Brain & Development 34 (2012) 459468

www.elsevier.com/locate/braindev

Mini review

Ohtahara syndrome with emphasis on recent genetic discovery

Piero Pavone a,, Alberto Spalice b, Agata Polizzi c, Pasquale Parisi d, Martino Ruggieri e
a

Department of Pediatrics and Pediatric Emergency Costanza Gravina, University Hospital Vittorio Emanuele-Policlinico, Catania, Italy
b
Division of Child Neurology, Department of Pediatrics, University of Rome La Sapienza, Rome, Italy
c
National Centre of Rare Diseases, Istituto Superiore di Sanita`, Rome, Italy
d
Child Neurology, Chair of Pediatrics, NESMOS Department, Second Faculty of Medicine, Sapienza University, Rome, Italy
e
Department of Formative Processes, University of Catania, Italy
Received 14 June 2011; received in revised form 27 August 2011; accepted 8 September 2011

Abstract
Ohtahara syndrome or Early Infantile Epileptic Encephalopathy (EIEE) with Suppression-Burst, is the most severe and the earliest developing age-related epileptic encephalopathy. Clinically, the syndrome is characterized by early onset tonic spasms associated with a severe and continuous pattern of burst activity. It is a debilitating and early progressive neurological disorder, resulting
in intractable seizures and severe mental retardation. Specic mutations in at least four genes (whose protein products are essential
in lower brains neuronal and interneuronal functions, including mitochondrial respiratory chains have been identied in unrelated
individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5
(SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1
(MUNC18-1) gene at 9q34-1 (EIEE-4 variant). A yet unresolved issue involves the relationship between early myoclonic encephalopathy (EMEErbB4 mutations) versus the EIEE spectrum of disorders.
2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Ohtahara syndrome; Infantile epileptic encephalopathy; EEG Suppression-burst; ARX; CDKL5; SLC25A22; Stxbp1

1. Introduction
Ohtahara syndrome, also known as Early Infantile
Epileptic Encephalopathy (EIEE) with SuppressionBurst (S-B), is the most severe and the earliest-developing age-related epileptic encephalopathy in children
[1,2]. The etiology is heterogeneous (Table 1) and the
spectrum of disorders encompassing EIEE, with the specic EEG ndings of suppression bursts pattern, is variable. Specic mutations in at least four dierent genes
cause overlapping EIEE phenotypes [322].

Corresponding author. Address: Department of Pediatrics, University of Catania, Via Plebiscito 7674, 95124 Catania, Italy. Tel.: +39
095 7435254; fax: +39 095 7436632.
E-mail address: ppavone@unict.it (P. Pavone).

Clinically, EIEE variants share either common or

overlapping phenotypes that typically evolve into similar syndromes (West Syndrome, WS, and/or Lennox
Gastaut Syndrome, LGS) (Table 2). Some of these phenotypes may have additional features, such as atypical
Rett or dyskinetic features (EIEE-2 variant), depending
on the functions of the defective protein. Consistent
with such a phenotypic continuum, the protein products
of the causative genes identied (Table 2) are all factors
or regulators of neuronal or interneuronal functions
expressed in the forebrain or brainstem [23], the sites
of origin of tonic seizures and the prominent feature
of Ohtahara syndrome [1]. Specic mutations in these
genes have been recorded in other-than-EIEE, or early
myoclonic encephalopathy (EME) phenotypes manifesting with an overlapping combination of early onset
spasms and moderate to profound mental retardation

0387-7604/$ - see front matter 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2011.09.004

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P. Pavone et al. / Brain & Development 34 (2012) 459468

