Brain & Development xxx (2013) xxx–xxx

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; accord-
ingly, 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 usu-
ally occurring in clusters whose most characteristic EEG finding is hypsarrhythmia [the spasms are often associated with develop-
mental 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 [hypsar-
rhythmia 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 asso-
ciations also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malforma-
tions. 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. Cur-
rently, 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 grow-
ing 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 publication by the English physician, William James

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: m.ruggieri@unict.it (M. Ruggieri).
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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2 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
laughter. . .and rolling of the head . . .. delighted by
music and gay colors” and “. . .a great tendency to
automatism and rhythmical actions. . .”, features com-
patible with those encountered in autism spectrum dis-
orders [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 obser-
vation 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 neuro-
physiologic [5] descriptions the clinicians involved with
the care of neurological and psychiatric children pro-
gressively noted that infantile spasms were often accom-
panied 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 interchange-
ably [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 epilep-
tic 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 hypsar-
rhythmia 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 consid-
eration 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 hypsar-
rhythmia. 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
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[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 with-
out hypsarrhythmia (ISW) when typical clinical spasms
may manifest in absence of hypsarrhythmia.
The recent ILAE classification [18] placed the “epi-
leptic spasms” into a separate (“unknown”) group of sei-
zures, 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, exten-
sor 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.
 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
Although the ILAE Glossary of Descriptive Termi-
nology for Ictal Semiology (paragraph 1.1.1.1) [30] sug-
gested 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 spe-
cific 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, grasp-
ing, 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. Hyp-
sarrhythmia 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 clus-
ters, 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 nor-
mal in five patients and impaired in eleven. Pattern dif-
ferent 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-convul-
sive status-epilepticus. The interictal phase of EEG is
permanently abnormal while the clinical attacks are
intermittent and manifest as repeated crises, but sepa-
rated 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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3
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 “cryptogenet-
ic” 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 develop-
ment 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 cri-
terion [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 spec-
trum of disorders associated to epileptic spasms still
remains obscure [8–13]. In the past, ISs and WS (inter-
changeably) 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 result-
ing 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 cur-
rently 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 under-
lying 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%), peri-
natal stroke (8%), tuberous sclerosis complex (7%), peri-
4 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
ventricular leukomalacia or hemorrhage. (5%) Recently,
an elevated level of voltage-gated potassium channel
complex antibodies was found in a 4 month-old female
with infantile spasms, indicating an additional likely
immune-mediated origin of infantile spasms [38].
The old concepts started to change and to be over-
came more recently, also because of the increasing atten-
tion 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-pro-
grammed 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 simulta-
neous onset (on the same day), and almost overlapping
disappearance of spasms suggesting a genetically deter-
mined 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], Ron-
ce 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 dem-
onstrating 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 associ-
ated 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 abnormali-
ties in the gene expressed at the synapse. In this respect,
a tentatively genetic and biologic classification of infan-
tile spasms, has been proposed by Paciorkowski et al.
[4].
We performed a systematic review of the genes/pro-
teins 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
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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 inter-
neuronopathy [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, GLYC-
TK, 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 encepha-
lopathies (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 epi-
leptic 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 regula-
tory network involved. Thus, infantile spasms could be
regarded as a (peculiar) type of clinical manifestation
underlying the involvement of many different neuro-
nal/interneuronal networks. In this respect, it is perhaps
not surprising that ISs children with mutations in differ-
ent genes have similar or overlapping phenotypes
(Table 1). Of note, children with these (ISs-associated)
genetic abnormalities also have phenotypes beyond epi-
lepsy, including dysmorphic features, autism, movement
disorders and systemic malformations (Table 1). Likely,
these complex (ISs-associated) phenotypes, as postu-
lated by Paciorkowski et al. [4], could be just the “tip
of the iceberg” of a broader group of developmental dis-
orders 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 Wil-
liams–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 com-
parative genomic hybridization (array-CGH) may help
to identify a genetic etiology in patients with isolated
infantile spasms of unknown aetiology [82].
Known chromosomal abnormalities associated to the
occurrence of infantile spasms in variable percentages
 Table 1
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Genes and proteins currently associated to phenotypes with infantile spasms and/or West syndrome.
