European Journal of Paediatric Neurology 36 (2022) 37e50

Contents lists available at ScienceDirect

European Journal of Paediatric Neurology

Epilepsy with myoclonic-atonic seizures, also known as Doose

syndrome: Modification of the diagnostic criteria
Hirokazu Oguni a, b, *
a
Department of Pediatrics, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
b
Epilepsy Center, TMG Asaka Medical Center, 1340-1 Mizonuma, Asaka-city, Saitama, 351-0023, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: The aim of this review is to propose the updated diagnostic criteria of epilepsy with
Received 29 April 2021 myoclonic-atonic seizures (EMAS), which is a recent subject of genetic studies. Although EMAS has
Received in revised form been well known as Doose syndrome, it is often difficult to diagnose due to a lack of consensus
20 September 2021
regarding some of the inclusion criteria. Along with progress in molecular genetic study on the
Accepted 16 November 2021
syndrome, it becomes important to recruit electroclinical homogeneous EMAS patients, hence the
validity of the clinical criteria should be verified based on recent clinical researches. At present, the
Keywords:
most updated ILAE diagnostic manual of EMAS includes: (1) normal development and cognition
Diagnostic criteria
Epilepsy with myoclonic-atonic seizures
before the onset of epilepsy; (2) onset of epilepsy between 6 months and 6 years of age (peak: 2e4
Myoclonic-atonic seizures years); (3) myoclonic-atonic seizures (MAS) are mandatory (4) presence of generalized spike-wave
Genetic heterogeneity discharges at 2e3 Hz without persistent focal spike discharges; and (5) exclusion of other
Doose syndrome myoclonic epilepsy syndromes. In the criteria, we should emphasize that the age at onset of MAS is
between 2e5 years in (2), presence of myoclonic-atonic, atonic or myoclonic-flexor seizures (MASs)
causing drop attacks associated with generalized spike-wave discharges is mandatory in (3), and
epileptic spasms causing drop attacks must be excluded in (5). In the modified criteria, I propose that
EMAS is redesignated as genetic generalized epilepsy with MASs, consistent with the familial genetic
study conducted by Doose and the recent identification of candidate genes. It should also be noted
that EMASs evolves to transient or long-lasting epileptic encephalopathy.
© 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
1.1. Myoclonic-atonic seizures, atonic seizures or myoclonic-flexor seizures (potentially) causing drop attacks are a mandatory seizure type in EMAS 38
1.1.1. Differential diagnosis of MASs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
1.1.2. Case examples mimicking MASs in EMASs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
1.2. Inclusion of mode of onset and rapid progression to epileptic encephalopathy in the criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
1.3. Importance of normal development and cognition as well as absence of neurological abnormality before the onset of epilepsy . . . . . . . . . . . . 45
1.4. Is the onset age of epilepsy between 6 months and 6 years of age appropriate? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
1.5. Associated seizure types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
1.6. EEG findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
1.6.1. Interictal EEG findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
1.6.2. Ictal EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
1.7. Is EMAS an appropriate term? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
1.8. Genetic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

* Department of Pediatrics, Tokyo Women's Medical University, 8-1 Kawada-cho,

Shinjuku-ku, Tokyo, 162-8666, Japan.
E-mail address: oguni.hirokazu@twmu.ac.jp.

https://doi.org/10.1016/j.ejpn.2021.11.009
1090-3798/© 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
H. Oguni European Journal of Paediatric Neurology 36 (2022) 37e50