Table 1
Heterogeneous etiologies reported in association with Ohtahara
syndrome phenotypes.
(1) Specic genetic defects [and genetic variants]:
ARX (aristaless-related homeobox) gene mutations at Xp22.13
[EIEE-1]
CLDK5 (cyclin dependant kinase like-5) (STK9) gene at Xp22
[EIEE-2]
SLC25A22 [solute carrier family 25 (mitochondrial carrier,
glutamate carrier-1/GC-1) member 22] gene at 11p15.5 [EIEE-3]
STXBP1 (MUNC18-1) gene microdeletion at 9q33.3q34.11 [EIEE4]
(2) Mitochondrial disease:
Mitochondrial respiratory chain (cytochrome oxidase and complex
1) defects
Likely due to mutations in the SLC25A22 (or similar) gene(s)
(3) Inborn errors of metabolism [other than mithocondrial disease]:
Glycine encephalopathy
(4) Cortical malformations:
Cerebral asymmetry
Megalencephaly
Hemimegalencephaly
Posterior fossa anomalies
Agenesis of mamilary bodies
Dentato-olivary dysplasia
Focal cortical dysplasia
Polymicrogyria
Poroencephaly
(5) Severe Perinatal Infectious Diseases
(6) Hypoxic-ischemic encephalopathy
(7) Miscellaneous:
Proteus syndrome
(8) Cryptogenic (idiopathic) EIEE

that may be associated with brain malformations such

as lissencephaly, and metabolic disorders [2430].
An important yet unresolved issue is related to the
nomenclature and classication of the so-called early
myoclonic encephalopathy versus Ohtahara syndrome
and the EIEE spectrum of disorders in general [31], which
are currently listed as two separate syndromes in the classication of epilepsies [32,33] but interchangeably used as
synonyms in the McKusick Catalog (OMIMe) [34]
(Table 2). Recent, preliminary molecular studies appear
to indicate genetic dierences between the two entities
(EME is likely caused by disruption of the neuregulin-1
receptor ErbB4) [33], despite a number of clinical and
neurophysiologic overlaps [35]. EIEE, EME, and other
early epileptic encephalopathies such as WS and LGS
are probably part of a phenotypic continuum, whose
clinical dierences (e.g., seizure type, EEG patterns, transition to other forms of epilepsy, natural history,
response to treatment) are dictated by the abnormal proteins functioning as a result of specic gene mutations.
2. Methods: search strategies
We reviewed articles identied through a PubMed
search of the terms Ohtahara syndrome, Early Infantile Epileptic Encephalopathy, EIEE, Early infantile
encephalopathy with Suppression-Burst, EIEE-1,

EIEE-2, EIEE-3, EIEE-4, Early myoclonic

encephalopathy, EME, epileptic encephalopathy,
West Syndrome, LennoxGastaut Syndrome,
ARX and Ohtahara syndrome, CDKL5 (SYK9) gene
and Ohtahara syndrome, SLC25A22 (GC1) gene and
Ohtahara syndrome, and Stxbp1 (MUNC18-1) gene
and Ohtahara syndrome between 1990 and May 2011.
Articles were also reviewed that were part of the authors
own les. Only papers published in English were
reviewed. The nal reference list was generated on the
basis of originality and relevance to the broad scope of
this review.
3. Historic background and epidemiology
The syndromic pattern proposed by Ohtahara [36,37]
had the following common clinical and bioelectric features [1]:
(1) Preferential age of onset at a specic developmental period of life (age dependency);
(2) Frequent minor generalized seizures;
(3) Severe
and
continuous
epileptic
EEG
abnormalities;
(4) Heterogeneous etiologies (Table 1);
(5) Comorbidity of mental defects;
(6) Seizure intractability and severe psychomotor
prognosis.
Most of the original characteristics proposed by
Ohtahara [37] were consistent over time. Other neurophysiologic features and etiological ndings have been
integrated as a result of more recent advancements
[1,322].
Ohtahara syndrome is uncommon; from an epidemiological standpoint, data are scant and controversial
with a prevalence ranging from 0.2% to 4% of childhood
epilepsies [3841].
4. Clinical features of ohtahara syndrome
Age at onset of seizures is limited to the neonatal or
very early infantile periods. Notably, in one study,
approximately 30% of cases rst manifested seizures
within 10 days of life, compared to approximately 70%
of children within 1 month of age [1,2,22]. The main seizure pattern is tonic spasms, with and without clustering,
which is observed in all cases and may be either generalized and symmetrical or lateralized. The duration of
spasms are short (up to 10 s). These spasms clinically
resemble those of WS but have some diering features:
they appear both during waking and sleeping states
and without clustering [1,2,22,42,43].
In addition to tonic spasms, partial motor seizures,
hemiconvulsions, or generalized tonic seizures are
observed in approximately 30% of cases.

