment can be withheld with out signi \201 cant risk in many children with single unprovoked seizures, febrile convuls ions, and in adolescents with isolated seizures ( 5 ). However, there are pediatric epileps y syndromes where delay- ing treatment may have devastating effects because ongoing clini- cal or subclinical epileptic activity exerts a disruptive interference on cognitive functio ning. Although this is the case with most child- hood epileptic encephalopathies, cognitive deterioration may be prominent even when seizures are rare ( 6 ). Knowledge of the main mechanisms of action and spectrum of ef \201 cacy of antiepileptic d rugs (AEDs), and correct syndrome diag- nosis are therefore essential for rationale treatme nt. However, ef \201 - cacy and safety data emerging from AED trials in children is dif \201 cult to interpret. In most trials, different epilepsy syndromes and aetiologies are lu mped together, and the studies were not designed in general to detect worsening of seizures or speci \201 c reactions in different syndromes. Furthermore, \201 nding that two or m ore drugs are equivalent when compared to one another on \200\230newly diagnosed \200\231 cases, does not rule out the possibility that all drugs are relatively ineffective and that spontaneous remissions or improvements signi \201 cantly in \202 uence the results. Info rmation on drug safety in children is scanty as AEDs are marketed for The risk for accidental death related to severe seizures should also be considered, especially in the neurologically impaired ( 7 ). Setting the targets of treatment: treating benign versus severe epilepsies The initial appr oach and the targets of treatment differ considerably, in the most common forms of epilepsy (e.g. absence epilepsy or a mild form of focal epilepsy) and in the severe epileptic encep halopa- thies (often with multiple seizure types). In the \201 rst group, seizure control without adverse events, and in the most convenient and least expensive manner, are reasona ble targets. Epileptic encephalopathies oxford textbook of epilepsy and epileptic seizures 188 adolescence in all patients ( 17 ). Typical seizures cause arousal soon after falling aslee p, with lateralized facial contraction, anarthria, dribbling, and a grunting sound, without loss of consciousness. Sometimes the homolateral upper limb is involved. Secondary general ization can supervene. Interictal electroencephalogram (EEG) shows typical biphasic centrot emporal spikes, with a tan- gential dipolar distribution, which often become bilateral duri ng sleep. The total number of seizures a child will suffer is variable but AED treatment ca n often be avoided ( 4 ). Atypical forms are not rare and can be associated with atonic sei zures and unusual EEG characteristics ( 18 ). Some EEG features, particularly spike and wav e discharges instead of the more typical rolandic sharp waves, may predict a complicated ev olution, including a paradoxical aggravation under carbamazepine treatment ( 19 ). present completely different challenges to both the physician \200\231s preferences and the patient \200\231s ef \201 cacy and tolerability response. Vigorous early pharmacological or surgical treatment is often advocated on the assumption that epileptic activity would ca use or worsen the encephalopathy per se. However, for many of these conditions there are no established endpoints of treatment and drug adjustments are very empirically established. Cognitive and behavioral effects of antiepileptic drugs in children Although a detrimental dose-dependent effect of some AEDs on cognitive functions is self-evident, only a few contr olled studies have formally addressed this important point in children ( 8 ). Clear evidenc e has only been obtained about reduction of IQ scores and increased P300 wave latency, an e lectrophysiological measure of cognitive processing speed reduction, in children treated wi th phe- nobarbital ( 9 , 10 ). Although such effects are believed to be reversi- ble upon d rug withdrawal, enduring consequences in academic achievement suggest that prolonged decrea ses in cognitive process- ing may not be compensated upon in prospect ( 10 ). Carbamazepine does not affect IQ ( 11 ), but may slightly impair children \200\231s memory, without affe cting academic achievement ( 12 , 13 ). Phenytoin might slightly affect IQ but its effects on academic