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

1. Introduction was also criticized because the cardinal seizure types of myoclonic,
myoclonic-astatic, and astatic ones were not fully clinically or
The classification of cryptogenic or idiopathic epilepsies with electroencephalographically examined even though the exact
primary generalized minor seizures, particularly myoclonic sei- seizure classification is a prerequisite for accurate diagnosis of the
zures, myoclonic-astatic seizures, and astatic seizures during early electroclinical syndrome [12]. However, most of the clinical and
childhood, was a matter of debate and difficult to achieve for some genetic studies of EMAS have employed the criteria that Doose
time in the 1970's and 1980's [1e6]. Doose et al. [2] reported 51 originally described to recruit patients [13e20]. Therefore, the
children with myoclonic and/or astatic seizures of primary gener- diagnosis of EMAS has been challenging due to the lack of
alized type, and designated the observed syndrome as cen- consensus and ambiguity regarding some of the criteria [19,21e23].
trencephalic myoclonic-astatic petit mal because they considered it The most recent genetic studies employing whole exome se-
a distinct entity from a pathophysiological point of view. Subse- quences on a large number of EMAS patients diagnosed with the
quently, Dravet et al. systematically examined 142 patients with criteria have strongly suggested the genetic heterogeneity of EMAS
myoclonic epilepsies in childhood using the polygraphic technique and questioned it as a discrete syndromic entity [24e26]. Almost all
[7], and separated benign myoclonic epilepsy in infancy and severe studies regarding EMAS employed the 1989 or 1992 ICEES criteria
myoclonic epilepsy in infancy, which were both later re-designated to recruit and analyze EMAS patients. In the 2006 and 2010 ICEES
as myoclonic epilepsy in infancy (MEI) and Dravet syndrome (DS) revisions, EMAS was considered an idiopathic or unknown etiology
[8], respectively, and included as independent epileptic syndromes and age-dependent electroclinical syndrome, respectively. Finally,
in the 1989 and 2010 [9] International Classification of Epilepsies most updated ILAE diagnostic manual of EMAS has modified some
and Epileptic Syndrome (ICEES) proposal. of the criteria along with the accumulated research evidence
Doose and colleagues further continued their study of cen- (Table 1) [27]. In this review, I assessed the validity of the each
trencephalic myoclonic-astatic petit mal, which was later re- criterion and propose modified criteria more accurately delineating
designated as myoclonic-astatic epilepsy (MAE) and epilepsy with EMAS, which may aid in future molecular and genetic studies or
myoclonic-atonic seizures (EMAS) in the 1989 and 2010 ICEES, therapeutic and prognostic studies of this unique epileptic
respectively, from a clinical and genetic perspective [10,11]. syndrome.
Although MAE was recognized in the 1989 ICEES [8], there was
controversy over the heterogeneity in this syndrome because his
original case series included MEI, DS and cryptogenic Lennox- 1.1. Myoclonic-atonic seizures, atonic seizures or myoclonic-flexor
Gastaut syndrome (LGS). However, Doose rejected the detailed seizures (potentially) causing drop attacks are a mandatory seizure
subclassification of these cases based solely on electroclinical type in EMAS
characteristics because he regarded MAE as a paradigmatic
example of a multifactorial determined disease entity rather than a Since the first description of this syndrome, myoclonic-astatic
rigidly defined electroclinical entity [10]. The classification of MAE seizures characterized by astatic falling with instantaneous recov-
ery have continuously received special attention because of their

Table 1
Epilepsy with myoclonic-atonic seizures by ILAE Epilepsy Diagnostic Manuala.

Overview
Epilepsy with myoclonic-atonic seizures (previously known as epilepsy with myoclonic astatic seizures, or Doose syndrome) is a syndrome characterized by the presence
of myoclonic-atonic seizures in an otherwise normal child who may have a history of febrile and/or afebrile seizures. There is often a family history of seizures.
Sex: Both sex affected, with a male predominance (ratio 2:1)
Development and cognition: Antecedent and birth history is unremarkable. Neurological examination and head size are normal. Development and cognition is typically
normal, however impairments may develop at or after seizure onset.
Caution: Glucose transporter type 1 deficiency syndrome should be excluded.
Epilepsy onset age: 6 months to 6 years of age (peak 2e4 years)
Seizure type
Mandatory seizures: myoclonic-atonic seizures with frequent combinations with myoclonic and atonic seizures, myoclonic-atonic status epilepticus is common.
Associated seizure types: Febrile seizures and GTCS (2/3 of cases), absence seizures (50%), typically with myoclonic jerks, facial myoclonia and atonia (not just loss of
awareness), atypical absence seizures, Nonconvulsive status epilepticus (common), Tonic seizures (linked to a higher frequency of cognitive impairment)
EEG
Interictal: The background may be normal or show generalized slowing. Background bi-parietal theta is usually seen. Generalized spike-and-wave and polyspike-and-
wave occur. Focal slowing or discharges are not seen.
Ictal: The myoclonic component is associated with a generalized spike or polyspike. The atonic component is associated with the after going high voltage slow wave.
Genetics
Pattern of inheritance
Complex/polygenic inheritance with variable penetrance
Known genes
A minority of cases may be explained by variants in SCN1A and SLC2A1.
Family history of seizures/epilepsy
There is frequently a family history of febrile seizures (in 50% of cases)
Differential diagnosis:
Atypical childhood epilepsy with centrotemporal spikes, Lennox-Gastaut syndrome, Dravet syndrome, Myoclonic epilepsy in infancy, Progressive myoclonus epilepsies,
a
The diagnostic manual was referred to Reference 27, and was partially shortened.