Table 2
Phenotypic variability associated with dierent gene abnormalities in EIEE and EME.
Gene abnormality
Locus
OMIM no.
Genetic variant
[alternative symbol]
Seizure type

Age at onset of
seizures
EEG features

ARX
Xp22.13
# 308350
EIEE-1 [ISSX1]

CDKL5 (STK9)a
Xp22
# 300672
EIEE-2 [ISSX2]

SLC25A22b
11p15.5
# 609304d
EIEE-3

Stbxp1 (MUNC181)
9q34.1
# 612164
EIEE-4

Tonic spasms, partial

Spasms; Blitz-Nick-Salaam-like seizures

Tonic spasms, partial

Neonatal

Neonatal (9 wks) 3 stages of epilepsy***

Myoclonic (erratic,
fragmentary /massive),
partial motor: late tonic
spasms
1st month of life

Periodic S-B, irrespective

of waking and sleeping

Periodic S-B, irrespective of waking and

sleeping

Myoclonic (erratic,
fragmentary/massive),
partial motor: late tonic
spasms
1st month of life (few hrs
to 2 days after birth)
Periodic S-B, irrespective
of waking and sleeping

Periodic S-B,
irrespective of waking
and sleeping
Transformed into
Hyps by age 3
6 months

S-B

Transformed into Hyps

by age 36 months

Other neurological
abnormalities

Dyskinetic
encephalopathy (chorea,
dystonia)*
MR (severe-profound)

Cognitive status
Behavioral
phenotype
Systemic features

Imaging ndings
Transition to WS
Transition to LGS
Transition to other
seizure type(s)
Progression to other
syndromes

Micropenis

Basal ganglia
abnormalities*
(75% of cases)
Later in life (60%)

Dystonia ! quadriplegic
dyskinesis; status
dystonicus

Long lasting

[# 609304d]
EME

Long lasting

Atypical Rett syndrome: hand-writing &

hand-mouthing stereotypies; spastic
quadriparesis: cortical** blindness;
Developmental arrest (global,
profound); autistic features
Mood swings; Repetitive

Hypotonia; Abnormal
VEP (low amplitude &
slow response)
MR (severe-profound)

MR (severe-profound)

MR (severe-profound)

Breathing dysfunction,
hyperventilation, breath-holding
episodes; acquired microcephaly;
kyphoscoliosis; small feet;
Microcephaly

Brain atrophy
Transient, if any

Mixed seizures

P. Pavone et al. / Brain & Development 34 (2012) 459468

EEG course of S-B

NrR-1 ErbB4c

Longest follow-up (41 yrs)***

Mutations in the CDKL5 (STK9) gene have been found also in males [[14], 2004; 18 2008].
One sibship of 4 aected children (2 boys, 2 girls) and 4 healthy children born to Arab Muslim parents in Jerusalem (with intermediate features between EIEE and EME) as reported by [[20],
2005].
c
Mutations in the ErbB4 gene have been found so far only in one patient [[14], 2008].
d
In the McKusick catalog the same entry [OMIM # 609304] is used interchangeably for the genetic variant EIEE-3 and for EME (see aboveb).
*
Infantile Epileptic-Dyskinetic Encephalopathy [[12], 2007].
**
Atypical Rett syndrome [[14], 2004; [15], 2004; [16], 2005; [17], 2008]; not all cases with mutations in the CDKL5 have a Rett-like phenotype [see [18], 2008].
***
Three stages of epilepsy have been recorded in patients with EIEE and CDKL5 mutations: (1) Stage I) early epilepsy (onset 1 to 10 weeks) with normal EEG despite frequent convulsive seizures;
(2) (Stage II) epileptic encephalopathy with infantile spasms and hypsarrhythmia; (Stage III) refractory epilepsy with tonic seizures and myoclonic [[19], 2008].
b

