Brain & Development 36 (2014) 739–751 www.elsevier.com/locate/braindev

Review article

Infantile spasms syndrome, West syndrome and related phenotypes: What we know in 2013 Piero Pavone a, Pasquale Striano b, Raffaele Falsaperla a, Lorenzo Pavone a, Martino Ruggieri c,⇑ a

Unit of Pediatrics and Pediatric Emergency “Costanza Gravina”, University Hospital “Policlinico-Vittorio Emanuele”, Catania, Italy b Unit of Pediatric Neurology and Muscular Diseases, “G. Gaslini” Research Hospital, University of Genoa, Italy c Department of Educational Science, Chair of Pediatrics, University of Catania, Italy Received 20 July 2012; received in revised form 12 July 2013; accepted 17 October 2013

Abstract The current spectrum of disorders associated to clinical spasms with onset in infancy is wider than previously thought; accordingly, its terminology has changed. Nowadays, the term Infantile spasms syndrome (ISs) defines an epileptic syndrome occurring in children younger than 1 year (rarely older than 2 years), with clinical (epileptic: i.e., associated to an epileptiform EEG) spasms usually occurring in clusters whose most characteristic EEG finding is hypsarrhythmia [the spasms are often associated with developmental arrest or regression]. The term West syndrome (WS) refers to a form (a subset) of ISs, characterised by the combination of clustered spasms and hypsarrhythmia on an EEG and delayed brain development or regression [currently, it is no longer required that delayed development occur before the onset of spasms]. Less usually, spasms may occur singly rather than in clusters [infantile spasms single-spasm variant (ISSV)], hypsarrhythmia can be (incidentally) recorded without any evidence of clinical spasms [hypsarrhythmia without infantile spasms (HWIS)] or typical clinical spasms may manifest in absence of hypsarrhythmia [infantile spasms without hypsarrhythmia (ISW)]. There is a growing evidence that ISs and related phenotypes may result, besides from acquired events, from disturbances in key genetic pathways of brain development: specifically, in the gene regulatory network of GABAergic forebrain dorsal–ventral development, and abnormalities in molecules expressed at the synapse. Children with these genetic associations also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malformations. The prognosis depends on: (a) the cause, which gives origin to the attacks (the complex malformation forms being more severe); (b) the EEG pattern(s); (c) the appearance of seizures prior to the spasms; and (d) the rapid response to treatment. Currently, the first-line treatment includes the adrenocorticotropic hormone ACTH and vigabatrin. In the near future the gold standard could be the development of new therapies that target specific pathways of pathogenesis. In this article we review the past and growing number of clinical, genetic, molecular and therapeutic discoveries on this expanding topic. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Infantile spasms; West syndrome; Hypsarrhythmia; Genetics; Treatment

1. Historical background The history of infantile spasms and West syndrome (WS) develops through three important steps: (1) the ⇑ Corresponding author. Address: Department of Educational Sciences, University of Catania, Via Casa Nutrizione 1, 95124 Catania, Italy. Tel.: +39 095 7466377; fax: +39 095 7466370. E-mail address: [email protected] (M. Ruggieri).

publication by the English physician, William James West (1793–1848), in 1841 in the scientific journal “The Lancet” [1], of his clinical experience with the condition on his own son – James Edwin West (1840–1860), aged 4 months at the time of onset of his first seizures. West originally named the seizures “Salaam tics” and, along with his colleague Langdon-Down, who cared for West’s son in later life [2,3], reported that James had at older ages “. . .lack of language and meaningless

0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.10.008

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laughter. . .and rolling of the head . . .. delighted by music and gay colors” and “. . .a great tendency to automatism and rhythmical actions. . .”, features compatible with those encountered in autism spectrum disorders [3,4]; (2) the description of a typical electroencephalographic (EEG) pattern associated to infantile spasms by Gibbs and Gibbs [5], who called these abnormalities “hypsarrhythmia”; and (3) the observation of Sorel and Dusaucy-Bauloye [6] who showed that treatment with the adrenocorticotropic hormone (ACTH) resulted in amelioration of either clinical and EEG anomalies. Since these first clinical [1] and neurophysiologic [5] descriptions the clinicians involved with the care of neurological and psychiatric children progressively noted that infantile spasms were often accompanied by psychomotor delay and/or developmental regression. As infantile spasms were the most representative signs of WS, many physicians did no longer distinguish between this seizure type and WS considering the two terms synonymous and used these names interchangeably [7]. Despite many progresses, in many cases the etiology of infantile spasms remained (and still remains) hidden [8–13]. According to the ILAE classification [14,15], infantile spasms and WS were grouped within the epileptic encephalopathies in which the epileptic abnormalities may contribute to progressive cerebral dysfunction. However, over the years, there have been a growing number of studies reporting that the occurrence of infantile spasms was not always associated to hypsarrhythmia and/or mental delay, the age range of onset of seizures of the spasms type was not confined to the first year of life, and that the clinical spectrum of spasms and associated EEG were wider than previously thought. Specific consensus statements took into consideration all these new aspects and controversies aiming to reach broader agreement and newer terminologies [16]. 2. Terminology Nowadays, the inclusive term infantile spasms defines an epileptic syndrome [infantile spasms syndrome – ISs] occurring in children younger than 1 year and rarely older than 2 years, with clinical spasms usually occurring in clusters and with EEG anomalies whose most characteristic pattern is hypsarrhythmia. The spasms are often associated with developmental arrest or regression. The term WS refers to a form (currently regarded as a subset of ISs) characterised by the combination of spasms in clusters and an EEG pattern of hypsarrhythmia and delayed brain development or regression, which must not necessarily occur before the onset of spasms, as it was in some previous definition of the syndrome itself. Additional forms and/or variants of ISs include