Clinical syndrome(s) [Eponyms/alternative titles Gene locus/gene (gene eponym) protein [MIM
phenotype MIM number]
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]
Early-onset epileptic encephalopathy 2a
X-linked infantile spasms syndrome-1 Rett
syndrome, variant/infantile spasms Rett
syndrome, atypical [CDKL5-related [EIEE2;
ISSX2; MIM # 300672]
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]
number] gene/protein function
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
Xp22.13/CDKL5 cyclin-dependent kinase-like
(serine/threonine protein kinase 9/STK9)
[MIM # 300203] [CDKL5 overlaps and/or
interacts with MECP2 in a common pathway]
regulates neural maturation synaptogenesis
11p15.5/SLC25A22 solute carrier family 25
[mitochondrial carrier] member 22 [MIM #
609302]
9q34.11/STXBP1 syntaxin-binding protein
(MUNC18-1) [MIM # 602926] syntaxin (STX)
is member of the family of SNARE [soluble
N-ethylmaleimide-N-ethylmaleimide-sensitive-
factor attachment protein receptor], which
regulate intracellular membrane fusion by
pairing of vesicle v-SNARE with target membrane
t-SNARE 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 [MIM # 182810] cytoskeletal protein regulating
cell shape and cell proliferation; in neurons is
essential for assembling myelin
WS features [%] EEG features
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
Infantile
spasms + hypsarrhythmia + various
degrees of developmental delay [including
language delay/lack of speech, inability to
walk, other forms of delay within the
spectrum
of autism/Rett syndrome]
[EEGs overlapping with Rett patterns]a
Transition to hypsarrhythmia (WS) in 75%
of EIEE
[EEGs overlapping with Ohtahara patterns:
suppression-burst + hypsarrhythmia]a
Tonic–clonic, tonic infantile
spasms + hypsarrhythmia + various
degrees of developmental delay [usually
profound]
[EEGs mixed patterns: suppression-
burst + hypsarrhythmia]a
Early infantile spasms (or febrile seizures
later
generalized) + hypsarrhythmia + profound
developmental delay
[EEGs mixed patterns: suppression-
burst + hypsarrhythmia]a
Additional features
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/
P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
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]
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]
5
 Early-onset epileptic encephalopathy 11a
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[EIEE11; MIM # 182390]
Early-onset epileptic encephalopathy 12a
[EIEE12; MIM # 613722]
Early-onset epileptic encephalopathy 15a
[EIEE15; MIM # 615006]
Rett syndrome, congenital variant X-linked
infantile spasms syndrome [MIM # 613454]
Mental retardation, autosomal dominant 8
[MRD8; MIM # 614254]
Mental retardation, autosomal dominant 20
mental retardation, stereotypic movements,
epilepsy and/or cerebral malformations X-linked (maintenance of the differentiated state),
infantile spasms syndrome [MRD20; MIM #
613454]
Epilepsy with neurodevelopmental defects
[EPND; MIM # 613971]
Lissencephaly, X-linked double cortex syndrome Xq23/DCX doublecortin [MIM # 300121] coupled
subcortical laminar heterotopia, X-linked
subcortical band heterotopia (SBH) [LISX1;
XLIS; SCLH; MIM # 300067]
Lissencephaly, LIS1, classic lissencephaly
sequence, isolated subcortical laminar
heterotopia, subcortical band heterotopia (SBH) 601545] coupled with DCX regulates microtubules
[LIS1; SCLH; MIM # 300067]
2q24.3/SCN2A sodium channel brain type II,
alpha subunit [MIM # 182810] voltage-sensitive
sodium channels are proteins essential for the
generation and propagation of action potentials in
neurons
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]
14q12/FOXG1 forkhead box protein G1
forkhead-like 1 (FKHL1) oncogene QIN
transcription-repressor protein; FOXG1 and
MECP2 differentiate cortical compartments and
neuronal subnuclear localization [MIM # 164874]
9q34.3/GRIN1 glutamate receptor, ionotropic, N-
methyl-D aspartate, subunit-1 or N-methyl-D-
aspartate receptor channel subunit zeta-1
[NMDAR1] [MIM # 138249] glutamate receptor
protein modulating neuronal survival, apoptosis,
neuronal plasticity