achievement are unknown ( 8 ). The effects of valproate on memory are suggested to be less pronounced than those of phenytoin and carbamazepine ( 14 ) but might not have been adequately studied. The neuropsy- chological effects of new AEDs in children are large ly unknown. Benign epilepsy of childhood with occipital paroxysms was origi- nally described as a form of focal epilepsy with age at onset between 2 \200\22317 years, visual ictal symptoms, such as illusions, elementary hallucinations, and blindness, evolving either to hemiclonic or c omplex partial seizures with possible generalization and migraine- type postictal headache ( 20 ). Remission occurs by adulthood. Interictal EEG shows unilateral or bilateral occipit al spike-and- waves, facilitated by eye closure. This forms accounts for no more than about 1 % of epilepsies. A different, more frequent form of childhood idiopathic occipi- tal epilepsy, observed in a bout 3 % of all children with epilepsy, appears between 2 \200\2238 years with prolonged se izures appearing during sleep, with tonic eye and head deviation, ictal vomiting, and hemic lonic jerks or generalization ( 21 ). Prominent autonomic manifestations and the inconstant presence of the typical occipital EEG abnormalities have cast some doubts on the occipital origin of seizures in all patients ( 22 ). Severe prolonged autonomic seizures may require differential diagnosis with acute symptomatic seizures or abdominal emergencies ( 23 ). Tr eatment is rarely necessary, with most children remitting by the age of 12, after presentin g just a few seizures ( 21 ). EEG and clinical manifestations are not as speci \201 c and constantly present as those of BECTS ( 22 , 24 ), which makes it mandatory to rule out a sy mptomatic origin. Lamotrigine, gabapentin, and levetiracetam, have been reported to increase the risk for agg ressive behavior, especially in cogni- tively impaired children ( 8 ). Clinical characteristics and response to treatment of the epileptic syndromes of childhood and adolescence The epileptic encephalopathies (infantile spasms, Lennox \200\223Gastaut sy ndrome, Dravet syndrome, myoclonic-astatic epilepsy, and epi- lepsy with continuous spikes and waves during sleep) and their treatment are considered in Chapter 7. Symptomatic focal epilepsies Symptomatic focal epilepsies account for about 40 % of all epi lep- sies in children ( 25 ) and are de \201 ned according to seizure semiology pointing t o lobar location. However, the epileptogenic area itself can involve multilobar networks. S eizures can include a single symptom or have complex symptomatology. The sequence of events is related to the origin and propagation of the discharge but in young children ictal symp toms can be limited to reduced activ- ity and interaction with motionless staring and unres ponsiveness, which reflects extensive seizure spread but not the origin or distribution. Po stictal sleepiness is frequent and has a major signi \201 cance for differential diagnosis . The surface EEG may be misleading. Focal epilepsies and epileptic syndromes Idiopathic focal epilepsies Idiopathic focal epile psies are the most frequently occurring epi- lepsy syndromes in children. They have an age- dependent course and may occur in more than one family member. Seizures are usu- ally brief and can cluster at the onset. Response to AEDs is usually satisfactory but it is unclear w hether treatment in \202 uences the long- term outcome. Therapy is not necessarily needed if seizures are infrequent, but is required if seizures are prolonged or if secondar- ily g eneralized. Parents usually accept withholding treatment if it is explained that the disord er is self-limiting and does not induce brain damage. Carbamazepine or valproate is usually the preferred option ( 15 ) but no controlled trials are available. Attributing seizure origin to a speci \201 c area is dif \201 cult when neu- roimaging is normal, unless a highly characteristic clustering of symptoms occurs. Focal symptomatic ep ilepsies are usually de \201 ned by seizure characteristics and only a few speci \201 c s yndromes are identi \201 able. Benign epilepsy of childhood with centrotemporal spikes (BECTS) represents 8 \200\22323 % o f childhood epilepsies ( 16 ). Seizure onset is between 3 \200\22313 years. Prognosis is ex cellent with remission within Mesial temporal lobe epilepsy is