[16,17]: (a) infantile spasms single-spasm variant (ISSV), a less common subgroup of ISs in which spasms may occur singly rather than in clusters (a spasm should be regarded as a single spasm if no other spasms occur for 1 min before and for 1 min afterward); (b) hypsarrhythmia without infantile spasms (HWIS) when hypsarrhythmia is (incidentally) recorded without any evidence of clinical spasms; and (c) infantile spasms without hypsarrhythmia (ISW) when typical clinical spasms may manifest in absence of hypsarrhythmia. The recent ILAE classification [18] placed the “epileptic spasms” into a separate (“unknown”) group of seizures, as it felt that there was “inadequate knowledge to understand whether these are focal, generalized or both”. 3. Main clinical features 3.1. Epidemiological aspects The ISs and related phenotypes is an age-related spectrum of disorders, representing the most frequent type of epilepsy in the first year of life [19]. The incidence is estimated at 2-5/10.000 newborns; the prevalence is around 1-2/10.000 children at the age of 10 years with onset within 1 year of life in 90% of cases [16–21]. The peak is between 4 and 7 months, with a male to female ratio of 6:4. The duration of spasms ranges from 25 to 32 months with 85% ceasing their spasms under the age of 5 years [9,10,20–23]. Late onset occurrence of epileptic spasms, up to 14 years of age, has been reported in rare cases [24] and in the 1991 workshop of the ILAE commission on Pediatric Epilepsy it was suggested that epileptic spasms might occur not only in infancy but also in childhood [15]. 3.2. Features of spasms Clinical spasms. A clinical spasm consists of an abrupt, brief contraction followed by less intense but sustained tonic contraction lasting approximately from a fraction of a second to 1–2 s. [7,9,10,16,18,21,24–26], which involves the muscles of neck, trunk and upper and lower legs [12–14]. The spasms may be flexor, extensor or mixed, the most common being flexor involving head and arms [27,28], with a wide individual variability as regards type and intensity. The jerks occur mostly in clusters, typically just before or on awaking or just before sleep [12,26–28]. They may be present on night. During the attack, arrest, deviation of the eyes and/or changes in respiratory pattern may be seen. Cry or a scream may precede or follow the ictal phase. After the crisis, children may show irritability or transient hyporeactivity [29]. In addition to spasms other type of seizures may be present.

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Although the ILAE Glossary of Descriptive Terminology for Ictal Semiology (paragraph 1.1.1.1) [30] suggested that the term, which describes the semiology of spasms, should be epileptic spasms, the Delphi West Group proposed the term clinical spasms to describe the ictal phenomenology and reserved the term epileptic spasms to describe the epileptic seizure-type of clinical spasms associated with an epileptiform EEG [16]. This latter term would include conditions such as the periodic spasms reported by Gobbi et al. [31] and implies that the EEG is consistent with the diagnosis of epilepsy, but does not itself imply hypsarrhythmia or any more specific EEG pattern. Subtle ictal events. Less common ictal events, described as subtle spasms [16], may constitute a clinical attack associated with an anomalous EEG pattern or can precede the recognized onset of epileptic spasms. These movements include episodes of yawning, grasping, facial grimacing, isolated eye movements, blinking (personal observation), and transient focal motor activities. 3.3. EEG patterns The pattern of hypsarrhythmia consists of a chaotic and disorganized basal activity with asynchronous large amplitude slow waves mixed with single, multifocal spikes and sharp waves followed by attenuation. Hypsarrhythmia is not found in all cases of epileptic spasms nor is it found throughout the clinical course of the spasm itself. Caraballo et al. [25] reported a follow-up study of 16 patients affected by epileptic spasms in clusters, without hypsarrhythmia and with or without focal or generalized paroxysmal discharges on interictal EEG. Among this group 13 patients were cryptogenetic and 3 symptomatic: neuropsychological development was normal in five patients and impaired in eleven. Pattern different from hypsarrhythmia (“atypical” or “modified” hypsarrhythmia) may be seen in ISs as asymmetric, focal discharges, semi-periodic burst suppression, generalized complex and partial preservation of background rhythm [9,12,26]. Lux [32] following the recent consensus definition and classification of non-convulsive status epilepticus (NCSE) maintains that the hypsarrhythmic pattern seen in WS could be endeavored in the group of non-convulsive status-epilepticus. The interictal phase of EEG is permanently abnormal while the clinical attacks are intermittent and manifest as repeated crises, but separated by seizure-free interictal periods. Therefore, this condition is classified as intermediary with dissociation between clinical features (non continuous seizures) and EEG pattern (continuous epileptic activity). Benign non-epileptic infantile spasms have been reported [33,34]. However, according to current knowl-

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edge, there is general agreement that a normal EEG excludes the diagnosis of ISs [35]. 3.4. Cognitive status and additional features Developmental delay is usually severe, however, some patients with infantile spasms may have partially or totally preserved cognitive profiles and this typically occurs in cases falling within the so-called “cryptogenetic” group (see below) [18]. Psychomotor retardation can precede the onset of spasms but may occur at the same time or just later on. Often, developmental delay is likely to be assessed unreliably because spasms could be so subtle to be unrecognized, and also because development delay might be hard to assess unequivocally in early infancy. For all the above reasons, developmental arrest or delay is no longer regarded as a diagnostic criterion [16]. Motor and visual deficits may be also present. There is a latent period of epileptogenesis following the trigger event before the appearance of spasms: the lag time between the cerebral insult and the onset of spasms is thought to vary from 6 weeks to 11 months [36]. 4. Etiology and pathogenesis Despite many progresses, the etiology of the spectrum of disorders associated to epileptic spasms still remains obscure [8–13]. In the past, ISs and WS (interchangeably) have been etiologically distinguished into three groups: (1) symptomatic; (2) cryptogenetic; and (3) idiopathic. Incomplete agreement remains on the use of these terms [4,16], even though such terms are also used in the classification of other epilepsies [14,15,30]. The term symptomatic has been used to refer to cases in which seizures resulted from an identifiable cause or to cases in which neurological features or an unequivocal developmental delay preceded the onset of spasms. Symptomatic ISs currently refers to cases resulting from an identified underlying disorder [16]. The term cryptogenetic infantile spasms has been used to define patients where a specific involvement of the brain was greatly presumable but could not be detected with the current investigation methods. Cryptogenic ISs is currently reserved for cases with neurological symptoms, signs, or developmental delay but no proven cause or etiology [16]. There has been a debate on the existence of an idiopathic group, which nowadays should include cases in which ISs occur without any identifiable underlying cause, other neurological signs or symptoms [16]. According to the United Kingdom Infantile Spams Study (UKISS) [37], the commonest causes of infantile spasms were hypoxic-ischemic encephalopathy (10%), chromosomal anomalies (8%), malformation (8%), perinatal stroke (8%), tuberous sclerosis complex (7%),