5q14.3/MEF2C myocyte enhancer factor 2C
[MIM # 600662] key role in myogenesis,
development of anterior heart fields, neural crest,
craniofacial and neurogenesis (calciumdependant
survival of neurons) transcription factor activator
16p13.2/GRIN2A Glutamate receptor, ionotropic,
N-methyl-D aspartate, subunit-2A or N-methyl-D-
aspartate receptor channel subunit epsilon-1
[NMDAR2A] [MIM # 138253] Glutamate
receptor protein modulating neuronal survival,
apoptosis, neuronal plasticity
with LIS1 regulates microtubules to function
during neuronal migration
Xq23/PAFAH1B1 platelet-activating factor
acetylhydrosilase isoform 1B (LIS1) [MIM #
to function during neuronal migration
Infantile spasms (11 mo) tonic–clonic (2–
3 yrs) atypical febrile (11 yrs) status
epilepticus (17 yrs) + profound
developmental delay
[EEGs mixed patterns]
Eye rolling, lip smacking, drooling, oral
cyanosis + refractory seizures (13
mo) + hypsarrhythmia (13 mo) later
degeneration death (2.9 yrs) [EEGs
hypsarrhythmia]
Infantile spasms (flexor) (age 3.7
mo) ! Lennox–Gastaut type + profound
developmental (preceding onset of spasms)
[EEGs hypsarrhythmia]
Infantile spasms (age 7 mo) ! reflex
seizures
[EEGs hypsarrhythmia]
Infantile spasms under study] + partial
complex seizures
Infantile spasms ! myoclonic febrile
seizures (refractory)
Early onset epileptic spasms [under
study] + febrile & generalised seizures
Infantile spasms
[EEGs hypsarrhythmia]
Infantile spasms
[EEGs hypsarrhythmia]
6
Quadriplegia, speech regression (after status
epilepticus) allelic variant EIEE11
[GLU1211LYS] [68]
Neurodegeneration, hypotonia, quadriparesis,
diffuse encephalopathy [69]
Poor eye contact, irritability, primitive reflexes,
hypotonia [70]
P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
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 3 [LIS3; MIM # 611603] 12q13.12 / TUBA1A tubulin, alpha 1 Infantile spasms tonic–clonic seizures Lissencephaly: gradient anterior >>
Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.008
Please cite this article in press as: Pavone P et al. Infantile spasms syndrome, West syndrome and related phenotypes: What we know in 2013..

Tuberous sclerosis complex
[Tuberous sclerosis-1; MIM # 191100]
[Tuberous sclerosis-2; MIM # 613254]
Neurofibromatosis type 1 [NF1;
MIM # 162200]
[MIM # 602529] one of the main isoforms
(alpha and beta) of microtubules which
contributes to tubule heterodimer formation
9q34.13/TSC1 [MIM # 605284]
16p13.3 / TSC2 [MIM # 191092] hamartin [TSC1]
tuberin [TSC2]
17q11.2/NF1 [MIM # 613113] neurofibromin
[EEGs hypsarrhythmia] posterior + corpus callosum hypoplasia,
cerebellar/brainstem hypoplasia microcephaly,
quadriparesis, severe mental retardation,
Infantile Infantile spasms/WS: TSC2 mutations = WS >>
spasms + hypsarrhythmia + mental associated to more severe TSC “neurocutaneous”
retardation [WS] phenotype: >> skin hypomelanotic macules, facial
[EEGs hypsarrhythmia] 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,
[EEGs hypsarrhythmia] symmetrical, typical spasms classical NF1
phenotype brain MRI = high signal lesions in the
subcortical white matter or >> higher portions of
brainstem/mesencephalon [79]

P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx

Sotos syndrome 1 [MIM # 615006] 5q35.2-q35.3 / NSD1 nuclear receptor Infantile spasms Overgrowth, behavioural abnormalities
binding SET domain protein 1 [EEGs hypsarrhythmia]
[MIM # 606681]
Williams–Beuren syndrome chromosome 7q11.23/MAGI2 membrane associated Epileptic spasms [under study] Supravalvular aortic stenosis pulmonary stenosis,
7q11.23 deletion syndrome [WBS; MIM # guanylate kinase WW and PDZ domains aortic hypoplasia mental retardation, facial
194050] containing, 2 [MIM # 606382] dysmorphism (elfin phace), infantile
interactions of phosphatase and hypercalcemia
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 # West syndrome Poor eye contact, autistic behaviour, head rocking
610516] ubiquitous enzyme: liver, brain, [EEGs hypsarrhythmia] movements, hypotonia, brain MRI = delayed
kidney, skeletal muscle 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.