38
H. Oguni
rarity and characteristic seizure phenomenon, whereas myoclonic
seizures (without astatic falling) are well known and more common
in childhood epilepsy. Guerrini et al. pointed out that it is unclear
whether falls are a necessary criterion for the inclusion of patients
with EMAS because the original description of the criterion only
stated the presence of primary generalized myoclonic, astatic or
myoclonic-astatic seizures, which can be interpreted as meeting
the criterion if any of them were present [22]. There was no
consensus regarding this issue because most of the published pa-
pers did not describe the details of the most important seizure type
(Table 2) [3,13,14,17e19,23e26,28e35].
Myoclonic-atonic seizures (MAS) themselves, literally indi-
cating massive myoclonic jerks immediately followed by global
axial atonia, was first introduced in the 2010 seizure type classi-
fication and considered a hallmark of EMAS, but only replaced the
term “myoclonic-astatic seizures” because of the accumulating
evidence from the polygraphic studies [36e39]. Kaminska et al.
first demonstrated that EMAS characterized by frequent massive
myoclonus and drop attacks was electroclinically distinct from
cryptogenic LGS using validated statistical method [30,40]. How-
ever, their “EMAS” were not exactly identical to the one proposed
by Doose who prioritized pathophysiological concept over
detailed electroclinical features, e.g., main seizure types included
myoclonic, myoclonic-astatic, or astatic seizures, onset age be-
tween 6 months and 6 years in the latter vs. massive myoclonus
and drop attacks, onset age>2 years in the former [28,40].
Therefore, I propose the well-defined electroclinical criteria ac-
cording to the accumulated evidence rather than sticking to the
original descriptions of Doose.
We have long made the video-polygraphic studies on the
massive myoclonus and drop attacks in EMAS and revealed that
they were exactly caused by myoclonic-atonic seizures, atonic
seizures or myoclonic-flexor seizures (potentially) causing drop
attacks, all associated with well-organized generalized high-
amplitude single- or polyspike-wave complexes (Fig. 1)13,36-38. In
this context, I propose that EMAS is more precisely re-designated as
epilepsy with myoclonic-atonic, atonic or myoclonic-flexor seizures
(these 3 seizure types are abbreviated as MASs), in which the
dropping is an essential feature. Sudden frequent drop attacks in
otherwise normal developing young children are a rare and striking
feature, sufficiently characterizing this syndrome. In our detailed
polygraphic study of 30 patients with EMASs, myoclonic-atonic,
atonic and myoclonic-flexor seizures were observed in 3 (10%),
11(37%) and 16 patients (53%), respectively, although the atonic
seizures were sometimes preceded by minor myoclonia recorded
either video or surface EMG [13,37]. Therefore, true myoclonic-
atonic seizures, defined as approximately equal involvement of
both myoclonic and atonic components were infrequent. As MASs
caused not only dropping on the floor but also head nodding
depending on the intensity of the attacks, they are described as
“(potentially) causing drop attacks” [13].
Most recent electroclinical studies of MASs have shown other
characteristic findings, in which we found that ictal vocalizations
are relatively common in MASs as compared to myoclonic seizures
(MS) in MEI [41]. They were always non-speech sounds and
immediately followed by head or body dropping. The ictal vocali-
zations precisely corresponded to the massive myoclonic EMG
potentials, hence being a result of strong contraction of axial
muscles. In addition, the morphometric ictal EEG study of MS and
myoclonic-flexor seizures in MASs demonstrated that the depth of
positive-sharp-components of generalized spike-wave complexes
(SWCs) was significantly correlated to the intensity of MS, i.e., it
was significantly deeper in the myoclonic-flexor seizures in EMASs
