Review Article Syndromes in Infancy

Christian M. Korff, MD and Douglas R. Nordli, Jr., MD

An increasing number of infantile epilepsy syndromes ognized as such by the majority, thanks to the recent have been recognized. However, a significant number developments in diagnostic techniques, such as video- of infants (children aged 1-24 months) do not fit in any , brain imaging, and cytogenetics. of the currently used subcategories. This article re- However, despite this remarkable progress, up to a quarter views the clinical presentation, electroencephalo- of infants with epilepsy do not fit in any of the proposed graphic findings, evolution, and management of the syndromes, or are classified into broad and unspecific following entities: early infantile epileptic encephalop- categories [8]. It is likely that additional entities are athy, early , infantile spasms/West waiting to be defined in this age group [1]. This article syndrome, severe myoclonic epilepsy of infancy, myo- reviews the clinical characteristics, electroencephalo- clonic-astatic epilepsy, with febrile graphic findings, evolution, and management of the infan- plus, malignant migrating partial seizures of tile epileptic syndromes identified in infancy so far. Their infancy, hemiconvulsions-hemiplegia-epilepsy, benign main features are summarized in Table 1, and specific myoclonic epilepsy, and benign familial/nonfamilial treatment options for some of them are presented in Table infantile seizures. Issues related to their classification 2. Issues related to their classification are addressed at the are addressed. © 2006 by Elsevier Inc. All rights end of the review, and suggestions for further improve- reserved. ments in the classification of infantile are proposed. Korff CM, Nordli Jr DR. Epilepsy syndromes in infancy. Pediatr Neurol 2006;34:253-263. Early Infantile Epileptic Encephalopathy With Suppression-Burst ()

Introduction Early infantile epileptic encephalopathy, or Ohtahara syndrome, is a severe neurologic condition first described An accurate diagnosis is considered the first and most in 1976 [9]. It is a rare entity, with a relative prevalence to critical step in the management of pediatric epilepsy [1,2]. West syndrome estimated at 1/40 or less [9]. It is charac- Delineating epilepsy syndromes serves that purpose. In terized by epileptic tonic spasms and a suppression-burst addition to improving communication between caregivers electroencephalogram (Fig 1). The suppression-burst pat- and establishing clear criteria for research studies, epilepsy tern is present in both waking and sleeping states, and syndromes can suggest underlying disease pathophysiol- appears in the first 3 months of life [9]. Partial tonic ogy, provide prognostic information to the families, and seizures can be observed, but myoclonic seizures are rare aid in the selection of appropriate diagnostic tests. Epi- [9]. Etiology is heterogeneous, and includes brain malfor- lepsy syndromes are the rational basis for selection of mations, migration disorders, mitochondrial diseases, and, appropriate antiepileptic drugs, surgical procedures, or rarely, inborn errors of metabolism, such as Leigh’s alternative treatment options [1,3,4]. disease or cytochrome oxidase deficiency [9,10]. The The epilepsy syndrome classification system adopted by seizures are usually intractable to antiepileptic medica- the International League Against Epilepsy in 1989 [5] has tions, and the developmental prognosis is uniformly poor been demonstrated to be reliable and applicable to children [9]. Surgery can be considered in those patients with [6,7]. Moreover, an increasing number of infantile (1-24 cortical malformations, such as cortical dysplasia or hemi- months) epileptic syndromes are being isolated and rec- megalencephaly. Ohtahara syndrome frequently evolves

From the Epilepsy Center, Children’s Memorial Hospital, Chicago, Communications should be addressed to: Illinois. Dr. Nordli; Director, Epilepsy Center; Children’s Memorial Hospital; Box #29; 2300 Children’s Plaza; Chicago, IL 60614-3394. E-mail: [email protected] Received May 5, 2005; accepted July 27, 2005.

© 2006 by Elsevier Inc. All rights reserved. Korff and Nordli: Epilepsy Syndromes in Infancy 253 doi:10.1016/j.pediatrneurol.2005.08.005 ● 0887-8994/06/$—see front matter Table 1. Main characteristics of the epileptic syndromes that present in infancy