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periventricular leukomalacia or hemorrhage. (5%) Recently, an elevated level of voltage-gated potassium channel complex antibodies was found in a 4 monthold female with infantile spasms, indicating an additional likely immune-mediated origin of infantile spasms [38]. The old concepts started to change and to be overcame more recently, also because of the increasing attention put to the number of studies reporting familial cases of infantile spasms. In 1980, Pavone et al. [39] first reported ISs in a set of monozygotic twins whose onset of spasms occurred, on the same day within an interval of only a few hours, when the twins were aged 6 months: the authors inferred that a time-dependent, pre-programmed event was responsible for the simultaneous onset of spasms. The clinical follow-up in these children at seven [40] and 15 years was fairly good, both for their cognitive phenotype and for their epileptic crises. Three additional sets of twins affected by ISs have been recently reported by Coppola et al. [41] with simultaneous onset (on the same day), and almost overlapping disappearance of spasms suggesting a genetically determined predisposing biological factor for the onset of spasms. Additional familial cases of ISs were reported by Rugtveit [42], Dulac et al. [43], Claes et al. [44], Ronce et al. [45], Reiter et al. [46], Tao et al. [47] and Kato et al. [48]. Recently, Hemminki et al. [49] reported that the risk of infantile spasms is higher in families having members affected by other types of epilepsy, thus demonstrating a genetic predisposition either for epileptic attacks and ISs. In parallel to these clinical observations – over the last two decades – the number of putative genetic loci, genes and proteins related to clinical phenotypes associated to infantile spasms, has largely expanded. Nowadays, there is growing evidence that ISs and related phenotypes may result from disturbances in key genetic regulatory pathways of brain development: specifically, the gene regulatory network of GABAergic forebrain dorsal–ventral development, and abnormalities in the gene expressed at the synapse. In this respect, a tentatively genetic and biologic classification of infantile spasms, has been proposed by Paciorkowski et al. [4]. We performed a systematic review of the genes/proteins so far associated to epileptic spasms in infancy, to hypsarrhythmia and more in general to ISs and WS and related phenotypes (the results of this search are detailed in Table 1). Initially, two genes, the Aristaless (ARX) and the cyclin-dependent kinase-like 5 (CDKL5) genes were unequivocally found to be associated to phenotypes with infantile spasms (specifically, to children having infantile spasms, hypsarrhythmia and developmental delay) [50–60]. Both genes are located in the human chromosome Xp22 region, which is mainly expressed

in fetal brain and plays an important role in neuronal development. Either gene plays key roles in regulating the overall human brain development causing a spectrum of disorders encompassing mental retardation and severe epileptic syndromes [50,51]. According to Kato [51], ARX is crucial for the development of GABAergic interneurons, and therefore mutations in the ARX gene could be implicated in the pathogenesis of ISs: in this respect, ISs could be regarded as an interneuronopathy [61]. Similarly, abnormalities in the first polyalanine tract in patients with expansion mutation of the ARX gene underlie the clinical severity of epilepsy in ARX-mutated patients [52]. Most recently (Table 1), mutations in several other well-known and new genes have been postulated to cause phenotypes with infantile spasms or ISs including SLC25A22, STXB1, SPTAN1, SCN2A, PLCB1, ST3GAL3, FOXG1, MEF2C, DCX, PAFAH1B1, TUBA1A, TSC1, TSC2, NF1, NSD1, KCNQ2, GLYCTK, GRIN1, GRIN2A, and MAGI2 genes [4,62–80]. Often patients harboring abnormalities in some of these (ISs-associated) genes initially present either with ISs (or with WS) or with other types of early epileptic encephalopathies (e.g., EIEE, Ohtahara syndrome) switching later on to another type of developmental epilepsy (e.g., WS itself or Lennox–Gastaut syndrome) (see Table 1) demonstrating a spectrum of infancy-onset epileptic encephalopathies [4]. The type(s) of early-onset epilepsy/epilepsies may be related to the type or severity of mutation or to the protein/molecule and/or regulatory network involved. Thus, infantile spasms could be regarded as a (peculiar) type of clinical manifestation underlying the involvement of many different neuronal/interneuronal networks. In this respect, it is perhaps not surprising that ISs children with mutations in different genes have similar or overlapping phenotypes (Table 1). Of note, children with these (ISs-associated) genetic abnormalities also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malformations (Table 1). Likely, these complex (ISs-associated) phenotypes, as postulated by Paciorkowski et al. [4], could be just the “tip of the iceberg” of a broader group of developmental disorders that overlap with autism, intractable epilepsy, and movement disorders. A recent study demonstrated that genomic deletions encompassing the MAGI2 gene (Chromosome 7q11.23 deletion syndrome), resulted in spasms associated to Williams–Beuren syndrome and further highlighted the important role of chromosomal abnormalities in the aetiology of infantile spasms [81]. In addition to that, a large Italian study revealed that high-resolution comparative genomic hybridization (array-CGH) may help to identify a genetic etiology in patients with isolated infantile spasms of unknown aetiology [82].