than MS in MEI [42]. Therefore, MASs themselves are found to have
characteristic semiology and ictal EEG pattern to represent the
39
European Journal of Paediatric Neurology 36 (2022) 37e50
main and mandatory seizure type in EMASs. A differential diagnosis
of MASs from drop attacks of other causes or other seizure types is
important to make a diagnosis of EMASs and may be difficult only
by visual inspection or history-taking as shown in the following
section.
Although most electroclinical syndromes evolve with age and
their characteristic clinical seizure types may change, over two-
thirds of EMASs patients exhibited remission of epilepsy within 3
years of epilepsy onset, but the characteristic clinical course was
not lost [37].
1.1.1. Differential diagnosis of MASs
A differential diagnosis of MASs from drop attacks of other
causes or other seizure types is at times difficult without video-
polygraphic examinations [27]. Epileptic spasms (ES) were re-
ported to cause flexor drop attacks or even atonic falling immedi-
ately after ES that is visually indistinguishable from MASs as shown
in the case examples. It commonly occurs in clusters, and the ictal
EEG pattern was distinct, presenting with either more disorganized
biphasic sharp activity, brief flattening of background activity, or a
short recruiting rhythm [29,43e46]. The differences in the ictal EEG
pattern should reflect the difference in cortical pathology, sug-
gesting that MASs in EMASs are caused by genetically-determined
cortical excitability associated with a well-preserved cortex,
whereas ES are mainly caused by diffuse structural cortical pa-
thology, including MRI-invisible cortical dysplasia type 1, often
observed in West syndrome and related disorders [47], and pre-
sumably by genetically-determined diffuse cortical pathology such
as in CDKL-5 or FOXG1 encephalopathy without structural brain
MRI abnormalities. Bonanni et al. neurophysiologically investigated
myoclonus in symptomatic LGS and EMAS, demonstrating that
myoclonus in the former originated from the frontal cortex
spreading unstably to the contralateral and ipsilateral cortex, sug-
gesting a secondary generalized origin, whereas the latter was
stable, reflecting a primary generalized origin [48]. Children with
repeated drop attacks should be carefully evaluated before diag-
nosing MASs and EMASs, especially when they have electroclinical
features of developmental and epileptic encephalopathies (DEE). As
drop attacks themselves are caused by different seizure types
including MASs, ES, generalized tonic seizures (GTS) and focal-
onset seizures, their presence does not lead to the specific
epileptic syndrome nor does it help to make a differential diagnosis
unless the underlying seizure type is clarified. Therefore, clinical
seizure diagnosis by history-taking or interview alone does not
always permit the correct diagnosis of MASs in EMASs, which may
have hampered to exclude cases with drop attacks of other causes
or other seizure types.
1.1.2. Case examples mimicking MASs in EMASs
CASE 1. ES causing flexor drop attacks in a 3-year-old girl with
frontal lobe epilepsy
The patient was developmentally and neurologically normal
before the onset of epilepsy. She started to have recurrent drop
attacks at 2 years and 8 months of age. She fell down frequently, at
times slightly on the left side of her body, but recovered quickly.
Interictal EEG demonstrated frequent intermittent sharp-slow
complexes and the video-polygraphic study revealed that her
drop attacks were caused by epileptic (flexor) spasms (Fig. 2). The
seizures were completely controlled by ACTH therapy. She was
seizure-free despite persistent localized epileptic EEG discharges in
the right frontal region (Fig. 3), but eventually developed a focal
seizure originating from the right frontal region at 16 years of age.
Repeated MRI was normal. This case illustrated that a frontal focus
 Table 2