Syndrome Main Characteristics

Early infantile epileptic encephalopathy First months; tonic seizures, spasms; suppression-burst; severe outcome Early myoclonic epilepsy First months; myoclonias, spasms; suppression-burst (sleep); severe outcome Infantile spasms First year; spasms; ; developmental delay First year; partial and generalized seizures, myoclonias; normal EEG at onset; later: generalized spike-waves and multifocal spikes; severe outcome Myoclonic astatic epilepsy First year; generalized myoclonic and astatic seizures; interictal parietal theta activity and bilateral spike-waves; variable outcome Malignant migrating partial seizures of infancy First year; continuous electrographic seizures, multiple areas of onset; severe outcome Generalized epilepsy with febrile seizures (ϩ) Variable and developmental phenotype in addition to febrile seizures and afebrile generalized Hemiconvulsion-hemiplegia-epilepsy Prolonged unilateral febrile seizures; subsequent hemiparesis and partial epilepsy Benign myoclonic epilepsy First 3 years; myoclonic seizures; normal interictal EEG; normal development Benign familial/nonfamilial seizures First year; partial seizures; normal development into West syndrome, and for some, later, into Lennox- helped two patients with cryptogenic etiology, but was Gastaut syndrome [4,11,12]. Controversies exist as to ineffective in all others. Three patients had their seizure whether Ohtahara syndrome, West syndrome, and Len- activity controlled on zonisamide. This publication was nox-Gastaut syndrome are part of the same spectrum of particularly important because of the prognostic findings. the age-dependent epileptic encephalopathies, or whether On evolution, two groups with different prognoses were they each represent isolated syndromes with specific identified: one of them included seven patients, who characteristics [12,13]. evolved from Ohtahara syndrome to West syndrome and A recent report on 16 patients diagnosed with early later to Lennox-Gastaut syndrome, and all of these patients infantile epileptic encephalopathy indicated that the age at died; the second included patients with spike foci on first seizure ranged from 1 day to 3 months. There was no electroencephalogram: only one patient died, and seven sex predominance. All of the patients had tonic spasms, were seizure-free. Nevertheless, all patients in the second either in clusters or isolated. Hemiconvulsions, erratic group were physically and mentally severely handicapped focal motor seizures, and asymmetric tonic seizures were [14]. observed in one third to one half of the patients. General- ized clonic seizures were observed in one patient. The interictal electroencephalogram was characterized by 1- to Early Myoclonic Epilepsy/Encephalopathy 3-second bursts of high-voltage (150-350 ␮V) slow waves This rare entity was termed “neonatal myoclonic en- and multifocal spikes, separated by suppression phases of cephalopathy” in its initial description [15]. It was further 2-5 seconds duration. This pattern was independent of the delineated and renamed “early myoclonic epileptic en- circadian rhythm. The spasms were accompanied by a cephalopathy” by Dalla Bernardina et al. in 1983 [16], and high-voltage slow wave followed by attenuation, some- “early myoclonic epilepsy” by Aicardi in 1985 [17]. Like times with low-voltage fast activity. The interictal sup- early infantile epileptic encephalopathy, it is characterized pression-burst pattern often disappeared during a cluster of by intractable seizures with onset during the first 3 months spasms. Partial seizures could precede or follow a cluster of life, suppression-burst interictal electroencephalogram, of spasms, but were also observed independently. Etiology and poor developmental prognosis [9]. Early myoclonic or associated conditions included two suspected cases of epilepsy is, however, distinguished from early infantile Aicardi syndrome, one case of hemimegalencephaly, one epileptic encephalopathy by its predominant clinical man- case of porencephaly, one case of hydrocephalus, one case ifestations, erratic myoclonias, and by the presence of a of lissencephaly, and four cases of nonspecific cerebral suppression-burst pattern mainly during sleep. Partial atrophy or dysgenesis. Adrenocorticotrophic hormone seizures are also observed, and include tonic spasms, isolated or in clusters, versive seizures, migrating clonic Table 2. Specific treatment options seizures, and asymmetric tonic seizures with occasional secondary generalization [9]. Patients with early myo- Epileptic Syndrome Treatment Options clonic epilepsy share most electroencephalographic char- Infantile spasms (West) Adrenocorticotrophic hormone, vigabatrin, acteristics with patients with early infantile epileptic en- cephalopathy, although the duration of bursts and Dravet Stiripentol–valproic acid–clobazam, suppression epochs, and the length of burst-burst intervals topiramate Myoclonic astatic epilepsy Valproic acid, levetiracetam, ketogenic are more variable in early myoclonic epilepsy [9,18]. Most diet myoclonias have no associated electroencephalographic Benign myoclonic Valproic acid changes, and are therefore considered nonepileptic [4,9]. epilepsy Partial seizures manifest various electrographic patterns of

254 PEDIATRIC NEUROLOGY Vol. 34 No. 4 Figure 1. Suppression-bursts. Six-month-old male, awake. Early infantile epileptic encephalopathy. rhythmic activity, or irregular spike-waves. Tonic spasms Infantile Spasms/West Syndrome are electrographically similar to the ones observed in early infantile epileptic encephalopathy and West syndrome [9]. Infantile spasms, or West syndrome, is a form of severe Based on a high incidence of familial cases, and on the epilepsy observed with a peak frequency between 4 and 9 usual absence of cerebral lesions at onset, genetic factors months of age [11,19]. It was first described in a report by and inborn errors of metabolism including nonketotic Dr. West regarding his unfortunate son, published in 1841 hyperglycinemia play a prominent etiologic role. On [20]. Its overall incidence is estimated at 3-4.5/10,000 live evolution, however, lesions such as progressive cortical births [21-23]. Males are more affected than females in a atrophy or delayed myelination are frequently observed ratio of 1.4:1 [22]. The spasms are extremely resistant to [9]. None of the conventional antiepileptic drugs has treatment. They are characterized by a brisk flexion, or, demonstrated efficacy. Severe developmental delay is the more rarely, extension of the trunk and an extension of the rule, and mortality is high [9]. extremities, sometimes followed by a brief tonic posture; Lombroso reported a series of 29 patients with early they appear in clusters. They may be subtle and may not be myoclonic epilepsy. Among them, six manifested perina- recognized as seizures. They can be asymmetric, particu- tal asphyxia, five had brain malformations, eight mani- larly in symptomatic cases, and appear in sleep or in fested inborn errors of metabolism, and 10 cases were wakefulness. Development may be normal at onset, but cryptogenic. Nonketotic hyperglycinemia was diagnosed some regression occurs in most children. The typical in four patients. Two patients had an abnormal immuno- interictal electroencephalogram reveals hypsarrhythmia, logic profile, and were treated with a course of intravenous characterized by high-amplitude (up to 500 ␮V) asynchro- gammaglobulins. A marked but transitory improvement nous slow waves intermixed with multifocal spikes (Fig was observed in one of them. A family history of epilepsy 2). It appears in sleep first, and later in wakefulness as was present in three patients of the cryptogenic category, well. A modified pattern, with some degree of synchrony and two patients were siblings [4]. In the series of Dalla and long spike-wave complexes is sometimes observed. Bernardina et al., two patients were brothers, and six males The typical electrographic correlate of a spasm is a sharp in four generations had died of an epileptic encephalopa- wave followed by attenuation (electrodecrement) and low- thy probably transmitted with an X-linked inheritance. voltage fast activity (Fig 3). Five patients died during the first 2 years of life. Neuro- Multiple etiologies have been associated with West pathologic studies were performed in two of them, but syndrome, including perinatal hypoxic-ischemic injuries, failed to reveal any pathologic macroscopic or micro- tuberous sclerosis, brain malformations, chromosomal ab- scopic findings. Decerebrate posture and microcephaly normalities, and inborn errors of metabolism. In 30% of developed in all survivors [16]. the cases, no specific etiology is found [2,11]. Infants with