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P. Pavone et al. / Brain & Development 34 (2012) 459468

The daily frequency of seizures remains very high,

ranging from 100 to 300 episodes in children with isolated seizures, and from 10 to 20 clusters in individuals
who experience clusters of seizures. Myoclonic seizures
are rarely recorded.
5. Interictal EEG ndings
The most specic EEG feature is the suppression
burst (SB) pattern. This pattern is characterized by high
voltage bursts of slow waves mixed with multifocal
spikes, alternating with at (isoelectric) suppression
phases at an approximately regular rate. Among the distinguishing features is the consistent appearance in both
waking and sleeping status and periodicity (Fig. 1). This
is a highly specic and diagnostic nding [1,42,43]. SB
patterns denitely dier from the periodic type of hypsarrhythmia in which periodicity becomes remarkable
in sleep. Regularity of periodicity and bursts containing
randomly appearing frequent multifocal epileptic discharges distinguish this pattern from burst suppression,
which is a non-specic EEG abnormality observable in
abnormal newborns with severe brain insults [4245].
Electroencephalographically, the suppression-burst
pattern gradually tapers from age 3 months and usually
disappears by 6 months, transforming to hypsarrhythmia in most cases from 2 to 6 months of age, or showing
further transition to diuse slow spike-and-waves or
multiple independent spike foci in other cases at age
1 year or later [44]. Occasionally, some patients demonstrate persistent suppression-burst on multiple EEGs
[45].
6. Brain imaging
An important feature of Ohtahara syndrome is the
underlying brain pathology, frequently encountered
upon imaging studies of the nervous system. Detectable
brain lesions usually allow gross distinction between
Ohtahara syndrome and EME (as the latter entity usually yields normal brain studies).
The most common structural abnormalities thus far
recorded include cerebral asymmetry, megalencephaly,
hemimegalencephaly, pachigyria, agyria, polymicrogyria, focal cortical dysplasia, dentate-olivary dysplasia,
dysgeneses of the collicoli, and posterior fossa anomalies
[4657]. A more common brain abnormality, however, is
hypodysmyelination and diuse to localized cortical
atrophy (Fig. 2).
7. Evolution of ohtahara syndrome into other early
epileptic encephalopathies
Ohtahara syndrome is one type and the earliest form
of the spectrum of age-dependent epileptic encephalopathies, along with EME, WS, severe myoclonic epilepsy

of infancy (SMEI), and LGS [1,2,22]. The term epileptic encephalopathy characterizes epileptic syndromes
with the following features: (a) the presence of serious
underlying disorders; (b) extremely frequent seizures;
(c) continuously and diusely appearing marked epileptic abnormalities; and (d) mental deterioration often
manifesting with the presence of seizures.
Consistent with the phenotypic continuum, patients
with either isolated or syndromic WS have similar (if
not identical, e.g., ISSX1 and ISSX2) genetic abnormalities as EIEE patients (Table 2). In addition, individuals
with EIEE and EME harbor mutations in genes whose
protein products share similar functions to those
involved in WS and LGS. For example, one patient with
LGS has been shown to have mutations in the JAK3
gene at 4q21.3 (OMIM # 606369), which encodes for
a transduction protein involved in the GTPase Ras
MAPK cascade responsible for dendrite and axonal
growth and regulation, and in turn for cognitive development [58].
8. ARX, CDKL5, SLC25A22 and Stxbp1: multiple genes
for a single phenotype?
8.1. ARX gene
Consistent with the idea of mutual transition between
the dierent early epileptic encephalopathies (Ohtahara
syndrome versus WS and LGS), specic mutations of
the ARX (aristaless-related homeobox) gene at Xp22.13
have been found in male subjects with EIEE and in cryptogenic infantile spasms of the West Syndrome type [2,3]
(EIEE1 or X-linked infantile spasm syndrome-1, ISSX1,
or West Syndrome X-linked) [OMIM # 308350; [29]]. In
most EIEE cases, however, no ARX mutations have
been identied (STXBP1 gene) [5,30]. Conversely,
ARX mutations have been demonstrated in familial
cases of Ohtahara syndrome [59,60].
ARX is a paired-type homeobox gene that contains
ve exons with four polyalanine (PolyA) tracts, a
homeodomain, and a conserved C-terminal aristaless
domain [61]. Studies in humans have demonstrated
remarkable pleiotropy in these genes. Malformation
phenotypes (e.g., X-linked lissencephaly with ambiguous genitalia, XLAG; or abnormalities of the basal ganglia and absence of the corpus callosum, ACC) are
associated with protein truncation mutations and missense mutations in the homeobox. Non-malformation
phenotypes (e.g., X-linked infantile spasms or ISS and
infantile spasm associated with severe quadriparetic dyskinesis) [29,30], are associated with missense mutations
outside of the homeobox and expansion of the PolyA
tracts. An expansion mutation of the rst PolyA tract
of ARX is more strongly related to infantile spasms than
is that of the second PolyA tract [4,30]. The ARX protein product is a transcription factor expressed in the