Table 1 Genes and proteins currently associated to phenotypes with infantile spasms and/or West syndrome. Clinical syndrome(s) [Eponyms/alternative titles phenotype MIM number]

Gene locus/gene (gene eponym) protein [MIM number] gene/protein function

Early-onset epileptic encephalopathy 1a X-linked infantile spasms syndrome-1 X-linked [subgroup] West syndrome infantile spasms without brain malformation (X-linked Ohtahara syndrome)b [EIEE1; ISSX1; MIM # 308350]

Xp22.13/ARX Aristaless-related homeobox proteinc X-linked [MIM # 300382] cell migration, axonal guidance in floor plate, transcription regulation, interneuron development, maintenance of specific neuronal subtypes in the cortex, neurogenesis

WS features [%] EEG features

Early-onset epileptic encephalopathy 3a Ohtahara syndrome ! infantile spasms [EIEE3; MIM # 609304] Early-onset epileptic encephalopathy 4a [EIEE4; MIM # 612164]

Early-onset epileptic encephalopathy 5a [EIEE5; MIM # 613477]

11p15.5/SLC25A22 solute carrier family 25 Transition to hypsarrhythmia (WS) in 75% [mitochondrial carrier] member 22 [MIM # 609302] of EIEE [EEGs overlapping with Ohtahara patterns: suppression-burst + hypsarrhythmia]a 9q34.11/STXBP1 syntaxin-binding protein Tonic–clonic, tonic infantile (MUNC18-1) [MIM # 602926] syntaxin (STX) spasms + hypsarrhythmia + various is member of the family of SNARE [soluble degrees of developmental delay [usually N-ethylmaleimide-N-ethylmaleimide-sensitive-factor profound] attachment protein receptor], which regulate [EEGs mixed patterns: suppressionintracellular membrane fusion by burst + hypsarrhythmia]a pairing of vesicle v-SNARE with target membrane tSNARE to form SNAREpins to bring two membranes into close apposition and fusion; STXBP1 is a neural specific protein, which regulates vesicular traffic in neurons 9q34.11/SPTAN1 spectrin alpha non-erythrocytic 1 Early infantile spasms (or febrile seizures [MIM # 182810] cytoskeletal protein regulating cell later shape and cell proliferation; in neurons is essential for generalized) + hypsarrhythmia + profound assembling myelin developmental delay [EEGs mixed patterns: suppressionburst + hypsarrhythmia]a

Early-onset epileptic encephalopathy 11a [EIEE11; 2q24.3/SCN2A sodium channel brain type II, alpha MIM # 182390] subunit [MIM # 182810] voltage-sensitive sodium channels are proteins essential for the generation and propagation of action potentials in neurons

Infantile spasms (11 mo) tonic–clonic (2– 3 yrs) atypical febrile (11 yrs) status epilepticus (17 yrs) + profound developmental delay [EEGs mixed patterns]

Spastic ataxia, developmental delay (early onset) XMESIDd [52] micropenis [48]; recurrent [severe] status dystonicu dyskinesis, chorea, quadriplegia basal ganglia lesions [53] epichantal folds, low-set ears [54]; growth delay, acquired microcephaly tetraparesis, brain atrophy (at age 2 years) [55];

Hand wringing, hand–mouth stereotypes, hyperventilation, breath-hold spell,small hands/feet, TL kyphoscoliosis, severe autistic features, microcephaly behavioural/mood swing, lack of eye [Rett phenotype] [47,56]; Males [more severe Rett phenotype] + high-arched palate, depressed nasal bridge, high sloping forehead, anteverted nostrils [57]; brain (white matter) atrophy, delayed myelination, cerebellar atrophy [58]; precocious puberty [59]; Angelman syndrome-like phenotype [60]

Tremulous arm movements, oral automatisms, spastic quadriplegia brain hypomyelination (in all cases), acquired microcephaly, cortical atrophy, thin corpus callosum [63–65]

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Transition to hypsarrhythmia (WS) in 75% of EIEE (including phenotypes with Ohtahara syndrome) infantile spasms + hypsarrhythmia + developmental delay ! probands or affected family members [EEGs overlapping with Ohtahara patterns: suppression-burst + hypsarrhythmia]a a Xp22.13/CDKL5 cyclin-dependent kinase-like Early-onset epileptic encephalopathy 2 Infantile X-linked infantile spasms syndrome-1 Rett (serine/threonine protein kinase 9/STK9) spasms + hypsarrhythmia + various syndrome, variant/infantile spasms Rett syndrome, [MIM # 300203] [CDKL5 overlaps and/or interacts degrees of developmental delay [including atypical [CDKL5-related [EIEE2; ISSX2; MIM # with MECP2 in a common pathway] regulates neural language delay/lack of speech, inability to 300672] maturation synaptogenesis walk, other forms of delay within the spectrum of autism/Rett syndrome] [EEGs overlapping with Rett patterns]a

Additional features

Milder phenotypes than EIEE4 with (milder) hypomyelination [myelination progressing at older ages: e.g., age 4 years], no brain structural changes; microdeletion STXBP1/SPTAN1; progressive microcephaly [66]; hypotonia, no microcephaly, no dysmorphic signs, cerebellar/brainstem atrophy no hypomyelination, no structural brain changes [67] Quadriplegia, speech regression (after status epilepticus) allelic variant EIEE11 [GLU1211LYS] [68]

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Table 1 (continued) Clinical syndrome(s) [Eponyms/alternative titles phenotype MIM number]