the best de \201 ned focal sympto- matic epilepsy syndrom e. Most affected children have hippocam- pal sclerosis, which is visible on magnetic resona nce imaging CHAPTER 16 principles of treatment of epilepsy in children and adolescents 189 but very few comparative controlled trials are available in children ( 42 ). Two class I st udies used topiramate in children older than 3 years ( 43 ) or older than 6 years ( 44 ) wi th new or recently diag- nosed focal epilepsy. In one study, higher doses of topiramate wer e more effective than lower doses ( 43 ). In the second study, topiram- ate at doses of 100 and 200 mg/day was equivalent in safety to 600 mg carbamazepine and 1250 mg valproate ( 44 ). Use of \201 xed doses, however, is \202 awed with respect to optimization dose stud ies. Oxcarbazepine and phenytoin had comparable ef \201 cacy, but the discontinuation rate was higher for phenytoin ( 45 ). (MRI) ( 26 ) and about 40 % of these have a history of prolonged febrile convulsions ( 27 ) . Seizures start in school age or earlier ( 28 ). Typical episodes include an initial risin g epigastric sensation with fear, oro-alimentary automatisms (chewing, swallowing, lip smac k- ing), alteration of consciousness with staring, and postictal confu- sion ( 29 ). Aphasi a is often observed when the dominant hemisphere is involved. In infants and small children reduction of motor activ- ity may be the prominent feature, without automatisms (so called \200\230hypomotor seizures \200\231) ( 30 ). Interictal EEGs can be normal or show unilat eral or bilateral temporal abnormalities. Memory distur- bances are common but are dif \201 cult to demonstrate before the child is of school age. Drug resistance is frequent. An terior tempo- ral lobectomy or more selective resections give excellent results in about 80 % of children ( 29 ). Studies on heterogeneous groups, such as it can be \200\230newly diag- nosed focal epileps y \200\231, may mask speci \201 c drug effects on aetiologi- cally homogeneous syndromes. In spite of this limitation, from the range of available studies it is recommended that chi ldren with newly diagnosed focal epilepsy are initiated on either car- bamazepine or valpro ate and that topiramate is considered as an alternative monotherapy ( 42 ). Lamotrigine and gabapentin are also potentially interesting initial monotherapies, although only two class I studies are available in adults, which did not include children. Evidence about the effe ctiveness of monotherapy with tiagabine, levetiracetam, and zonisamide is still insuf \201 cient. Frontal lobe epilepsy is relatively frequent in children. Seizures are usually sleep relate d and brief, lasting seconds to tens of seconds, with complex motor manifestations. They ar e highly stereotyped in the same patient. Arousal from sleep, with opening of the eyes and a frightened expression is often the \201 rst ictal manifestation ( 31 ). Consciousness d isruption is variable but postictal recovery of aware- ness is usually fast. Subjective sym ptoms are ill de \201 ned. Onset of motor phenomena is with tonic asymmetric posturing or repetitive \200\230hyperkinetic \200\231 automatisms. Most children also exhibit organized movements of the proximal limbs (so-called \200\230 hypermotor seizures \200\231) ( 32 ) . Epileptic nocturnal wanderings are longer attacks (2 \200\2233 min- utes) with arousal fr om sleep and an ambulatory behavior during which a frightened child may scream and attempt to escape ( 33 ). Ictal fear is often misdiagnosed as pavor nocturnus. Frontal lobe seizure s in the awake child may cause violent drop attacks ( 34 ). Interictal and even ictal EEG i s often normal, or shows abnormali- ties that enable neither lateralization nor localizatio n ( 32 ). Controlled trials in pharmacoresistant focal epilepsies have dem- onstrated the ef \201 ca cy of add-on topiramate ( 46 ), lamotrigine ( 47 ), oxcarbazepine ( 48 ), gabapentin ( 49 ) , and clobazam ( 50 , 51 ). Development of tolerance after a few months seems to hamper the long-term use of clobazam. Evidence about add-on ef \201 cacy of levetiracetam, tiagabine , and zonisamide is insuf \201 cient. While assessing the patient \200\231s response to the different drugs, it is wise to explor e whether a surgical option is possible. However, as there are many drugs now available, a deadline of about 2 years ( 52 ) should be