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 regard- ing 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 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 162 Seizure disorders 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 trans- mission. 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. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this