P. Pavone et al. / Brain & Development 34 (2012) 459468

463

Fig. 1. Typical suppression burst patterns (a and b) in a 2-month-old child with Ohtahara syndrome: high voltage bursts of slow waves mixed with
multifocal spikes alternating with almost at (isoelectric) suppression phases at an approximately regular rate (sensibility 10.0 v; time constant 0.10 s;
lter HF1 15.0 Hz; speed 20 s/page).

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P. Pavone et al. / Brain & Development 34 (2012) 459468

Fig. 2. Sagittal (a) and axial (b) brain magnetic resonance images in a 3-month-old patient with Ohtahara syndrome show hypodysmyelination and
diuse-to-localized cortical atrophy; (c) altered spectroscopic patterns in the area with myelin abnormalities.

forebrain, which acts as regulator of proliferation and

dierentiation of neuronal progenitors, and involved in
the tangential migration of interneurons from ventral
regions to the developing cortex. The severe seizures
associated with less severe mutations of this gene (i.e.,
cryptogenic infantile spasms) are presumably related to
a severe deciency of inhibitory interneurons despite
normal brain imaging [12,30]. The intractable seizures
associated with more severe mutations of the gene
(i.e., lissencephaly or EIEE and WS) are likely related
to severe impairment of interneurons with abnormal
brain imaging.

known as GC1 (glutamate carrier 1), is one of two mitochondrial glutamate/H + symporters, the other being
SLC25A18 (OMIM # 609303).
The SLC25A22 protein catalyzes either the cotransporter of L-glutamate with hydrogen protons or its
exchange with hydroxide ions [64]. By in situ hybridization, SLC25A22 expression has been demonstrated in
areas of the brain proposed to contribute to the genesis
and control of myoclonic seizures. Mutations in the
SLC25A22 gene could likely explain the EIEE phenotypes associated with mitochondrial abnormalities
reported in the literature [6568].

8.2. CDKL5 (STK9) gene

8.4. Stxbp1 gene

The CDKL5 (cyclin dependant kinase like-5) gene is

a member of the Ser/Thr protein kinase family and
encodes a phosphorylated protein (STK9) with protein
kinase activity [62,13]. The STK9 gene contains at least
23 exons - the rst three (1, 1a, and 1b) are untranslated
and probably represent two transcription start sites. The
protein product is composed of 1022 or 1030 amino
acids, depending on which initiating methionine is used.
The STK9 RNA isoform containing exons 1a and 1b
(isoform II) is transcribed at very low levels in the
human fetal brain, whereas the STK9 RNA isoform
containing exon 1 (isoform I) is expressed in a wide
range of cells, including human broblasts and lymphoblastoid cell lines.
Kalscheuer et al. [13] determined that mutations in
this gene have been thus far associated with EIEE-2
(including the phenotypes associated with the atypical
form of Rett Syndrome).