set within which surgery will be performed. Occipital lobe epilepsy of symptomatic origin may be dif \201 cult to diagnose in children because seizure spread masks initial symp- toms ( 35 ). Ictal elementary visual hallucinat ions (colored blobs, \202 ashes of light) associated to peripheral visual \201 eld de \201 cit (hemi- anopia) are typical ( 36 ). Lateral movements of the eyes, either ocu- locl onic or tonic, are frequent. Perinatal ischemic insults and cortical malformations are the most frequent causes ( 35 ). Sturge \200\223 Weber syndrome, coeliac disease, Lafora diseas e, and mitochon- drial disorders also cause occipital seizures. Interictal EEG abnormalitie s are usually increased during eye-closure. Early dif- ferential diagnosis from idiopathic occipital epilepsy may be dif \201 - cult and requires an MRI study. Idiopathic generalized epilepsies Idiopathic generalized epilepsies (IGEs) are frequent and have an age at onset that spans from early childhood to adolescence. They are genetically determined (see Chapter 2). Due to the overlapping features between different IGEs, the ter m IGEs with variable pheno- types has been suggested as all inclusive ( 53 , 54 ). Social a djustment is usually good but some patients experience learning dif \201 culties. Seizures are primarily generalized absence, myoclonic and tonic \200\223 clonic. Interictal EEG abn ormalities are generalized spike-and wave or polyspike-and wave discharges at 3 Hz. Most patients respond to antiepileptic drugs, but response is drug speci \201 c. Valproate is effective in about 80 % of patients ( 42 ) while other drugs for long term treatment, s uch as ethosuximide, lamotrigine, topiramate and levetiracetam have a more selective action . There is no evidence that any other drug is effective in the absence or myoclonic seizure s ( 42 ) and some drugs precipitate or worsen these seizure types in speci \201 c syndrome s ( 1 ). Pharmacological treatment of focal epilepsies in children and adolescents Monotherapy with valproate or carbamazepine have shown similar effectiveness and good tolerability in childr en with newly diag- nosed focal epilepsy with or without secondary generalization ( 37 ). I n one study, phenytoin, phenobarbital, carbamazepine, and val- proate have comparable ef \201 cacy, with 20 % of children being sei- zure free and 73 % achieving a 1-year remission by 3 years of follow-up ( 38 ). However, the severe sedative side effects of pheno- barbit al and less good tolerability of phenytoin, make these two drugs unsuitable \201 rst choi ces. In two studies, vigabatrin had an ef \201 cacy comparable to carbamazepine, but was b etter tolerated ( 39 , 40 ). However, the potential for irreversible visual \201 eld defe cts ( 41 ) now limits the use of vigabatrin to a few selected, very severe cases. Most of t he newer drugs can also be used in monotherapy, Benign myoclonic epilepsy in infants (BMEI) represents less than 2 % of the epilepsies begi nning in the \201 rst 3 years of life ( 55 ). Generalized myoclonic seizures cause noddin g or falls in otherwise normal infants. Generalized spike and wave discharges are rare inte rictally but are always present during jerks. Valproate is effec- tive but treatment is not necessary in mild cases. Use of the term \200\230benign \200\231 is questionable ( 53 ) s ince at follow-up about half of the children have cognitive or behavioral disorders and som e develop GTCSs. Distinction from mild forms of myoclonic astatic epilepsy is dif \201 cul t and in some cases the two forms can merge ( 56 ). oxford textbook of epilepsy and epileptic seizures 190 Childhood absence epilepsy and juvenile absence epilepsy Childhood absence epilepsy represe nts about 12 % of childhood epilepsy ( 57 ). Onset is in school age. A genetic background i s often observed (see Chapter 2). Very frequent, typical absence seizures (up to hundreds p er day) are observed, lasting about 10 seconds, accompanied by rhythmic 3 Hz generalized sp ike and wave dis- charges. Absences disappear before adulthood in up to 90 % of patients in which no other seizure types are associated ( 58 ). If absences persist, GTCSs usually app ear. Early and late onset (below 4 years and above age 9), initial drug resistance, associa ted photo- sensitivity and subsequent appearance of other neurological symp- toms are relat ed to a less favorable prognosis ( 59 , 60 ). Early-onset absence seizures may be an isolat ed expression of glucose trans- porter type1 (GLUT-1) de \201 ciency syndrome, due to muta tions of the SLC2 gene ( 61 ). Recognition of this condition is particularly important as i nitiation of the ketogenic diet produces a dramatic clinical improvement ( 62 ). Valproate is the drug of choice ( 75 ), but primidone, and benzodi- azepines have proven us eful alternatives ( 73 ). Add-on levetira- cetam has been reported to reduce myoclonic jerk s in one trial ( 76 ). Lamotrigine exacerbated GTCSs in some patients ( 77 ). Withdrawal of AEDs is associated to 90 % relapse, even late in life ( 75 ). Seizure clusters or status e pilepticus can be precipitated by withdrawal of effective drugs or by introducing carbamaze pine ( 73 ), although carbamazepine can improve tonic \200\223clonic seizures when these ar e refractory to other medication ( 78 ). Epilepsy with seizures precipitated by light stimulation Visual sensitive (or photosensitiv e) epilepsies are characterized by seizures precipitated by environmental photic stimuli ( 79 ). The age at onset peaks at 11 years. Sensitivity to visual stimuli is associated with the inability of the visual cortex to process afferent inputs of high luminance and contras t through the normal mechanisms of cortical gain control ( 80 ). Photic-induced absences, myoclonic seizures, and GTCs are typ- ically observed in the idiop athic generalized epilepsies and in Dravet syndrome ( 81 ) but can rarely be observed in pa tients with other types of epilepsy. Single or repeated seizures while playing video games or in front of the television (especially with a 50 Hz screen) can be observed in children without a history of spontane- ous seizures. They manifest as either GTCSs or prolonged att acks with visual symptoms and vomiting ( 82 ). An outbreak was reported in Japan, where sev eral hundred children and adolescents experi- enced a seizure while watching television bro adcasting a popular cartoon ( 83 ). Self-induction is possible, especially in children with absences or myoclonic jerks who indulge in compulsively staring or blinking in front of li ght sources or contrasted patterns. Juvenile absence epilepsy starts around age 10 \200\22312. Its clinical manifestations and those of juvenile myoclonic epilepsy are par- tially overlapping. Absence seizures cluster upon awakening ( 63 ). GTCSs, often precipitated by sleep deprivation, occur in up to 80 % of patients and photosensitivity in 20 % ( 64 ). Absences tend to remit within a few years but GTCSs may recur, especially following sleep deprivation. The long-term prognosis is unc lear. In two early comparative trials, valproate and ethosuximide showed similar ef \201 cacy co ntrolling absence seizures ( 65 , 66 ). Lamotrigine was effective as monotherapy in a doubl e blind trial of new-onset absence seizures ( 67 ) and was also effective as an add-on trea tment of resistant absence seizures ( 68 ). However, such trials were not considered to pro vide suf \201 cient evidence to inform clini- cal practice ( 69 ). A more recent trial con \201 rmed previous results, showing that valproate and ethosuximide are more effective th an lamotrigine but also suggested that ethosuximide has fewer adverse attentional effects t han valproate ( 70 ). Some children may require combinations of drugs. If attacks are infrequent, preventive measures can be suf \201 cient. Video games should b e avoided. The triggering power of 50 Hz tel- evision screens is lowered by increasing the ambient light and by watching at a distance greater than 2.5 meters; 100 Hz television scr eens are much less provocative ( 84 ). If treatment is necessary, sodium valproate is the d rug of choice ( 85 ). Preliminary results have also been obtained with levetiracetam ( 86 ) . Polarized glasses or opti- cal \201 lters for screens have proven helpful in severe cas es ( 87 , 88 ). Epilepsy with myoclonic absences is a rare disorder (around 0.5 \200\2231 % of epilepsy) wi th onset between age 1 \200\22312 years ( 71 ). About 50 % of children have pre-existing co gnitive impairment. Myoclonic absences appear several times per day, as rhythmic jerking of shoul- ders, head, and arms. Impairment of consciousness is variable. The EEG \201 nding s are identical to those in childhood absence epilepsy. Evolution to different seizure type s with