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 ). Myoclonic and myoclonic-astatic seizures are present in all chil- dren and are prominent in most. Clinically, myoclonic seizures are brief, generalized jerks, isolated or repeated in short series. A wide range of severity is observed, ranging from head nodding to falls wit h injury. The duration of these episodes is brief (0.3 \200\2231 seconds according to video -EEG analysis) ( 110 ). Falls can either be caused by massive myoclonic jerks or by from a post-myoclonic atonic component, or both. In some children, myoclonic seizures are also tri ggered by photic stimulation. Tonic \200\223clonic seizures are the second most frequent se izure type, present in 75 \200\22395 % of children ( 61 , 105 ) and are usually the \201 rst manifestation to appear. Absence seizures are present in 62 \200\22389 % of patients ( 61 , 105 ). Most often, they present as atypical absences ( 105 ). Episodes of non-convulsi ve status, presenting as stupor and apathy, associated to multifocal, arrhythmic twitching might be present. CBZ and GVG treatment has been reported to precipitate non-convulsive sta tus ( 111 , 112 ). Tonic seizures have been described in 30 \200\22395 % of patients ( 61 , 105 ). Mutations of the PCDH19 gene have been described in girls with early onset epileptic enceph alopathy mimicking Dravet syndrome ( 96 , 97 ). PCDH19 encodes a protocadherin 19, a transm embrane protein of the cadherin family of calcium-dependent cell-cell adhe- sion molecules, which is strongly expressed in the central nervous system. PCDH19 should be tested in pati ents with Dravet syn- drome in whom no SCN1A abnormalities can be found. Despite intensive investigation, the etiology of about 15 % of patients shar- ing features with Dravet syndro me remains unknown. oxford textbook of epilepsy and epileptic seizures 182 by the presence of severe epilepsy. Likewise, children having rela- tively few seizures who experience worsening of seizure and motor or cognitive impairment should be re-evaluated f or possible meta- bolic defects. They can manifest as typical axial, tonic attacks during sleep or as tonic-vibratory seizur es, especially at the end of night time sleep. Only about one-third of children with favora ble course have tonic seizures ( 61 ). Febrile seizures, usually simple in type, are report ed to precede non-febrile seizures in 11 \200\22328 % of children ( 61 , 105 ). Examples of metabolic disorders with speci \201 c treatments include pyridoxine-responsive epilepsies, central creatinine de \201 ciency, phenylketonuria; glucose transporter defic iency syndrome (GLUT-1 DS), pyruvate dehydrogenase de \201 ciency, disorders of lactic aci dosis, biotinadase de \201 ciency, Menkes disease. Background EEG activity is normal at seizure onset, although a characteristic 4 \200\2237 H z, monomorphic theta activity with diffuse dis- tribution, but prominent on centro-parietal areas, is often observed. Interictal abnormalities consist of bursts of 2 \200\2233 Hz gen eralized (poly) spike-and-wave discharges that increase during sleep ( 105 ). Myoclonic sei zures are electrographically characterized by a gener- alized (poly) spike-and-wave complex es ( 110 ). A series of 2 \200\2233 jerks is most commonly observed. The atonic component o f myoclonic- atonic seizures is accompanied by EMG inhibition, lasting 60 \200\223400 msec, time-locked to the onset of the slow wave ( 110 , 113 ). Tonic seizures are accompanied by 10 \200\22315 Hz polyspike discharges lasting as long as the tonic contraction on EMG. Myo clonic status is asso- ciated to a chaotic EEG with independent spike-and-wave dis- charges , sometimes resembling hypsarrhythmia ( 105 ). Some peculiar EEG abnormalities may be helpful. A suppression burst pattern is noted in non -ketotic hyperglycinaemia, phenylke- tonuria, maple syrup urine disease, molybdenum cofacto r de \201 - ciency, and disorders of biotin metabolism ( 120 ). A comb-like rhythm with 7 \200\2239 Hz central activity may be demonstrated in chil- dren with maple syrup urine dise ase, vertex positive spikes in sial- idosis type 1, bi-occipital polymorphic delta activity in X-linked adrenal leucodystrophia, and 14 \200\22322 Hz persistent rhythm is fre- quentl y noted with infantile neuroaxonal dystrophy. Numerous mitochondrial disorders are accompanied by enceph- alopathy and seizures. The best -known mitochondrial disorders transmitted with maternal inheritance are myoclonus epilepsy with ragged red \201 bres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Other