Korff and Nordli: Epilepsy Syndromes in Infancy 255 Figure 2. Hypsarrhythmia. Sixteen-month-old female, asleep. West syndrome, cortical dysplasia. cryptogenic etiology have a better prognosis regarding infantile has even been described in seizure control and development. In the study by Luth- cryptogenic cases: infants had normal development at vigsson et al., all 6 infants with cryptogenic spasms had a onset, and only exhibited a subtle and transitory regres- normal or satisfactory outcome [21]. A “benign” form of sion, if any, during the period of spasms [24,25].Of

Figure 3. Spike and electrodecrement. Five-month-old male, drowsy. Idiopathic infantile spasms.

256 PEDIATRIC NEUROLOGY Vol. 34 No. 4 particular note was that their visual function was preserved death for adrenocorticotrophic hormone; and irreversible [25]. In these infants, the interictal electroencephalogram peripheral retinopathy for vigabatrin. These potential com- between spasms and during a cluster returned to the plications underline the need for detailed pretreatment baseline hypsarrhythmia, and no focal anomalies were investigations and closely monitored follow-up visits present [24,25]. However, extensive neuropsychological when these drugs are used. assessment in cryptogenic cases revealed that the risk of cognitive deficits in preschool children was significantly Dravet Syndrome (Severe Myoclonic increased, even in those with rapid control of spasms. Epilepsy of Infancy) Cognitive dysfunction could vary from mild learning disability to specific deficits with normal intelligence [26]. Dravet syndrome was described in 1978 [29].Itisa Epilepsy with other types of seizures follows West severe epilepsy characterized by generalized and unilateral syndrome in 50-60% of the cases, Lennox-Gastaut syn- clonic or tonic-clonic seizures appearing in the first year of drome being the most common form observed [13]. The life, later evolution to other types of seizures, including optimal treatment of infantile spasms remains uncertain. myoclonias, atypical absences, alternating unilateral sei- Adrenocorticotrophic hormone, prednisolone and, more zures, or nonconvulsive . Progressive recently, vigabatrin have been traditionally considered developmental delay is invariably observed on evolution, first choices. usually from the second year on. Tonic seizures are An evidence-based review of the literature on the exceptional. All seizures are resistant to treatment [29,30]. treatment of infantile spasms revealed the following ob- Because Dravet syndrome typically presents with a seizure servations that summarize the current situation: “1) Adre- triggered by fever in an otherwise normal infant, it may be nocorticotropic hormone is probably effective for the indistinguishable from febrile seizures at onset. However, short-term treatment of infantile spasms, but there is the prolonged character of the first event and the rapid insufficient evidence to recommend the optimum dosage appearance of additional seizures usually allow differen- and duration of treatment; 2) There is insufficient evidence tiation of Dravet syndrome from febrile seizures. The term to determine whether oral corticosteroids are effective; 3) Dravet syndrome was progressively preferred to other Vigabatrin is possibly effective for the short-term treat- proposed denominations, such as severe myoclonic epi- ment of infantile spasm and is possibly also effective for lepsy in infancy, because myoclonias are not invariably children with tuberous sclerosis; 4) Concerns about retinal present at onset. toxicity suggest that serial ophthalmologic screening is In a recent series, Dravet syndrome accounted for 8.2% required in patients on vigabatrin; however, the data are of patients who had their first seizure before the age of 3 insufficient to make recommendations regarding the fre- [29]. Males are more affected than females in a ratio of 2:1 quency or type of screening; 5) There is insufficient [29]. The interictal electroencephalogram is usually nor- evidence to recommend any other treatment of infantile mal at presentation, and later manifests generalized spike- spasms; 6) There is insufficient evidence to conclude that and-wave complexes, as well as focal and multifocal successful treatment of infantile spasms improves the spikes. A theta rhythm in the central and vertex region is long-term prognosis” [27]. observed early in the majority, but tends to disappear with A randomized, prospective, multicenter, controlled age [13]. Photosensitivity is frequently demonstrated, but study on 208 infants with spasms compared vigabatrin is inconstant during the course of the disease [29,30].Itis (minimum 100 mg/kg/day) with oral prednisolone (mini- often a cause of self-stimulation. Massive myoclonias are mum 40 mg/day) or intramuscular adrenocorticotrophic associated with bursts of irregular spike-and-waves; on the hormone (minimum 40 international units on alternate other hand, erratic myoclonias do not correlate with days) using control of spasms at 13 and 14 days after electroencephalographic changes [13]. randomization as the principal outcome measure. The Convulsive seizures are thought to have a focal onset in results indicated that spasms were significantly more the majority of cases, with several foci firing successively likely to cease in infants assigned adrenocorticotrophic and giving them a “falsely generalized” or “unstable” hormone or prednisolone (73% controlled) than in those aspect; truly generalized seizures could in fact be less given vigabatrin (54% controlled). There were no differ- frequent than reported [29]. Atypical absences correspond ences between the two hormonal treatments, in contrast to generalized 2-3.5 Hz irregular spike-waves [29]. Non- with the previously mentioned evidence-based report. convulsive status epilepticus is electrographically charac- Response to treatment was not affected by the underlying terized by diffuse slow waves and intermixed spikes [29]. etiology, but children with tuberous sclerosis were ex- Neuroimaging studies usually do not reveal brain lesions cluded on the assumption that vigabatrin was more effi- at onset, but may reveal hippocampal sclerosis on evolu- cient in such cases. No deaths were observed. Outcome tion [31]. Genetics plays an important role in Dravet measures at 14 months are expected to be reported [28]. syndrome, and a family history of epilepsy or febrile Both adrenocorticotrophic hormone and vigabatrin seizures is present in approximately 25% [29]. Affected carry potentially serious side effects, namely immunosup- monozygotic pairs of twins have been reported. The pression, gastric hemorrhage, cardiac insufficiency, and association with a mutation in the sodium-channel gene