cognitive impairment occurs in about 60 % of children. A combination of valproate an d ethosuximide seems to be the most effective treatment ( 72 ). Myoclonic absences are also observed in symptomatic forms of epilepsies with variable aetiologies, where they represen t just one seizure type, often amongst others. Ketogenic diet The ketogenic diet is widely used to treat children with severe drug- resist ant epilepsies, especially the epileptic encephalopathies ( 89 ) but no comparative trials are available. The diet has shown some ef \201 cacy in a randomized clinical trial and is worth trying in drug- resistant cases ( 90 ), although no speci \201 c syndrome has shown to respond better than others and assessment of risk and bene \201 ts requires further stu dy. The mechanisms of action are not known but the predominantly fat nutrition maintains ke tosis in the long term and high concentrations of ketone bodies have been corre- lated with better seizure control. The diet may result too restrictive, and cause diarrhea, vitamin d e \201 ciency, renal stones, and cardiac complications ( 91 ). Juvenile myoclonic epilepsy (JME) represents about 2 % of epilep- sies ( 57 ) and is a gene tically determined syndrome (see Chapter 2). Peak incidence is between 12 \200\22318 years. The clinical presentation is often with myoclonic jerks which involve the proximal limbs a nd cause dropping of objects on awakening. GTCSs occur in 90 % of patients, with an average frequency of two per year ( 73 ), often fol- lowing sleep deprivation. It is not unusual t hat the myoclonic jerks are recognized for what they are only after a GTCS has occurred. Ab out 35 % of patients have absences and 5 % photic-induced sei- zures. Interictal EEG abnorm alities are characteristically activated upon awakening ( 74 ). AEDs control seizures in 85 % of patients ( 73 ). Surgical treatment Some of children who are refractory to AEDs may bene \201 t from surgic al treatment and the bene \201 ts of early intervention have been CHAPTER 16 principles of treatment of epilepsy in children and adolescents 191 progressive disorder, and in 31 % of those with malformations ( 97 ). These results are obt ained at the cost of worsening any pre-existing hemiplegia and visual \201 eld defect. He mispherotomy (hemispheric disconnection) is now preferred to hemispherectomy in an increas- ing number of centers. emphasized. However, the average delay from seizure onset to sur- gery is too long, ranging from 12 \200\22315 years ( 92 ). The aim of surgery is to reach complete control or to signi \201 - cantly reduce seizure f requency, while minimizing the harmful effects of epileptic activity and of AEDs on cogniti ve functions. Resective surgery, implies removal of the neuronal aggregate that is responsi ble for seizure generation; palliative or functional surgery aims at preventing or limiting propagation of seizure activity, with- out targeting seizure control. Palliative surgery Corpus callosotomy is a midline disconnection procedure, aimed at inhibi ting interhemispheric seizure spread in patients with disa- bling seizures with falls due t o bilateral synchronization. In order to limit disconnection symptoms, the anterior two-thi rds of the corpus are sectioned. Complete section can be carried out at a second operation if anterior resection is ineffective. Focal seizures may persist after the procedure but im pairment related to falling to the ground can be reduced ( 98 ). Identifying a child who can bene \201 t from surgery involves several steps. Medical intra ctability should be ascertained, possibly limited to the more appropriate drugs. Idiopathic and non-lesional genetic epilepsies should be ruled out as surgery is contraindicated in t hese cases. The level of seizure-related disability should be established on the basis of e ach patient \200\231s clinical presentation. Vagus nerve stimulation is used as an adjunct to treat drug-resist- ant epilepsy . A stimul ator is placed under the skin and emanates adjustable pulsed stimuli to an electrode that i s wrapped around the left vagus nerve ( 99 ). Interesting results have been obtained in chi ldren with severe epilepsies that are not treatable by surgery but epilepsy syndromes that are likely to bene \201 t electively are still undetermined. Adverse effects of hoarseness , cough, and pain are usually reasonably well tolerated.