Gene locus/gene (gene eponym) protein [MIM number] gene/protein function

WS features [%] EEG features

Additional features

Early-onset epileptic encephalopathy 12a [EIEE12; MIM # 613722]

20p12.3/PLCB1 phospholipase C-beta [MIM # 607120] PLCB catalyzes the intracellular transduction of extracellular signals by generating inositol 1,4,5-trisphosphate (ICP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2) 1p34.1/ST3GAL3 beta-galactoside-alpha 2,3-sialyltransferase III [MIM # 606494]

Eye rolling, lip smacking, drooling, oral cyanosis + refractory seizures (13 mo) + hypsarrhythmia (13 mo) later degeneration death (2.9 yrs) [EEGs hypsarrhythmia]

Neurodegeneration, hypotonia, quadriparesis, diffuse encephalopathy [69]

Early-onset epileptic encephalopathy 15a [EIEE15; MIM # 615006]

Poor eye contact, irritability, primitive reflexes, hypotonia [70]

Autistic behaviour severe developmental delay “FOXG1 syndrome” [71–73]

Mental retardation brain MRI = normal

Hyperkinetic/stereotypic movements absent speech, dysmorphic features [high forehead, prominent eyebrows, large open mouth], dental anomalies, ADHD, MRI = mild delayed myelination abnormal corpus callosum [74–78] Mental retardation, behavioural abnormalities, dysmorphic features, hypotonia

Lissencephaly: gradient frontal >> parietal/occipital regions [reverse gradient = LIS1] + cerebellar anomalies severe intellectual disability Lissencephaly: gradient parietal/occipital >> frontal regions [reverse gradient = DCX] severe intellectual disability choreiform movements Lissencephaly: gradient anterior >> posterior + corpus callosum hypoplasia, cerebellar/ brainstem hypoplasia microcephaly, quadriparesis, severe mental retardation,

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Infantile spasms (flexor) (age 3.7 mo) ! Lennox–Gastaut type + profound developmental (preceding onset of spasms) [EEGs hypsarrhythmia] 14q12/FOXG1 forkhead box protein G1 Rett syndrome, congenital variant X-linked Infantile spasms (age 7 mo) ! reflex infantile spasms syndrome [MIM # 613454] forkhead-like 1 (FKHL1) oncogene QIN seizures transcription-repressor protein; FOXG1 and MECP2 [EEGs hypsarrhythmia] differentiate cortical compartments and neuronal subnuclear localization [MIM # 164874] 9q34.3/GRIN1 glutamate receptor, ionotropic, NMental retardation, autosomal dominant 8 Infantile spasms under study] + partial methyl-D aspartate, subunit-1 or N-methyl-D[MRD8; MIM # 614254] complex seizures aspartate receptor channel subunit zeta-1 [NMDAR1] [MIM # 138249] glutamate receptor protein modulating neuronal survival, apoptosis, neuronal plasticity Mental retardation, autosomal dominant 20 mental 5q14.3/MEF2C myocyte enhancer factor 2C [MIM # Infantile spasms ! myoclonic febrile retardation, stereotypic movements, epilepsy and/ 600662] key role in myogenesis, (maintenance of the seizures (refractory) or cerebral malformations X-linked infantile differentiated state), development of anterior heart spasms syndrome [MRD20; MIM # 613454] fields, neural crest, craniofacial and neurogenesis (calciumdependant survival of neurons) transcription factor activator Epilepsy with neurodevelopmental defects [EPND; 16p13.2/GRIN2A Glutamate receptor, ionotropic, N- Early onset epileptic spasms [under MIM # 613971] methyl-D aspartate, subunit-2A or N-methyl-Dstudy] + febrile & generalised seizures aspartate receptor channel subunit epsilon-1 [NMDAR2A] [MIM # 138253] Glutamate receptor protein modulating neuronal survival, apoptosis, neuronal plasticity Lissencephaly, X-linked double cortex syndrome Xq23/DCX doublecortin [MIM # 300121] coupled Infantile spasms with LIS1 regulates microtubules to function during [EEGs hypsarrhythmia] subcortical laminar heterotopia, X-linked neuronal migration subcortical band heterotopia (SBH) [LISX1; XLIS; SCLH; MIM # 300067] Xq23/PAFAH1B1 platelet-activating factor Infantile spasms Lissencephaly, LIS1, classic lissencephaly sequence, isolated subcortical laminar heterotopia, acetylhydrosilase isoform 1B (LIS1) [MIM # 601545] [EEGs hypsarrhythmia] subcortical band heterotopia (SBH) [LIS1; SCLH; coupled with DCX regulates microtubules to MIM # 300067] function during neuronal migration 12q13.12 / TUBA1A tubulin, alpha 1 Lissencephaly 3 [LIS3; MIM # 611603] Infantile spasms tonic–clonic seizures [MIM # 602529] one of the main isoforms [EEGs hypsarrhythmia] (alpha and beta) of microtubules which contributes to tubule heterodimer formation

Tuberous sclerosis complex [Tuberous sclerosis-1; MIM # 191100] [Tuberous sclerosis-2; MIM # 613254]

9q34.13/TSC1 [MIM # 605284] 16p13.3 / TSC2 [MIM # 191092] hamartin [TSC1] tuberin [TSC2]

Neurofibromatosis type 1 [NF1; MIM # 162200]

17q11.2/NF1 [MIM # 613113] neurofibromin

Sotos syndrome 1 [MIM # 615006]

Infantile spasms + hypsarrhythmia + mental retardation [WS] [EEGs hypsarrhythmia]