Korff and Nordli: Epilepsy Syndromes in Infancy 257 SCN1A has been recently discovered, and is present in types encountered in the families in which generalized various proportions of patients. Recent abstracts suggest epilepsy with febrile seizures (ϩ) syndrome was initially that de novo truncation mutations are particularly associ- described [40]. Outcome is variable. In a study on 52 ated with Dravet syndrome. The presence of this mutation patients, 85% were developmentally normal at onset, and is considered supportive, but not necessary to make the 77% remained so at 7.5 years follow-up [41,42].Onthe diagnosis of Dravet syndrome. ␥-aminobutyric acid other hand, severe developmental delay and intractable (GABA) receptor gene GABRG2 mutations have also been seizures have also been described. The persistence of theta described, but only rarely [29]. For some authors, Dravet rhythms until adolescence and adulthood, failure to de- syndrome is the most severe phenotype in the generalized velop a stable occipital alpha rhythm, generalized tonic- epilepsy with febrile seizures (ϩ) spectrum [32]. The clonic convulsions during the first year of life, nonconvul- signification of de novo mutations in families with other sive status epilepticus, and tonic seizures are considered forms of epilepsy remains unclear, but a heterogeneous prognostically unfavorable [43]. In our experience, how- genetic background is likely [29,33]. The long-term prog- ever, patients with myoclonic-astatic epilepsy and tonic nosis is universally poor. Seizures are extremely difficult seizures can have a normal development. Valproic acid is to control and remain sensitive to fever or hyperthermia; advocated by many [39]. Ethosuximide is effective in developmental delay is present in all infants; neurologic treating absence seizures. Levetiracetam and the ketogenic abnormalities, such as ataxia and pyramidal signs are diet have demonstrated promising results in our hands. frequent; and the mortality rate is high (15.9% in Dravet’s Comparative drug trials are definitely wanting in this series) [34]. Topiramate is effective [35,36], and stiripen- disorder. tol (not approved in the United States), as add-on therapy to valproic acid and clobazam, has demonstrated signifi- Malignant Migrating Partial Seizures of Infancy cant efficacy on convulsive seizures in a placebo-con- trolled study on 41 patients [37]. Additional treatment Malignant migrating partial seizures in infancy is a options, such as zonisamide and the ketogenic diet, have severe epileptic disorder described in 1995 [44].Itis also yielded some efficacy in controlling seizure activity characterized by nearly continuous electrographic seizures [29]. On the other hand, certain drugs, such as phenobar- involving multiple independent areas of onset, beginning bital, phenytoin, carbamazepine, and lamotrigine, may in the first 6 months of life in normal infants with exacerbate seizures [4,29]. Prophylaxis of fever and hy- developmental delay and intractable seizures. No under- perthermia should be specifically emphasized in patients lying etiology is evident, but a functional or metabolic with Dravet syndrome. dysfunction is suspected. Its prevalence is unknown; series involving only small numbers of patients have been Myoclonic-Astatic Epilepsy (Doose Syndrome) published [44-46]. Coppola et al. reported a series of 14 patients fulfilling Myoclonic-astatic epilepsy was described in 1970 [38]. these criteria. The spectrum of clinical manifestations was The main characteristics of the epileptic syndrome were large. All seizures had a motor component; most were already recognized in the initial description. The seizures focal and accompanied by autonomic manifestations; are primary generalized with myoclonic or astatic compo- many migrated from one side of the body to the other, and nents that often lead to severe injuries. They are observed six of them secondarily generalized. Two patients pre- in combination with absences, generalized tonic-clonic or sented with status epilepticus. Mild clinical features were clonic-tonic-clonic seizures (personal observations), tonic observed during habitual seizures. The interictal electro- seizures, and nonconvulsive status epilepticus with subtle encephalogram was normal in three patients at onset, but myoclonias. The onset is between 1 and 5 years, most was always abnormal during evolution, with multifocal often between 3 and 4 years, in an otherwise normal child. spikes and sleep abnormalities. The ictal electroencepha- Males are more often affected than females. The interictal logram was characterized by monomorphic rhythmic theta electroencephalogram is characterized by bilateral syn- or alpha activity progressively involving adjacent areas chronous irregular 2-3 Hz spike-and-wave complexes. before decreasing. Additional seizures beginning in other Parietal rhythmic theta may be observed independent of areas in either hemisphere could commence before the end the state of vigilance. Myoclonic seizures are accompanied of the first event, or immediately follow it (Fig 4). by irregular spikes and polyspikes. The astatic component Cerebral magnetic resonance imaging was performed in is characterized by electrographic silence on electromyo- 10 patients and did not reveal any abnormalities. Eleven graphy, and can present as subtle head drops or massive patients developed microcephaly during the first year of loss of muscle tone and fall to the ground. Organic brain life. Three patients died. Conventional treatments were lesions are rarely encountered [39]. As with Dravet syn- ineffective, except for the combination of stiripentol and drome, a genetic role is strongly suspected. A family clonazepam in two children, in whom some neurologic history of seizures or electroencephalographic abnormali- improvement was also observed [44]. ties was documented in up to 80% of the cases [38], and We and others [47] suspect that there is a wider clinical myoclonic-astatic epilepsy was one of the clinical pheno- spectrum of this disorder. In particular, we have observed