7
8 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
include, so far, deletion 1p36 syndrome, deletion
7q11.23 (Williams syndrome plus), tetrasomy 12p (Pall-
ister–Killiam syndrome), maternal duplication
15q11q13 (Duplication 15q syndrome), deletion 17p13
(Miller–Dieker syndrome) and Trisomy 21 (Down syn-
drome – 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 devel-
opment 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 con-
sequence 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 fre-
quently drug-resistant forms of ISs more often associ-
ated 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 diabe-
tes) 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 occa-
sionally reported with several other well-characterised
predisposing genotypes, often in reports predating
molecular characterisation of the disorder, including
autosomal recessive severe microcephaly with perinodu-
lar heterotopia/PNH (ARFGEF2 gene), Freeman–Shel-
don 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
Please cite this article in press as: Pavone P et al. Infantile spasms syndrome, West syndrome and related phenotypes: What we know in 2013..
Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.008
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 hemim-
egalencephaly (HMEG), mythocondrial dysfunction,
neonatal hypoglycemia, the pyridoxine-dependent/
responsive epilepsies, some of the epidermal nevus syn-
dromes (e.g., nevus sebaceous syndrome), schizenceph-
aly, 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 pop-
ulation (e.g., emerging GABAergic interneuron synaptic
networks) made vulnerable to spasms by yet undiscov-
ered 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 anom-
alies, and to attempt to avoid and improve neurodevel-
opmental 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, lead-
ing 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 fea-
tures. Hypertension and hypokalemia and, in rare cases,
fulminant infections secondary to immunosuppression
are reported [85]. A survey on pediatric epilepsy, per-
formed by the European Expert opinion [86], reports
as first line option ACTH and prednisone for initial
therapy in symptomatic ISs. Vigabatrin was also a treat-
ment of choice [85–86]. Patients treated with ACTH
 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
within one month show a lower rate of relapses and bet-
ter 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 treat-
ments in the setting of ISs [21]. This study deals with sev-
eral queries regarding the short-term treatment of ISs
and specifically the effectiveness of ACTH vs. other cor-
ticosteroids; 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 conclu-
sions: low dose ACTH, as well as vigabatrin, may be
useful for the short treatment of ISs. ACTH or prednis-
olone 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 sei-
zures [88].
It is unclear how ACTH acts in patients with ISs con-
sidering that the blood–brain barrier is relatively imper-
meable to ACTH. According to Stafstrom et al. [87]
ACTH may act through the pro-opiomelanocortin-posi-
tive 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 neuroster-
oids in the periphery, exerting an anticonvulsant action.
Other hypotheses argue that ACTH may increase the
synthesis of deoxycorticosteroids, which can be con-
verted to the neurosteroid allotetrahydrodeoxycorticos-
terone, 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 particu-
larly when associated to TSC. Lux et al. [88], in a mul-
ticentre 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
time, under careful and strict control of visual fields
(which is however not easy to carry out in infants)
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9
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 vigabat-
rin 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 hypsar-
rhythmia 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 recom-
mended 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-
hit rat model refractory to ACTH treatment, reported
good results on seizure-control.
10 P. Pavone et al. / Brain & Development xxx (2013) xxx–xxx
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 compli-
cations 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 treat-
ment 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 path-
ways 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 epi-
lepsy, 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 disabil-
ities. 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 disor-
ders [4]. Mental retardation is recorded in approxi-
mately 70–80% of cryptogenic ISs and 85–90% of
symptomatic ISs [5,7,29].
Overall, factors that have been recognized as predic-
tive 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 treat-
ment [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 sei-
zures while 25.2% had been seizure-free for at least
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Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.10.008
3 years [104–105]. According to Arce-Portillo [106] the
statistically significant poor prognostic factors were
linked to the age at onset of spasms (<4 months) and
the presence of epileptic seizures and delayed psychomo-
tor development before the onset of spasms.
Overall, what is emerging from the most recent liter-
ature is the better prognosis for survival in ISs patients
that exists today. In the near future the gold standard
could be the development of new therapies that target
specific pathways of pathogenesis. In this respect, these
new emerging therapies [107] could interfere not only
on seizures but also on the ISs-associated phenotypic
features beyond epilepsy [108,109].
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