Infantile spasms/WS: TSC2 mutations = WS >> associated to more severe TSC “neurocutaneous” phenotype: >> skin hypomelanotic macules, facial and diffuse fibromas, more resistant seizures, autism spectrum disorders, psychomotor delay, behavioural abnormalities [84] (1) Infantile spasms; (2) classic WS [0.76%] Psychomotor delay preceding spasms, symmetrical, [EEGs hypsarrhythmia] typical spasms classical NF1 phenotype brain MRI = high signal lesions in the subcortical white matter or >> higher portions of brainstem/ mesencephalon [79] Infantile spasms Overgrowth, behavioural abnormalities [EEGs hypsarrhythmia] Supravalvular aortic stenosis pulmonary stenosis, aortic hypoplasia mental retardation, facial dysmorphism (elfin phace), infantile hypercalcemia

Poor eye contact, autistic behaviour, head rocking movements, hypotonia, brain MRI = delayed myelination cerebral atrophy [80]

a Early onset epileptic encephalopathy [EIEE] is a genetically heterogeneous disorder (so far) subdivided into 15 forms [EIEE1–EIEE15]: some of these phenotypes manifest infantile spasms/ hypsarrhythmia and/or progress to classical WS during their natural history (see the table above). In some EIEE cases the EEG pattern is mixed with suppression-bursts and hypsarrhythmia [in the table above we listed only the specific EIEE cases with EEG patterns showing isolated or mixed patterns with hypsarrhythmia]. b Ohtahara syndrome, in its X-linked variant, is used interchangeably with EIEE1 (they share common entries in the OMIM database) despite the clinical (e.g., brief tonic or myoclonic seizures, which are typical of Ohtahara syndrome) and EEG (e.g., suppression-bursts EEG patterns, which are typical of Ohtahara syndrome) differences: this is due to the fact that some affected families (or affected members within large families) with typical Ohtahara syndrome manifest hypsarrhythmia and/or progress to classical WS during their natural history. c ARX [Aristaless]-related disorders = The phenotypic spectrum associated with mutations in the ARX gene is wide and extremely variable comprising a nearly continuous series of X-linked developmental disorders including: (1) EIEE1 [MIM # 308350]; (2) Hydranencephaly with abnormal genitalia [MIM # 300215]; (3) X-linked lissencephaly with abnormal genitalia [XLAG; MIM # 300215]; (4) agenesis of corpus callosum with abnormal genitalia [Proud syndrome; MIM # 300004]; (5) (non-specific) X-linked mental retardation ARX-related with or without seizures [mental retardation MRX29,32,33,38,43,54,76,87; MIM # 300419]; (6) Partington syndrome [X-linked mental retardation 36 (XMR36 or syndromic mental retardation 1; MRXS1) with episodic dystonic movements, ataxia and seizures; MIM # 309510]. The ARX gene up- and down-regulates at least 84 other genes involved in embryonic brain development. Some of these regulations are mediated via contraction/expansion(s) of the polyalanine tracts (polyA) of the ARX gene homeodomain: defects in polyA expansion are thought to cause ARX protein aggregation. The longer expansion(s) of the polyA tract seen in EEIE vs. WS (e.g., from the original 16 residues to 27 residues) are consistent with the findings of earlier onset and more severe phenotypes in EEIE than in WS. d XMESID = This form, [myoclonic epilepsy, spasticity and intellectual disability] reported by Scheffer et al. [2002] in 6 boys over two generations, includes X-linked myoclonic (and tonic–clonic) epilepsy (associated to hypsarrhythmia in one affected family member) associated to hyperreflexia, generalised spasticity (spastic ataxia, sometimes with onset > age 40 years) and developmental delay since birth.

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5q35.2-q35.3 / NSD1 nuclear receptor binding SET domain protein 1 [MIM # 606681] Williams–Beuren syndrome chromosome 7q11.23/MAGI2 membrane associated Epileptic spasms [under study] 7q11.23 deletion syndrome [WBS; MIM # 194050] guanylate kinase WW and PDZ domains containing, 2 [MIM # 606382] interactions of phosphatase and tensin homolog [PTEN] with the PDZ domains of rat Magi2 (a synaptic scaffolding protein) increases PTEN stability; interaction of PTEN with the microtubule-associated sertine/threonine kinase1 [MAST1] facilitates phosphorylation of PTEN D-glyceric aciduria glycerate kinase deficiency 3p21.1/GLYCTK glycerate kinase [MIM # 610516] West syndrome [EEGs hypsarrhythmia] ubiquitous enzyme: liver, brain, kidney, skeletal muscle

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Known chromosomal abnormalities associated to the occurrence of infantile spasms in variable percentages include, so far, deletion 1p36 syndrome, deletion 7q11.23 (Williams syndrome plus), tetrasomy 12p (Pallister–Killiam syndrome), maternal duplication 15q11q13 (Duplication 15q syndrome), deletion 17p13 (Miller–Dieker syndrome) and Trisomy 21 (Down syndrome – DS) [reviewed in 4]. Among 113 patients with DS, 7.9% showed epilepsy and within this group four presented infantile spasms [83]: these DS patients reacted better to anticonvulsants. Infantile spasms are particularly prevalent in children with specific brain (cortical) malformations including tuberous sclerosis complex (TSC): data are accumulating that the natural history of infantile spasms, within the context of TSC, is somewhat different from the spasms seen in classical ISs and a strong correlation has been established between TSC, ISs and the subsequent development of autism spectrum disorders, although the mechanism of this relationship still remains unclear. Even though some argue that the subsequent autistic spectrum disorder in TSC (and similarly in DS) is a consequence of the severe epileptic encephalopathy, the most recent data suggest a primary biologic link between autism and ISs: in this respect the link could result from the dysregulation of the molecular [e.g., mammalian target of rapamycin (mTOR)] pathway involved, which is likely perturbed in a specific neuronal population at a key neurodevelopmental stage leading to the abnormal brain morphogenesis [4,84]. Notably, patients harboring TSC2 gene mutations have more frequently drug-resistant forms of ISs more often associated to later development of autism vs. the TSC1 patients who have milder neurocutaneous phenotypes (see Table 1) [84]. An association between infantile spasms and certain inborn errors of metabolism has long been recognised. The best known examples include the phenylketonuria (PAH gene) and nonketotic hyperglycinemia or glycine encephalopathy (GLDC, GCSH and GCST genes); the DEND (developmental delay, epilepsy, neonatal diabetes) syndrome (KCNJ11 gene, a ion channel gene); the organic acidemias methylmalonic aciduria (MUT gene), maple syrup urine disease (BCKDHA, BCKDHB, DBT and DLD genes), proprionic acidemia (PCCA and PCCB genes); and Menkes disease (ATP7A gene) [reviewed in 4]. In addition to that, infantile spasms have been occasionally reported with several other well-characterised predisposing genotypes, often in reports predating molecular characterisation of the disorder, including autosomal recessive severe microcephaly with perinodular heterotopia/PNH (ARFGEF2 gene), Freeman–Sheldon syndrome (MYH3 gene), mitochondrial encephalomyopathy with elevated methylmalonic acid (SUCLA2 gene), neurogenic muscle weakness, ataxia,

