Epileptic Syndromes in Infancy and Childhood Rima Nabbouta,B and Olivier Dulaca,B

Home , Dravet syndrome, Epilepsy in children

Epileptic syndromes in infancy and childhood Rima Nabbouta,b and Olivier Dulaca,b

aDepartment of Neuropediatrics, Centre de re´fe´rence Purpose of review e´pilepsies rares, Hoˆpital Necker-Enfants malades, APHP, Necker-Enfants malades and bUniversity Paris The aim of this article is to review new epilepsy syndromes, acquire a new Descartes, Paris, France understanding of older ones and emphasize the impact of this concept on basic

Correspondence to Rima Nabbout, MD, PhD, research regarding aetiology and treatment. Department of Neuropediatrics, Centre de re´fe´rence Recent ﬁndings e´pilepsies rares, Hoˆpital Necker-Enfants malades, APHP, 149 rue de Se`vres, Paris Cedex 15, F-75743, In addition to those included in the classiﬁcation of the International League Against France Epilepsy, new epilepsy syndromes comprise febrile seizures plus, benign familial Tel: +33 1 42192695; fax: +33 1 42192692; e-mail: [email protected], neonatal–infantile seizures (BFNIS), benign infantile focal epilepsy with midline spikes [email protected] and waves during sleep (BFIS), malignant migrating partial seizures in infancy, devastating epilepsy in school age children and late onset cryptogenic spasms.

Current Opinion in Neurology 2008, 21:161–166 Genetics played a central role in identifying some new entities (BFNIS, BFIS with choreoathetosis), to delineate older syndromes (Dravet syndrome and myoclonic astatic epilepsy) and determine their mechanisms (infantile spasms, pyridoxine dependent seizures, neonatal encephalopathy with suppression bursts). Summary A significant number of children, mainly infants, do not fit in any of the described epilepsy syndromes. Still many patients with infantile epilepsy require the identification of cause or recognition of an epilepsy syndrome.

Keywords classiﬁcation, epilepsy genetics, epilepsy syndrome, epileptic encephalopathies

Curr Opin Neurol 21:161–166 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540

date, a total of 10 families with mutations in SCN2A were Introduction reported. An Italian family with a strict phenotype of The course of epilepsy in children is most variable and the BFIC and a mutation in SCN2A suggested that BFNIS prognosiscannotbedeterminedonthebasisofageofonset, and BFIC show overlapping clinical features [2]. No seizure types, interictal condition, electroencephalography SCN2A mutations are reported in families with BFNC (EEG) pattern or cause. The combination of age of onset, although the neonatal onset is emphasized by a recent seizure types, interictal condition and EEG pattern, called review of the clinical spectrum [3]. epilepsy syndrome, however, does give some clue regarding cause and prognosis. It allows refined communication between caregivers. It is useful for research regarding treatment strategy and aetiology, including the eventual Familial infantile convulsions and geneticbackground.Recentadvancesinbasicepileptology choreoathetosis reinforced this concept and led to the identification of Benign familial infantile seizures with paroxysmal chor- specific cause for a given syndrome. eoathetosis inherited as an autosomal dominant trait were first recognized in 1997 [4]. Over 20 families have We will focus on new understanding of previously recog- since been reported in different countries. Seizures nized syndromes and on new epilepsy syndromes. appear at 3–12 months, and are partial and may secon- darily generalize as previously described [5]. Seizures soon stop but paroxysmal choreoathetosis starts between Benign familial neonatal–infantile seizures 5 and 9 years. It occurs in paroxysmal attacks, at rest or This condition is intermediate between benign familial induced by exercising and anxiety. Neurological exam- neonatal convulsions (BFNCs) and benign familial infan- ination and EEG tracings between these attacks are tile convulsions (BFICs), called benign familial neonatal– normal, as is psychomotor development. Genetic studies infantile seizures (BFNIS) [1]. The identification of these reveal a strong evidence of linkage to the pericentromeric families is based on the mean age of onset, which ranges region of chromosome 16. No causative gene has been from that of BFNC to BFIC, from 2 days to 6 months. To found to date.