258 PEDIATRIC NEUROLOGY Vol. 34 No. 4 Figure 4. (a) Migrating seizure, right-sided onset. Seventeen-month-old female, awake. Mitochondrial disorder. (b) Migrating seizure, transition phase: right-sided fading and independent left onset. (c) Migrating seizure, left-sided continuation and termination.

Korff and Nordli: Epilepsy Syndromes in Infancy 259 patients with less-than-constant seizures, and Marsh et al. ment was supported by the fact that the frequency of [47] report patients with slightly better outcomes than hemiconvulsions-hemiplegia-epilepsy had considerably those reported by Coppola et al. decreased in parallel to the introduction of the early use of benzodiazepines in the treatment of febrile convulsions Generalized Epilepsy With Febrile Seizures and unilateral seizures [53]. Neuroimaging descriptions Plus (GEFS؉) also favor the idea that febrile status epilepticus can cause brain injuries, with the demonstration of cytotoxic edema Generalized epilepsy with febrile seizures (ϩ) was de- on diffusion-weighted magnetic resonance imaging in the scribed in 1997 [40]. It is characterized by the association of acute phase [54-56], and of atrophy [54] and hypoperfu- generalized febrile seizures beyond the age of 6 years and sion on single-photon emission computed tomography afebrile generalized convulsions; a positive family history of studies in later stages [57]. A recent report described the epilepsy with variable phenotypes; and a benign evolution in detection of human herpesvirus 6 and 7 deoxyribonucleic the majority of cases. The first description in a large family acid, and specific antibodies for human herpesvirus 7 in revealed that the clinical spectrum of generalized epilepsy the serum of an 18-month-old patient with generalized with febrile seizures (ϩ) comprised cases of simple febrile febrile convulsions who exhibited early hemispheric seizures; febrile seizures beyond the age of 6 years [febrile edema and late atrophy [56], but the underlying patho- seizures (ϩ)]; febrile seizures (ϩ) and absences; febrile physiologic mechanism remains unknown. Studies specif- seizures (ϩ) and myoclonic seizures; febrile seizures (ϩ) and ically addressing the influence of prolonged febrile sei- atonic seizures; and myoclonic-astatic epilepsy. This spec- zures on are currently under way. trum was further extended with other types of epilepsy, such as febrile seizures (ϩ) and temporal lobe epilepsy [48], Dravet syndrome, and cryptogenic Lennox-Gastaut syn- Benign Myoclonic Epilepsy of Infancy drome [32]. The pattern of transmission in the first family suggested an autosomal dominant inheritance. The authors Benign myoclonic epilepsy of infancy was described in hypothesized that a single major gene defect, with possible 1981 [58]. It was initially characterized by the occurrence additive gene effect, was responsible for the phenotypic of easily treatable myoclonic seizures in the first 3 years of variability on the entire spectrum of the generalized epilep- life in infants who remained normal on evolution. Except sies [40,48]. Extensive genetic analyses in these families for rare simple febrile seizures, no other types of seizures allowed the identification of a mutation in the sodium- are usually observed [59]. A family history of epilepsy or channel ␤1 subunit gene (SCN␤1) on chromosome region febrile convulsions is present in 30% of the cases [60]. 19q13.1 [49]. Additional mutations were later discovered in Benign myoclonic epilepsy of infancy accounted for less other genes, such as the sodium-channel ␣1 subunit gene on than 1% of all the epilepsies, and 2% of all generalized chromosome region 2q24 [50], or the GABAA receptor epilepsies, in unpublished data from the Centre Saint-Paul ␥2-subunit gene on chromosome region 5q34 [51]. These in Marseilles. Males are more often affected than females findings underline the genetic complexity of this disorder, in a ratio of approximately 2:1 [59]. The seizures are which remains to be completely understood. Some have characterized as brief myoclonic jerks, particularly during argued that this is not a specific epilepsy syndrome, but rather drowsiness and, in some cases, are activated by photic a description of genetic susceptibility. stimulation or sudden external stimuli [59]. They usually disappear during sleep. Although generalized tonic-clonic Hemiconvulsions-Hemiplegia-Epilepsy seizures and absence seizures have been described [59], others regard these seizures as exclusionary criteria. The Hemiconvulsions-hemiplegia-epilepsy was described in interictal electroencephalogram is normal. The myoclonias 1960 [52]. It is characterized by prolonged unilateral are accompanied by generalized spike-waves or febrile seizures followed by ipsilateral hemiparesis, and, polyspike-waves. In contrast, in benign nonepileptic my- later, epilepsy. Pathologic studies in the acute stage oclonus of infancy, no electroencephalographic changes revealed hemispheric swelling, hemorrhagic necrotic le- are observed during myoclonias. Neuroradiologic investi- sions, and neuronal degeneration. In the chronic stage, gations do not reveal abnormalities. Seizures are sensitive atrophy, cystic necrosis, and foci of demyelination were to valproic acid, which is considered the drug of choice. observed. The temporal lobe was by far the most com- Sixty-seven of 76 patients (88%) with benign myoclonic monly involved region [52]. Vascular causes, such as epilepsy of infancy became seizure-free on valproate venous thromboses, were believed to be the most preva- monotherapy [59]. In most cases they disappear in less lent. According to other authors, this may have been than 1 year of evolution. Recent data suggest that the explained by infections involving the head and face, neurodevelopmental outcome depends on an early recog- commonly associated with cerebral thromboses. The sug- nition and on appropriate treatment. It is favorable in the gestion was advanced that these cases did not differ in great majority, but mild mental retardation can be ob- etiology from benign febrile seizures, and that the sequelae served and the real benignity of the syndrome has been were caused by status epilepticus itself [53]. This state- questioned [59].