retinitis pigmentosa/NARP (MT-ATP6 gene), Shinzel– Giedion syndrome (SRTBP1 gene), Smith–Lemli–Opitz syndrome (DHCR7 gene), Smith–Magenis syndrome (deletion 17p11.2), Sotos syndrome (NSD1 gene) and X-linked perinodular heterotopia/PNH (FLNA gene) [4]. Lastly, there is a growing group of well-described developmental disorders with unknown genotype but unifying phenotypes that have infantile spasms as a core finding or have a clear association with infantile spasms, which include Aicardi syndrome, PEHO (progressive encephalopathy with edema, hypsarrhythmia and optic atrophy) and PEHO-like syndromes, isolated hemimegalencephaly (HMEG), mythocondrial dysfunction, neonatal hypoglycemia, the pyridoxine-dependent/ responsive epilepsies, some of the epidermal nevus syndromes (e.g., nevus sebaceous syndrome), schizencephaly, and the groups of perinatal stroke or other cerebral hypoxic events or post-infectious injuries (e.g., TORCH, other viruses or bacterial meningitides) [4]. In this latter respect, hypoxia or infections, have been argued to act as “second hits” in a specific neuronal population (e.g., emerging GABAergic interneuron synaptic networks) made vulnerable to spasms by yet undiscovered predisposing genotypes [4]. 5. Therapeutic strategies in ISs The aim of ISs treatment is to block the epileptic attacks and their relapses, to normalize the EEG anomalies, and to attempt to avoid and improve neurodevelopmental delay. According to the American Academy of Neurology and the Child Neurology Society a treatment response is defined effective when there is complete cessation of spasms and abolition of the hypsarrhytmic pattern: more specifically cessation of the spasms should include absence of spasms within 14 days of onset of treatment and about 28 consecutive days from the last spasm [19]. ACTH is the most effective treatment for the short term therapy of ISs, but there is difference among the experts regarding the optimum dosage and duration of treatment with the spectrum of dosage ranging from 20 to 120 UI/L. High-dose ACTH is presumably thought to be more effective compared with low dosage since high-dosage seems to allow the passage of a higher amount of ACTH across the blood–brain barrier, leading to a direct action on the nervous system. On the other hand, high-dosage in the long treatment with ACTH lead to several side effects, the most frequent being irritability, increased appetite and cushingoid features. Hypertension and hypokalemia and, in rare cases, fulminant infections secondary to immunosuppression are reported [85]. A survey on pediatric epilepsy, performed by the European Expert opinion [86], reports as first line option ACTH and prednisone for initial

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therapy in symptomatic ISs. Vigabatrin was also a treatment of choice [85–86]. Patients treated with ACTH within one month show a lower rate of relapses and better long-term cognitive outcome and lower incidence of later epileptic attacks [87]. Recently, an evidence-based guideline update by the Guideline Development Sub-committee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, reported on medical treatments in the setting of ISs [21]. This study deals with several queries regarding the short-term treatment of ISs and specifically the effectiveness of ACTH vs. other corticosteroids; efficacy of low-dose ACTH; effectiveness of ACTH vs. vigabatrin; the role of ketogenic diet and other antiepileptic drugs (AEDS) other than vigabatrin; whether the successful short-term treatment of ISs improves the chances of neurodevelopmental outcomes; and the frequency of the epileptic attacks. The results of this important evidence-based study led to some conclusions: low dose ACTH, as well as vigabatrin, may be useful for the short treatment of ISs. ACTH or prednisolone may be used preferably vs. vigabatrin in infants with cryptogenetic ISs, as it can improve developmental outcome. Furthermore, a shorter lag-time to treatment of ISs with ACTH or vigabatrin improves the long-term developmental outcomes. ACTH is notoriously effective with approximately 60–80% of spasm-free and dosages of 20–40 U/m2/day are considered sufficient to stop seizures [88]. It is unclear how ACTH acts in patients with ISs considering that the blood–brain barrier is relatively impermeable to ACTH. According to Stafstrom et al. [87] ACTH may act through the pro-opiomelanocortin-positive neurons of the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius of the medulla favoring the access of ACTH to the brain. ACTH may, also, act stimulating the production of neurosteroids in the periphery, exerting an anticonvulsant action. Other hypotheses argue that ACTH may increase the synthesis of deoxycorticosteroids, which can be converted to the neurosteroid allotetrahydrodeoxycorticosterone, which in turn is a modulator of GABA and also a strong anticonvulsant. The anticonvulsants of old and new generation are also used in ISs treatment. Vigabatrin is used at the initial dosage of 50 mg/Kg/ day: dosage of 150 mg/Kg/day has been used with good tolerability. Side effects are hypotonia, somnolence or insomnia along with visual field constriction. With the thorough control of visual fields, vigabatrin remains one of the drugs of choice for children with ISs particularly when associated to TSC. Lux et al. [88], in a multicentre randomized controlled trial, reported a cessation of spasms more likely in infants treated with hormonal treatment vs. vigabatrin (73 vs. 54%). Many experts advise to use vigabatrin for a short period of