1350-7540 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

seizures, was observed in two unrelated cases of EIEE Benign infantile focal epilepsy with midline with normal brain MRI [15]. spikes and waves during sleep Seizures onset is between 4 and 30 months. Seizure manifestations are typical, characterized by cyanosis, Infantile spasms and West syndrome staring and rare lateralizing signs, of short duration. There The combination of clusters of spasms, psychomotor is a strong EEG marker, a spike followed by a bell-shaped deterioration and hypsarrhythmia defines West syndrome slow-wave, localized in the midline regions, present in all that occurs mainly between 3 and 12 months of age. subjects only during sleep. The prognosis is naturally favourable and the majority of patients do not require antiepileptic drugs (AEDs) [6]. Cryptogenic cases account for 9–15% of the cases, the rest being symptomatic. The symptomatic cases are associated with several prenatal, perinatal and postnatal factors. Var- Epileptic encephalopathy with suppression ious brain dysgenesis (lissencephaly, hemimegalence- bursts phaly, focal cortical dysplasia, septal dysplasia or callosal This severe condition begins within the first 3 months of agenesis), chromosomal (including Down syndrome, life. EEG demonstrates bursts of paroxysmal activity del1p36) or single gene (mutations of ARX or STK9 gene) (polyspikes) lasting several seconds and alternating with [16,17 ] causes are reported. Untreated phenylketonuria, episodes of flat or low amplitude tracing, a combination tetrahydrobiopterine deficiency and mitochondrial cyto- called suppression bursts. This pattern is present in both pathy including the NARP mutation are occasionally awake and sleep states, or mainly during sleep. It is observed. Infantile spasms are particularly frequent in associated with partial seizures variably combined with the course of Menkes disease. myoclonus or spasms. Vigabatrin and steroids are the basis of treatment. Early The classification of the International League Against treatment results in a better outcome [18]. Controlled Epilepsy [7] recognized two conditions with suppression studies in patients with other conditions than tuberous bursts: the early infantile epileptic encephalopathy sclerosis found better short term but similar long term (EIEE) or Ohtahara syndrome [8] and the neonatal effect of steroids compared to vigabatrin, due to the high myoclonic encephalopathy (EME) [9]. relapse rate with hormonal treatment [19–21]. Radiologi- cal work-up should be performed for surgery before going In EIEE, there are spasms and the suppression burst to topiramate that may have some effect [22], although pattern is often asymmetrical, mainly affecting the side worsening has been reported [23]. The place of the of a cortical malformation, usually hemimegalencephaly or ketogenic diet also needs to be determined [24]. focal cortical dysplasia [8]. Aicardi syndrome, olivary- dentate dysplasia and schizencephaly are other conditions We reported a transient decrease of diffusion in subcor- in which such tracings are encountered [10]. In EME, tical structures in six patients with pharmacoresistant there is no radiological evidence of a brain lesion, the West syndrome of unknown cause. The eventuality of patients exhibit erratic and massive myoclonus and there is toxic lesions, including some inborn error of metabolism familial recurrence [11]. Non-ketotic hyperglycinaemia, or drug toxicity, was considered but the contribution of Menkes disease, pyridoxine and pyridoxal phosphate the epileptic encephalopathy appears the most likely dependencies, and glutamate transporter defect [12] [25]. may be involved and share excess of glutamate transmission. Antiquitin, the gene for pyridoxine dependency causes an excessive renal excretion of a-aminoadipic- Cryptogenic late-onset epileptic spasms semi-aldehyde that chelates pyridoxine and causes the When cryptogenic, late onset epileptic spasms beginning defect [13]. between 12 and 48 months of age have a particular pattern that is intermediary between West and Lennox–Gastaut Although the distinction between both entities is import- syndromes [26]. EEG does not show classical hypsar- ant from both the aetiologic and the therapeutic points rhythmia but a temporal or temporofrontal slow wave or of view, it may be difficult for a given patient since spike focus combined with slow spike-waves. Ictal events myoclonus and spasms may be confused at that age, combine spasms in clusters, tonic seizures and atypical because suppression bursts may be an early variant of absences. Ictal EEG discloses a generalized high-voltage fragmented hypsarrhythmia, and since all patients do slow wave followed by diffuse voltage attenuation with not fulfil the criteria for either EIEE or EME [14]. superimposed fast activity, typical of the epileptic spasms, Recently, a polyalanine expansion in the ARX gene occurring in clusters. The classical treatment of infantile (Aristales-related homeobox), longer than for infantile spasms was efficient in almost half the cases.