Recently, four unrelated children (three males and

one female) with EIEE have been found to harbor heterozygous missense mutations in the Stxbp1 gene, which
encodes syntaxin binding protein 1 (STXBP1, also
known as MUNC18-1), a protein essential for regulating synaptic vesicle release. This occurs, at least in part,
by syntaxin 1A (Stx1a) and SNARE complex binding
[EIEE4; OMIM # 612164; [5]]. STBXP1 binds to Stx1a
in two ways: binding to a closed form of Stx1a and binding to the N-terminus of an open form of Stx1a compatible with SNARE complex formation. The interaction
with the N-terminus of open form Stx1a is important
in synaptic vesicle release, whereas interaction with
closed form Stx1a is involved in synaptic vesicle docking. Thus, STBXP1 acts as a regulator of the synaptic
vesicular machinery and ultimately regulates the kinetics
of neurotransmitter release during priming of synaptic
vesicles.
An additional pathogenic mechanism, related to
Stbxp1 impairment, explains the spectrum of clinical
and bioelectrical abnormalities seen in EIEE. This
mechanism is the extensive cell death observed in Stbxp1
null mice that rst occurs in hindbrain areas (lower
brainstem), the site of origin of tonic seizures in EIEE.
The delayed myelination or hypomyelination seen in
some EIEE subjects can also be explained by impaired

8.3. SLC25A22 gene

The SLC25 (solute carrier family 25) is a gene family,
which encodes mitochondrial carriers that transport a
variety of metabolites across the inner mitochondrial
membrane [63]. SLC25A22 (solute carrier family 25,
mitochondrial carrier, glutamate, member 22) also

P. Pavone et al. / Brain & Development 34 (2012) 459468

cortico-subcortical (e.g., brainstem) connections. This

nding is consistent with the suggestion that tonic seizures in EIEE may originate from subcortical structures,
including the brainstem. Thus, it is possible that EIEE
genes (e.g., Stxbp1) haploinsuciency may lead to
EIEE through impaired neuronal cell death in lower
brain areas [23]. Interestingly, Stbxp1 mutations seem
to cause not only the Ohtahara phenotype but also West
Syndrome phenotypes, likely reecting the genetic spectrum of a disorder comprising Ohtahara syndrome and
later evolving into West Syndrome [69,70].
9. Other-than-genetic causes of EIEE
The pathogenesis of EIEE is still unknown. Besides
mutations in the four genes discussed above, other etiological factors, when identiable, include perinatal
asphyxia, metabolic disorders, severe perinatal infectious disease, and major brain malformations including
olivo-ponto-cerebellar atrophy (which is considered as a
part of multiple systemic atrophy) (Table 1) [4657,65
68,71].
Thus, as occurs for neuronal migration disorders
(NMD) and other cortical developmental disorders,
EIEE could be regarded as the nal common phenotype of many etiological insults.
Increased (up to seven fold) levels of neopterins have
been also observed in patients with Ohtahara syndrome
and are associated with increased mortality [71].
Histologically, EIEE might be the result of extensive
cellular death of mature neurons in the brainstem or a
disconnect between brainstem nuclei and specic cortical areas [22]. The latter in turn could be responsible
for the clinical (tonic spasms) and EEG (burst suppression) abnormalities observed [1,20].
10. Diagnosis and dierential diagnosis
According to the ILAE classication, the diagnostic
criteria of EME are: (a) early onset (within 3 months
of age); (b) fragmentary myoclonia as the main seizure
type; (c) frequent association of erratic partial seizures;
(d) massive myoclonias or tonic spasms; (e) SB in
EEG; (f) poor prognosis; and (g) unknown etiology
despite frequent familial cases [31]. However,
EIEE and EME share common characteristics, such
as very early onset of seizures, intractability, and SB on
EEG. Other distinctive features clearly indicate that
EIEE should be regarded as an independent clinicoelectrical entity diering from EME. Aicardi and Ohtahara
report the main clinical and EEG features of EIEE,
EME and WS: according to these Authors in EIEE seizure types are mainly early tonic spasms and partial;
SB are observed both awake and asleep, paroxysmal
bursts are longer and neurological signs are frequently
asymmetric and caused by brain malformations and