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time, under careful and strict control of visual fields (which is however not easy to carry out in infants) because of the known retinal toxicity. Concentric peripheral visual field defects and retinopathy with loss of peripheral vision in both eyes are the main possible permanent side-effect related to the use of vigabatrin. Children with ISs who are under treatment with vigabatrin must receive periodic full ophthalmic evaluation from the initiation of therapy: every 3 months during vigabatrin administration and then every 3–6 months after cessation of treatment [89]. Vigabatrin has also been associated with reversible signal changes at brain MRI localized in the thalamus, basal ganglia, corpus callosum, and midbrain [90]. Felbamate turned out to be successful in the initial phase after its introduction as anticonvulsant in ISs, but its serious side effects including aplastic anemia have reduced its indication in the treatment of ISs. Sodium valproate has been used in the treatment of ISs with dosage ranging from 20 to 300 mg/Kg/day. As monotherapy, at the dosage of 30 mg/Kg/day spasms cessation or decreased number of spasms by more than 80% were obtained in 36 out of 91 children with ISs in one study [91]. Pavone et al. [92] by using a dosage of 20 mg/Kg/day in 18 children with ISs had excellent results in 4/18; a reduction of more than 50% in 8/18; poor results or null were recorded in 6/18 children. High doses of sodium valproate, were given in children with ISs by Siemes et al. [93]. The results obtained by Prats et al. [94] were fairly good with control of the hypsarrhythmia achieved after 2 weeks for more of 3/4 of cases. Zonisamide has been used in the treatment of WS with doses ranging from 4 to 8 mg/Kg/day. The response rate ranged between 20% and 38% [95] and was rapid (within 1–2 weeks in the responding cases). The real efficacy, the proper doses in children and the side-effects are not well known, restricting the use of this drug in ISs. The usual dosage of lamotrigine is 6–10 mg/Kg/day but its use in the treatment of ISs is no longer recommended since the dosage should be slowly increased over 2 months to avoid the not uncommon side-effects, and the too long wait period in ISs [88]. Topiramate is used as first-line therapy in ISs but the results obtained were less effective as compared to ACTH and in a study the positive response to this drug was reported in 4/19 children (21%) [96]. Treatment with topiramate has been carried out also by Hosain et al. [97]: the initial dosage was 3 mg/kg/day progressively rising to a dosage of 27 mg/kg/day; three (20%) out of 15 children became spam-free, 5 had a reduction of more than 50% of clusters, 3 (25%) a 25% reduction and 4 did not respond. Recently, Raffo et al. [98] using rapamycin, an mTOR inhibitor, as a potential treatment of ISs in a multiple-

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hit rat model refractory to ACTH treatment, reported good results on seizure-control. Children with ISs were treated with nitrazepam at the dosage of 0.5–3.6 mg/kg/day: cessation of seizures was obtained in 7 out 20 patients and in 8 there was no response [99]. Pyridoxine has been demonstrated to be not effective in the experience of Mackay et al. [19]. Ohtuka et al. [100] reported 12/118 seizure free ISs with high-dose pyridoxal phosphate. Ketogenic diet, consisting of calories intake obtained almost exclusively by fat and proteins and low support of carbohydrates, has also been proposed in cases of particular severity of ISs, but this treatment is not easily undertaken since patients experience frequently complications including diarrhea, hypovitaminosis, weight loss and kidney stones. Despite that, Kossoff et al. [35] report a good response (spasm-free period) within 2 weeks in a total of 11/19 infants (58%): according to this author ketogenic diet plays an important role as a viable first line treatment in ISs. Epilepsy surgery has been proposed as an early treatment in drug-resistant cases and in well-documented focal epileptogenesis [101]. Good results were obtained in 15/23 infants treated by Loddenkemper et al. [102]. In the near future the gold standard could be the development of new therapies that target specific pathways of pathogenesis (see above and Table 1). 6. Prognosis By far the most important factors in prognosis, including developmental outcome and the long-term risk of developing drug-resistant or other forms of epilepsy, depend on the etiologic events underlying ISs (Table 1). In general, the majority of patients with ISs suffer a poor prognosis for their mental retardation, chronic epilepsy and other neurodevelopmental disabilities. ISs tend to cease after the fifth year [103]. However, other seizure types may arise in about 50–70% of cases. From 20% to 50% of the drug-resistant cases evolve into a Lennox–Gastaut syndrome (LGS). A close link between ISs, WS and LGS has been observed, with some overlapping features and a relationship to one another, including the risk of developing autism spectrum disorders [4]. Mental retardation is recorded in approximately 70–80% of cryptogenic ISs and 85–90% of symptomatic ISs [5,7,29]. Overall, factors that have been recognized as predictive for a better prognosis are: (a) cryptogenic etiology; (b) age at onset of the spasms older than 4 months; (c) absence of seizures before spasms; (d) no asymmetry at EEG recording; (e) early and rapid response to treatment [35,103]. In a long term (>20 years) study, performed on 259 ISs patients in Japan 2/259 had died: among

the 257/259 patients who survived, 40% had daily or weekly seizures while 25.2% had been seizure-free for at least 3 years [104–105]. According to Arce-Portillo [106] the statistically significant poor prognostic factors were linked to the age at onset of spasms (