This newly delineated cryptogenic syndrome is not merely generalized or unilateral clonic or tonic–clonic seizures, a late variant of infantile seizures but could correspond to mostly with fever, in the first year of life [31]. Later, other maturation dysfunction of the temporal lobes, in contrast seizure types occur, including myoclonus, atypical with West syndrome combined with posterior and Len- absences and partial seizures. Developmental delay pro- nox–Gastaut syndrome with anterior maturation features. gressively appears from the second year. Seizures remain fever sensitive and tend to evolve to status epilepticus [32]. The term Dravet syndrome is preferred to that of Malignant migrating partial seizures in severe myoclonic epilepsy in infancy since all patients do infancy not develop myoclonia. The first seizure can be mistaken First reported in 1995 in 14 infants [27], malignant for complex febrile seizures, although early recurrence migrating partial seizure in infancy (MMPSI) is an epi- allows the distinction. This sensitivity to fever seizures leptic encephalopathy characterized by onset in the first led to the identification of mutations in SCN1A [33], 6 months of life, of rapidly progressive partial seizures a gene first described in families with generalized that become subcontinuous. Their onset migrates from epilepsy with febrile seizures plus (GEFSþ) [34]. one area of the cortex to the other and major deterioration Febrile seizures plus (FSþ) defined febrile seizures of the psychomotor abilities appears. Cases were later lasting beyond 6 years or associated with non-febrile identified in European, Asian and American countries. seizures [35]. Dravet syndrome was proposed as the most severe form of the spectrum of the FSþ linked epilepsies. Early seizures have motor and autonomic components, SCN1A mutations account for 75% of Dravet syndrome later seizures are more polymorphic, varying from one cases. Recently, almost 10% of patients with reported seizure to the next in a given patient. Seizures last several negative mutations showed partial or complete deletion minutes longer than usual partial seizures in infancy. of the gene and less frequently duplication [36,37]. They tend to be more frequently generalized as time Inherited cases were also reported with parental mosai- goes by. Myoclonus is rare, and spasms exceptional. By cism [38,39]. SCN1A mutations were shown to cause the end of the first year of life, seizures become almost vaccine encephalopathies [40]. continuous and occur in clusters: seizures lasting several weeks, during which the infant deteriorates considerably, Seizures in Dravet syndrome are highly pharmacoresis- and followed by disappearance of seizures during a few tant. The ultimate goal is to reduce seizures, mainly weeks with slow improvement of the condition. Micro- status epilepticus, during the first years [41]. A prospec- cephaly progressively occurs. tive randomized trial [42] proved the efficacy of the association of clobazam, valproate and stiripentol in redu- To date, no cause has been identified by historical, cing status epilepticus and the frequency of tonic–clonic biochemical, radiological or histological investigations. seizures. In patients responding partially, the adjunction No familial case or consanguinity has been reported. A of topiramate or levetiracetam might be effective. genetic study failed to find mutations in sodium (SCN1A, SCN2A), potassium (KCNQ2, KCNQ3), and chloride The incidence of hippocampal lesions [43] could be under- (CLCN2) ion channels in three children with migrating estimated. A T2 weighted coronal MRI performed after partial seizures in infancy [28]. the second or third year of life could help in disclosure.

The course is most severe because seizures never come The mechanism of sudden death that is particularly under control. For the rare patients whose seizures are frequent in this syndrome may result from the SCN1A controlled before the end of the ﬁrst year of life, walking is mutation [44]. possible. Only a single patient, however, is said to have had normal development at age 7 years [29] and levetiracetam was reported recently in a possible case with early neonatal Myoclonic astatic epilepsy onset [30]. This contrast in the course raises doubts regard- The patients collected under the term ‘centrencephalic ing the syndromic diagnosis for these patients. Open data myoclonic–astatic petit mal’, because they were supposed on the effect of the combination of clonazepam and to share a genetic predisposition related to idiopathic stiripentol have been reported. Bromide may be efﬁcient generalized epilepsy, combine generalized tonic–clonic but AEDs for partial epilepsy, mainly carbamazepine and seizures, myoclonus and generalized spike-waves [45]. vigabatrin, seem to worsen the condition. The condition consists of an aetiological concept sharing features of the Lennox–Gastaut syndrome although there is no brain lesion, pharmacoresistance, episodes of status Dravet syndrome epilepticus and impact on cognitive functions. It comprises First described in 1978, Dravet syndrome is characterized several subgroups, each subgroup consisting of an epilepsy by the occurrence, in an otherwise normal infant, of syndrome reported as the Dravet syndrome [32], ‘benign