mitochon- drial encephalopathies are associated with nu clear mutations rather than mitochondrial DNA mutation; they include Leigh syndrome, Alpers syndrome, and co-enzyme Q10 de \201 ciency. These encepha- lopathic diseases have variabl e presentation with multisystemic involvement and epilepsy. Mitochondrial disorders are tre ated through metabolic therapy typically made up of cocktails contain- ing co-enzyme Q10, L -carnitine, dichloroacetate, and multivita- mins but the effects of such treatment approach to seizure severity has not been assessed ( 120 ). Evolution of myoclonic-astatic epilepsy can be either favorable with seizure remission with in 3 years from onset and normal cog- nitive development or unfavorable with multiple drug- resistant seizure types and cognitive impairment ( 7 , 61 ). There are no distinguishable c luster of clinical or EEG characteristics at epilepsy onset that can help predicting the ou tcome ( 61 ). Myoclonic-astatic epilepsy must be differentiated from cryp- togenic Lennox \200\223Gastaut syndrome, and atypical benign rolandic epilepsy ( 63 ), and from epilepsy with continuous spike wave activ- ity during slow sleep ( 114 ). Differential diagnosis is sometimes necess ary with late infantile ceroid-lipofuscinosis at its clinical onset. VPA is the \201 rst choice drug, because of its wide spectrum of action. No controlled tr ials are available, however. If VPA fails, a combination of VPA with LTG should be the next step. ESM can be effective, in particular when myoclonus and absence seizures are prominen t in the clinical picture. Alternatively small doses of ben- zodiazepine associated to VPA can sometimes prove effective. LTG, which can aggravate some epilepsies with myoclonic seiz ures, such as Dravet syndrome and juvenile myoclonic epilepsy ( 104 , 115 ) has however pro ven useful in myoclonic-astatic epilepsy ( 116 ). CBZ and GVG should be avoided due to thei r potential to precipitate non-convulsive status ( 61 , 112 , 117 ). Epileptic encephalopathies and multilobar brain malformations A particular subgroup of epil eptic encephalopathies are those that originate from the spreading to the whole brain of se vere epileptic activity that originates from a large dysplastic cortical area. This is also the case of West syndrome in association with focal cortical dysplasia (FCD). However, the re may be other forms of epileptic encephalopathies that are manifested with electroclinica l charac- teristics which are more in relation to the speci \201 c etiology than with a gi ven epilepsy syndrome. The prototype of these conditions is hemimegalencephaly, a nosologic ally heterogeneous condition in which one cerebral hemisphere is enlarged and structurally abnormal. The abnormality is unilateral based on gross structure. The histopathological cha racteristics of hemimegalencephaly are similar to those of FCD, with which differences are more quantita- tive than qualitative. In the most severe cases one entire hemisphere is inv olved. Encephalopathic childhood epilepsies associated with inherited metabolic disorders Over 50 genetically determined metabolic diseases have been asso- ciated with seizures. Most presen t in infancy or childhood as intractable epilepsies and are, at their onset, dif \201 cult to distinguish from epileptic encephalopathies due to a non-progressive disorder, as those forms discussed earlier. However, they often present early in life with multiple seizure t ypes and a few, if any, speci \201 c \201 ndings ( 118 , 119 ). The degree of encephalop athy depends upon the sever- ity of the metabolic defect. A metabolic disorder should be su s- pected when a speci \201 c etiology or a well-recognized syndrome is not established or clinical worsening cannot be simply explained The clinical appearance of hemimegalencephaly ranges from cases with severe epileptic encep halopathy beginning in the neona- tal period, to rare patients who may have normal cognitiv e level, with or without epilepsy. However, the most typical presentation is with hemipares is and hemianopia, cognitive impairment, and early-onset seizures. The most severely affect ed children have almost continuous focal seizures, accompanied by infantile spasms CHAPTER 15 epileptic encephalopathies 183 and a suppression-burst pattern on EEG ( 121 ). The healthy hemi- sphere is therefore conne cted with a structurally abnormal contral- ateral hemisphere that is highly epileptogenic. Early surgery with hemispherectomy often controls the seizures. 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