465

structural CNS damages. In this kind of aection no

familiarity has been observed. In EME the seizures are
erratic myoclonus and massive myoclonus types, with
tonic spams appearing late; SB appear enhanced in sleep,
burst paroxysmal are short and SB pattern may last for
prolonged period; hypotonia, respiratory problems and
severe neurological distress are the main neurological
signs; metabolic disorders are frequently observed with
high proportion of cryptogenetic cases [72]. Whether
these phenotypic dierences account for the genotypic
ndings has to be proven. Notably, mutual transition
has never occurred between EIEE and EME, even in
long term follow-up. Recently, preliminary molecular
studies have indicated that EME is likely caused by disruption of the neuregulin-1 receptor ErbB4 [33].
11. Are EIEE and EME independent entities?
With clinical seizures, the main seizure pattern in
EIEE is tonic spasms, present in all cases in one series
[1]. Partial seizures are also found in more than 30%
of cases and myoclonia in more than 25% [1]. In contrast, in EME, myoclonia is seen in all cases, characteristically presenting for prolonged periods. In addition,
the majority of myoclonic seizures seen in EME are
non-epileptic [1]. During the clinical course, the main
seizure type is partial (appearing in various parts of
the body with a tendency of clustering in the early period), noted in more than 80% of cases. Tonic spasms
are present in more than 80% of patients, and appear
only transiently in more than 65% of cases [1].
Suppression burst is typically evident both in EIEE
and EME. In EIEE these are typically characterized
by their consistent appearance in both waking and sleeping states. In contrast, SB in EME generally becomes
more distinct during sleep; thus, recording EEGs during
sleep is of the outmost importance in the diagnostic
workup. Of note, SBs in EIEE are found from onset
only in limited cases (these usually disappear within
six months), while in EME they are persistently found
in all cases even after the age of 1 year and also until
the nal follow-up. In contrast to EIEE, transient shifts
to hypsarrhythmia, with subsequent returns to SB patterns, are observed in EME.
Other dierences may be seen in the evolutional
changes of the epileptic syndrome or in transition
between syndromes. Most cases of EIEE evolve into
WS with further transition in some cases into LGS.
Transition into WS is not very frequently recorded in
EME and is usually transient, with subsequent returns
to the EME state again. In addition, the WS phenotype
observed in EME is atypical in that it coexists with frequent partial seizures and the SB are observed during
deep sleep.
Concerning the underlying pathology, most reported
cases of EIEE have gross brain ndings [4657]; only a

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P. Pavone et al. / Brain & Development 34 (2012) 459468

few are cryptogenic. In contrast, the underlying etiology

is often obscure in EME. It must be noted, however,
that according to the ndings of Ohtahara and Yamatogi in their EME series, the rst brain imaging studies
never showed abnormalities, but appeared several
months later and consisted of diuse cortical atrophy
without asymmetry, suggesting a progressive (metabolic
or degenerative) disease [1].
12. Natural history
Ohtahara syndrome remains the earliest form of the
age-dependent epileptic encephalopathies. Thus, it is
extremely important to underline the age-dependency
and the developmentally related changes in clinical
and EEG features. To date, there are a generous number
of patients who have been followed for as long as
30 years [1]. Seizures are intractable and the overall
prognosis is very severe, with profound psychomotor
retardation. Notably, mutual transition has never
occurred between Ohtahara syndrome and early myoclonic encephalopathy (EME), even upon long term follow-up. Most children die within the rst year of life.
13. Therapeutic strategies
ACTH administration has been proven to be eective
in Ohtahara syndrome and, in some cases, even after the
transition to WS [1,73,74]. Similarly, in anecdotal cases,
clonazepam and acetazolamide were eective in Ohtahara syndrome. In addition, high doses of vitamin B6,
sodium valproate, vigabatrin, or a ketogenic diet have
been tried, though yielding poor results [7479].
Recently, zonisamide suppressed seizures in all cases
treated in one study [8082]. However, these results
should be interpreted with caution. Very early hemispherectomy in selected infants with brain abnormalities
(e.g., megalencephaly or callosotomy) [19,83] has demonstrated promising results, suggesting that early age
is not a contraindication for surgery.
References
[1] Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special
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