myoclonic epilepsy in infancy’ [32], and cases that begin in to occur with lower spiking activity in various conditions, school age with myoclonic-astatic seizures. namely worsening of idiopathic focal epilepsy in childhood also called atypical benign focal epilepsy, with negative Myoclonic astatic epilepsy (MAE) begins between 2 and myoclonus or facial dyspraxia [53,54], symptomatic 5 years, often explosively, with either tonic–clonic sei- epilepsy usually due to vascular prenatal or perinatal zures or drop attacks. A first tonic–clonic seizure at that lesions involving the rolandic area and eventually the age requires an EEG and treatment in cases of spike wave thalamus, cryptogenic involving the temporal lobe with activity. Multiple seizure types include myoclonic–asta- aphasia and auditory agnosia [55,56] or the frontal lobes tic, tonic–clonic and absences. Non-convulsive status with frontal syndrome [57]. The story of a clear motor or epilepticus is a classically underdiagnosed complication. cognitive deterioration is crucial for diagnosis and thera- Tonic seizures are a risk factor for poor prognosis [46]. peutic strategy. Expressive dysphasia has been related to Cognitive deterioration is distinct from that observed in an SRPX2 monogenic mutation [58]. Lennox–Gastaut and usually combines apraxia and dys- arthria. This predominance is explained by the major involvement of the rolandic strip that contributes to Devastating epileptic encephalopathy in generate the myoclonus. school aged children Devastating epileptic encephalopathy in school aged chil- A genetic predisposition plays a role in MAE. Very few dren (DESC) presents in previously normal children as cases were reported in families affected by febrile sei- intractable convulsive status epilepticus lasting several zures plus with mutations in GEFSþ genes [34,47]. In a weeks and followed without a silent period by pharma- study of 22 sporadic patients affected with MAE, how- coresistant perisylvian epilepsy associated with a dramatic ever, no mutation was found in the three major GEFSþ deterioration of cognitive function that predominates on genes (SCN1A, SCN1B and GABRG2) [48]. MAE has a temporal lobe function [59]. It begins between 4 and 11 different genetic background than Dravet syndrome and years, with fever without evidence of intracranial infection, may be inherited as a polygenic disorder involving differ- and intractable status epilepticus followed immediately ent families of genes. by pharmacoresistant epilepsy with clinical and EEG evidence of perisylvian involvement, bilateral temporal The course is variable. Most patients recover within 1– and frontal dysfunction on neuropsychological tests pre- 3 years but others develop myoclonic status and major dominating on limbic structures, consistent with MRI and cognitive decline in the context of an epileptic encepha- PET findings. This condition easily goes unrecognized lopathy. Therapy for epilepsy with myoclonic–astatic since it presents in a febrile setting and can be easily seizures in early childhood remains empirical. Some diagnosed as ‘grey matter encephalitis’ [60,61]. compounds may worsen the condition: phenytoin, carbamazepine, and vigabatrin [49]. Valproate, ethosuximide There is no evidence of brain inflammation whereas and benzodiazepines (clobazam more than clonazepam) status epilepticus causes bilateral temporal epilepto- have been used successfully. The most efficient combi- genic lesions: it may merely be a previously overlooked nation, however, seems to be valproate with lamotrigine epileptic encephalopathy. Another non-inflammatory [50]. The use of benzodiazepines should be restricted to epileptic encephalopathy triggered by fever with episodes of myoclonic status epilepticus. Pharmacoresis- massive involvement of both frontal lobes has been tance is frequent, however, in patients who develop reported [62]. epileptic encephalopathy, in the sense of cognitive and motor deterioration with ongoing tonic and myoclonic seizures. A ketogenic diet should be started as soon as Conclusion such a course is identified [51,52]. In non-responders to The concept of epilepsy syndromes, developed four the diet and in those who do not tolerate it, the indication decades ago by the school of Marseille [63] and established of steroids should be considered. The dose needs to be by the International League Against Epilepsy [7], remains moderate, however, in order to avoid precipitation of a golden standard in paediatric epileptology. The Dravet convulsive seizures. The treatment needs to be pro- syndrome was described on clinical and EEG criteria long longed in order to prevent relapse during the period of before the basic mechanism, a mutation in SCN1A gene risk, which lasts 1–2 years. was recently identified. Clinical and EEG delineation from MAE was confirmed by a different genetic background.

Epileptic encephalopathy with continuous This concept allows the identiﬁcation of new syndromes spike waves in slow sleep such as DESC and MMPS, based mainly on clinical and This condition was initially reported with over 85% of EEG criteria. Advances in neuroimaging and genetics slow wave sleep with spike waves. It was later recognized have by no means contradicted this concept. Therapeutic

trials based on this approach have generated specific 17 Guerrini R, Moro F, Kato M, et al. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 2007; 69:427– indications, such as vigabatrin for infantile spasms and 433. stiripentol for Dravet syndrome. The recent description Authors refine the phenotype and the frequency of ARX mutations in infantile seizures in boys. The ‘classical’ phenotype is that of infantile seizures with severe of epilepsy syndromes in adults adds to this validation. dyskinetic quadriparesis. They suggest that ARX gene testing should be con- Autosomal dominant lateral temporal lobe epilepsy sidered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history. (ADLTLE) and autosomal-dominant nocturnal frontal 18 Eisermann MM, DeLaRaillere A, Dellatolas G, et al. 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