260 PEDIATRIC NEUROLOGY Vol. 34 No. 4 Benign Familial/Nonfamilial Infantile Seizures classification and for further work in classifying epilepsy syndromes. We suspect that there are new syndromes This entity is characterized by partial seizures appearing waiting to be discovered within this ill-defined group of in the first year of life in otherwise normal infants [61,62]. epilepsies. We furthermore speculate that severe inborn A family history of similar seizures at the same age is errors of metabolism, severe channelopathies, and neuro- frequent, and an autosomal dominant inheritance with degenerative disorders may be responsible for some of incomplete penetrance is suspected [63]. Linkage to chro- these infantile epilepsies with mixtures of focal and mosome regions 19q, 2q24, and 16p12-q12 has been generalized features. demonstrated [63,64]. The seizures are characterized by Finally, the International League Against Epilepsy has behavioral arrest with versive components, cyanosis, gen- proposed a diagnostic scheme that is useful for the eralized hypertonia, and unilateral myoclonic jerks. Sec- analysis of patients with epilepsy. This scheme consists of ondary generalization can occur. They resumed at a five axes that would allow a variety of approaches depen- median age of 14-15 months in a series on 64 cases [62]. dent on the particular purpose. These axes include ictal The interictal electroencephalogram is normal [61,62]. semiology, seizure type, epileptic syndrome, etiology, and The ictal electroencephalographic recordings indicate a degree of impairment [65]. Whatever the adopted scheme, parieto-occipital onset, with occasional generalization we agree that, implicit in this ordering of diagnoses, one [61,63]. Seizures are well controlled on valproic acid [63]; must arrive at an accurate seizure classification before an in mild cases, treatment might not even be necessary. The epilepsy syndrome can be established. We believe infan- neurodevelopmental prognosis is always favorable. Its tile seizures require an electroclinical diagnosis in order to separation from the benign nonfamilial form of infantile achieve appropriate diagnostic precision. Current efforts partial seizures is controversial. In a study comparing the are under way to thoroughly establish electroclinical two entities, Caraballo et al. did not find any electroclini- definitions of infantile seizures. cal differences. The only parameter that varied was the presence, in benign familial infantile seizures, of a family Christian Korff, MD is the recipient of a scholarship from the Eugenio history of seizures. Paroxysmal choreoathetosis, a move- Litta Foundation, Vaduz, Liechtenstein. ment disorder occasionally associated with this entity on evolution, was also solely observed in familial cases, but in too small numbers to be considered as a significant References finding [62]. [1] Nordli DR Jr. Diagnostic difficulty in infants and children. J Child Neurol 2002;17(Suppl. 1):S28-35. [2] Shields WD. Diagnosis of infantile spasms, Lennox-Gastaut Issues and Needs syndrome, and progressive myoclonic epilepsy. Epilepsia 2004; 45(Suppl. 5):2-4. Some major issues characterize the current classifica- [3] Aicardi J. Syndromic classification in the management of child- tion of epileptic syndromes in infants. First, most of the hood epilepsy. J Child Neurol 1994;9(Suppl. 2):14-8. [4] Lombroso CT. Early myoclonic encephalopathy, early infantile reported epileptic syndromes are rare and may not be epileptic encephalopathy, and benign and severe infantile myoclonic easily recognized. The available data suggest that while epilepsies: A critical review and personal contributions. J Clin Neuro- these syndromes often carry severe prognoses, they may physiol 1990;7:380-408. benefit from specific forms of treatment. Patients with [5] Commission on Classification and Terminology of the Inter- infantile epilepsies should therefore be referred to centers national League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. with experience in this domain. [6] Berg AT, Shinnar S, Levy SR, Testa FM. Newly diagnosed Second, there is a conspicuous absence of precise epilepsy in children: Presentation at diagnosis. Epilepsia 1999;40:445- correlation between metabolic diseases and epilepsy syn- 52. dromes. It is likely that more detailed reports of seizures [7] Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, and electroencephalographic findings in patients with Beckerman B. How well can epilepsy syndromes be identified at diagnosis? A reassessment 2 years after initial diagnosis. Epilepsia metabolic defects will help identify additional epilepsy 2000;41:1269-75. syndromes. Exceptions include early myoclonic epilepsy [8] Sarisjulis N, Gamboni B, Plouin P, Kaminska A, Dulac O. and West syndrome where metabolic etiologies have Diagnosing idiopathic/cryptogenic epilepsy syndromes in infancy. Arch clearly been identified. Dis Child 2000;82:226-30. Third, there is a small, but important group of infants [9] Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003;20:398-407. with devastating encephalopathies that cannot be classi- [10] Williams AN, Gray RG, Poulton K, Ramani P, Whitehouse fied into specific syndromes. These unclear cases often WP. A case of Ohtahara syndrome with cytochrome oxidase deficiency. end up in broad, ill-defined seizure categories, such as Dev Med Child Neurol 1998;40:568-70. “unclassified seizures”, and epilepsy subtypes, such as [11] Aicardi J. Myoclonic epilepsies of infancy and childhood. Adv “epilepsies with both generalized and focal seizures not Neurol 1986;43:11-31. [12] Kelley KR, Shinnar S, Moshe SL. A 5-month-old with intrac- otherwise specified” (3.1.0), or “epilepsies without un- table epilepsy. Semin Pediatr Neurol 1999;6:138-44; discussion 144-5. equivocal generalized or focal seizures” (3.2). These cases [13] Arzimanoglou A, Guerrini R, Aicardi J. Infantile spasms and illustrate that there is a need for more precise seizure related syndromes. In: Arzimanoglou A, Guerrini R, Aicardi J, eds.

Korff and Nordli: Epilepsy Syndromes in Infancy 261 Aicardi’s epilepsy in children, 3rd ed. Philadelphia: Lippincott Williams [36] Nieto-Barrera M, Candau R, Nieto-Jimenez M, Correa A, del & Wilkins, 2004:14-37. Portal LR. Topiramate in the treatment of severe myoclonic epilepsy in [14] Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalop- infancy. Seizure 2000;9:590-4. athy with suppression-bursts, Ohtahara syndrome; its overview referring [37] Chiron C, Marchand MC, Tran A, et al., and the STICLO study to our 16 cases. Brain Dev 2002;24:13-23. group. Stiripentol in severe myoclonic epilepsy in infancy: A randomised [15] Aicardi J, Goutières F. [Neonatal myoclonic encephalopathy placebo-controlled syndrome-dedicated trial. Lancet 2000;356:1638-42. (author’s transl.)] Rev Electroencephalogr Neurophysiol Clin 1978;8:99- [38] Doose H, Gerken H, Leonhardt R, Volzke E, Volz C. Centren- 101. cephalic myoclonic-astatic petit mal: Clinical and genetic investigation. [16] Dalla Bernardina B, Dulac O, Fejerman N, et al. Early Neuropädiatrie 1970;2:59-78. myoclonic epileptic encephalopathy (E.M.E.E.). Eur J Pediatr 1983;140: [39] Neubauer BA, Hahn A, Doose H, Tuxhorn I. Myoclonic-astatic 248-52. epilepsy of early childhood: Definition, course, nosography, and genet- [17] Aicardi J. Early myoclonic epilepsy. In: Roger J, Dravet C, ics. Adv Neurol 2005;95:147-55. Bureau M, Dreifuss FE, Perret A, Wolf P, eds. Epileptic syndromes in [40] Scheffer IE, Berkovic SF. Generalized epilepsy with febrile infancy, childhood and adolescence, 2nd ed. London: John Libbey seizures plus: A genetic disorder with heterogeneous clinical phenotypes. Eurotext, 1985:12-20. Brain 1997;120:479-90. [18] Otani K, Abe J, Futagi Y, Yabuuchi H, Aotani H, Takeuchi T. [41] Lagenstein I. [Epilepsies with myoclonic-astatic seizures. A Clinical and electroencephalographical follow-up study of early myo- clinical and electroencephalographical study in 95 patients. I. Clinical clonic encephalopathy. Brain Dev 1989;11:332-7. results (author’s transl.)] [Article in German]. Monatsschr Kinderheilkd [19] Zupanc ML. Infantile spasms. Expert Opin Pharmacother 1980;128:711-6. 2003;4:2039-48. [42] Lagenstein I. [Myoclonic-astatic petit mal and its course. A [20] West WJ. On a peculiar form of infantile convulsions. Lancet clinical and electroencephalographic study on 95 patients] [Article in 1841;1:724-5. German]. Fortschr Med 1980;98:573-9. [21] Luthvigsson P, Olafsson E, Sigurthardottir S, Hauser WA. [43] Doose H. Myoclonic-astatic epilepsy. Epilepsy Res 1992(Suppl. Epidemiologic features of infantile spasms in Iceland. Epilepsia 1994; 6):163-8. 35:802-5. [44] Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating [22] Brna PM, Gordon KE, Dooley JM, Wood EP. The epidemiol- partial seizures in infancy: A malignant disorder with developmental ogy of infantile spasms. Can J Neurol Sci 2001;28:309-12. arrest. Epilepsia 1995;36:1017-24. [23] Sidenvall R, Eeg-Olofsson O. Epidemiology of infantile [45] Veneselli E, Perrone MV, Di Rocco M, Gaggero R, Biancheri spasms in Sweden. Epilepsia 1995;36:572-4. R. Malignant migrating partial seizures in infancy. Epilepsy Res 2001; [24] Dulac O, Plouin P, Jambaque I, Motte J. [Benign epileptic 46:27-32. infantile spasms]. Rev Electroencephalogr Neurophysiol Clin 1986;16: [46] Gross-Tsur V, Ben-Zeev B, Shalev RS. Malignant migrating 371-82. partial seizures in infancy. Pediatr Neurol 2004;31:287-90. [25] Dulac O, Plouin P, Jambaque I. Predicting favorable outcome in [47] Marsh E, Melamed SE, Barron T, Clancy RR. Migrating partial idiopathic West syndrome. Epilepsia 1993;34:747-56. seizures in infancy: Expanding the phenotype of a rare seizure syndrome. [26] Gaily E, Appelqvist K, Kantola-Sorsa E, et al. Cognitive Epilepsia 2005;46:568-72. deficits after cryptogenic infantile spasms with benign seizure evolution. [48] Singh R, Scheffer IE, Crossland K, Berkovic SF. Generalized Dev Med Child Neurol 1999;41:660-4. epilepsy with febrile seizures plus: A common childhood-onset genetic [27] Mackay MT, Weiss SK, Adams-Webber T, et al. American epilepsy syndrome. Ann Neurol 1999;45:75-81. Academy of Neurology; Child Neurology Society. Practice parameter: [49] Wallace RH, Wang DW, Singh R, et al. Febrile seizures and Medical treatment of infantile spasms: Report of the American Academy generalized epilepsy associated with a mutation in the Naϩ-channel ␤1 of Neurology and the Child Neurology Society. Neurology 2004;62: subunit gene SCN1B. Nat Genet 1998;19:366-70. 1668-81. [50] Escayg A, MacDonald BT, Meisler MH, et al. Mutations of [28] Lux AL, Edwards SW, Hancock E, et al. The United Kingdom SCN1A, encoding a neuronal sodium channel, in two families with Infantile Spasms Study comparing vigabatrin with prednisolone or GEFSϩ2. Nat Genet 2000;24:343-5. tetracosactide at 14 days: A multicentre, randomised controlled trial. [51] Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic Lancet 2004;364:1773-8. evidence of GABA(A) receptor dysfunction in epilepsy: A mutation in [29] Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe the gamma2-subunit gene. Nat Genet 2001;28:46-8. myoclonic epilepsy in infancy: Dravet syndrome. Adv Neurol 2005;95: [52] Gastaut H, Poirier F, Payan H, Salamon G, Toga M, Vigouroux 71-102. M. H.H.E. syndrome; hemiconvulsions, hemiplegia, epilepsy. Epilepsia [30] Dravet C. Severe myoclonic epilepsy in infants and its related 1960;1:418-47. syndromes. Epilepsia 2000;41(Suppl. 9):7. [53] Roger J, Dravet C, Bureau M. Unilateral seizures: Hemicon- [31] Siegler Z, Barsi P, Neuwirth M, et al. Hippocampal sclerosis in vulsions-hemiplegia syndrome (HH) and hemiconvulsions-hemiplegia- severe myoclonic epilepsy in infancy: A retrospective MRI study. epilepsy syndrome (HHE). Electroencephalogr Clin Neurophysiol 1982; Epilepsia 2005;46:704-8. 35(Suppl.):211-21. [32] Singh R, Andermann E, Whitehouse WP, et al. Severe myo- [54] Freeman JL, Coleman LT, Smith LJ, Shield LK. Hemiconvul- clonic epilepsy of infancy: Extended spectrum of GEFSϩ? Epilepsia sion-hemiplegia-epilepsy syndrome: Characteristic early magnetic reso- 2001;42:837-44. nance imaging findings. J Child Neurol 2002;17:10-6. [33] Guerrini R, Aicardi J. Epileptic encephalopathies with myo- [55] Herbst F, Heckmann M, Reiss I, Hugens-Penzel M, Gortner L, clonic seizures in infants and children (severe myoclonic epilepsy and Neubauer B. [Hemiconvulsion-Hemiplegia-Epilepsy-Syndrome (HHE)]. myoclonic-astatic epilepsy). J Clin Neurophysiol 2003;20:449-61. Klin Padiatr 2002;214:126-7. [34] Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe [56] Kawada J, Kimura H, Yoshikawa T, et al. Hemiconvulsion- myoclonic epilepsy in infancy (Dravet syndrome). In: Roger J, Dravet C, hemiplegia syndrome and primary human herpesvirus 7 infection. Brain Bureau M, Dreifuss FE, Perret A, Wolf P, eds. Epileptic syndromes in Dev 2004;26:412-4. infancy, childhood and adolescence, 2nd ed. London: John Libbey, [57] Salih MA, Kabiraj M, Al-Jarallah AS, El Desouki M, Othman 1992:75-88. S, Palkar VA. Hemiconvulsion-hemiplegia-epilepsy syndrome: A clini- [35] Coppola G, Capovilla G, Montagnini A, et al. Topiramate as cal, electroencephalographic and neuroradiological study. Childs Nerv add-on drug in severe myoclonic epilepsy in infancy: An Italian Syst 1997;13:257-63. multicenter open trial. Epilepsy Res 2002;49:45-8. [58] Dravet C, Bureau M. The benign myoclonic epilepsy of infancy

262 PEDIATRIC NEUROLOGY Vol. 34 No. 4 (author’s transl.) [Article in French]. Rev Electroencephalogr familial and non-familial infantile seizures: A study of 64 patients. Neurophysiol Clin 1981;11:438-44. Epileptic Disord 2003;5:45-9. [59] Dravet C, Bureau M. Benign myoclonic epilepsy in infancy. [63] Callenbach PM, de Coo RF, Vein AA, et al. Benign familial Adv Neurol 2005;95:127-37. infantile convulsions: A clinical study of seven Dutch families. Eur J [60] Dravet C, Bureau M, Genton P. Benign myoclonic epilepsy of Paediatr Neurol 2002;6:269-83. infancy: Electroclinical symptomatology and differential diagnosis from [64] Caraballo RH, Cersosimo RO, Amartino H, Szepetowski P, the other types of generalized epilepsy of infancy. Epilepsy Res 1992; Fejerman N. Benign familial infantile seizures: Further delineation of the 6(Suppl.):131-5. syndrome. J Child Neurol 2002;17:696-9. [61] Vigevano F, Fusco L, Di Capua M, Ricci S, Sebastianelli R, [65] Engel J Jr; International League Against Epilepsy (ILAE). A Lucchini P. Benign infantile familial convulsions. Eur J Pediatr 1992; proposed diagnostic scheme for people with epileptic seizures and with 151:608-12. epilepsy: Report of the ILAE Task Force on Classification and Termi- [62] Caraballo RH, Cersosimo RO, Espeche A, Fejerman N. Benign nology. Epilepsia 2001;42:796-803.

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