H. Oguni
Major clinical studies of EMAS or related conditions.

Authors Publication Year Methods N Inclusion criteria Age at onset Development Main Other EEG findings Favorable Unfavorable Others related to
before onset of seizure type seizure outcome outcome EMAS criteria
epilepsy types

Doose H. Neuropediatrics 1970 Retrospective chart 51 MS and/or AS, 2 1-5th yrs. Normal in 76% MS, AS, GTC: 60%, BGA: 57.9% (38) 42% (less than Genetic
et al.[2] review e3 Hz G(P)SW, (usually 3-4th at the first MAS GTS: rare, monomorphic 2 yrs Seizure- predisposition plays a
excluding focal yrs.) examinations Ab sz: 59%, theta and delta, free at the decisive role in
spikes and waves or Petit mal 2-3-Hz GSW, final etiology, strongly
multifocal and only status: 45% No focal or examination) suggested by a large
generalized sharp multifocal familial EEG study
slow waves spikes
Aicardi J Neuropediatrics 1971 Retrospective chart 90 MS and <15 yrs of Median: 2 y variable MS variable MS associated ND ND EMAS was included in
and review age 11 m with 3-Hz G(P) petit mal variant with
Chevrie JJ Mean: 3.8 yrs. SW short, myoclonic jerks
[3] longer (n ¼ 14; drop attack
duration, and n ¼ 9) and
2-Hz GSW cryptogenic
myoclonic epilepsy
(n ¼ 31; drop attacks
n ¼ 15)
Doose H. Epileptic 1992 Retrospective chart 117 Described in Table 1 1-5th yrs. of Normal in 84% MS, AS, GTC: 75%, BG: 54% (Sz free> 46% Risk factors for
[28] syndromes 2nd review age and sign of MAS Ab sz: 62%; monomorphic 2 yrs) unfavorable outcome:
edition developmental Status theta and delta, frequent febrile and
retardation and minor GSW at 2 afebrile GTCS, petit
high-risk seizures: e3 Hz, No focal mal status, onset of
factors in their 36%, Tonic or multifocal epilepsy during the
history in 16%. sz: 30% spikes first 18 months of life
with GTCS, and
40

persistence of a
rhythmic slowing
until adolescence
Kaminska Epilepsy Res 1999 Retrospective chart 55 (Group Massive epileptic Group 1: 1 Normal Massive GTCS: 84%, Irregular GSW 67% (37) 33% (18) EMAS was a distinct
et al. [30] review 1þGroup 2) myoclonus, no brain e5 yrs (2 psychomotor myoclonus, Ab sz: 71%, and 3-Hz GSW entity separated from
MRI abnormality e4 yrs), Group development drop Tonic sz: LGS and reasonably
2: 2e5 yrs (2 including a attacks 44% classified into
e4 yrs) mild speech favorable and
delay unfavorable outcome
groups by multiple
correspondence

European Journal of Paediatric Neurology 36 (2022) 37e50

analysis
Oguni H Brain Dev 2001 Retrospective chart 30 ILAE1989þictal Mean age at Normal MS/MAS/AS GTC: 87%, 2-3-Hz G(P)SW 20 (66%) 10 (34%) The differences in the
et al.[13] review video-polygraph of onset of MAS with falls Atypical ab precise seizure types
MAS 32e38 m sz: 47%, among MS, MAS, and
Minor AS did not have a
epileptic significant impact on
status: 17% the outcome of EMAS
Oguni H Neuropediatrics 2002 Retrospective chart 81 ILAE1989 6 me52 m Normal MS/MAS/AS GTC, BGA: 4-7-Hz 68% (þ14% 18% MAE is considered to
et al.[14] review (mean: 32 m) Atypical ab theta rhythm, intermediate) form a clinical
MAS: 7 m sz, Minor 2-3-Hz G(P)SW spectrum and the
e63 m (mean epileptic overall prognosis,
36 m) status despite initial
resistance to
treatment, is better
than originally
thought.
 H. Oguni
Kilaru S and Epilepsia 2007 Retrospective chart 23 ILAE1989 Mean: 36 m ND MS/AS/MAS GTC: 70%, BGA: mainly Q 67% þ 14% 19% Definitions of EMAS
Bergqvist review (12e64 m) Ab sz: 52%, and d: 40%, are inconsistent in
AGC [32] Status: 1% Focal BG prior series, especially
abnormality: in the parameters of
9% age onset, the
existence of prior
developmental delay,
and the presence of
tonic seizures
Trivisano M Epilepsy Res 2011 Cross-sectional 18 Age at onset of 2.3e4.9 yrs Normal MS with Ab sz: Ictal EEG: G(P) 16 (89%) 2 (11%) Although cognitive
et al. [18] retrospective chart epilepsy between (mean: 3.6 y) falls 88.9%, GTC: SW, Interictal function may
review in 2000 and 18 m and 60 m. (66.7%), AS 77.8%, Brief EEG: 2-3-Hz deteriorate, the
2008 MAS þ at least one (72.2%) tonic sz: GSW, BGA: CP outcome is good
other type of GS 38.9%, theta (88.9%), regarding seizures.
(excluding ES and NCSE: high-voltage
typical absence), 16.7% delta waves (1
normal psychomotor e3 Hz) (77.8%)
development before
the first seizure,
excluding MEI and
DS and LGS
Caraballo Pediatric 2013 Retrospective chart 69 ILAE1989 Mean: 3.4 yrs, Unremarkable MS þ MAS GTC: 72.5%, BG: CP theta 39 (56%) 30 (44%) EMAS cover a broad
et al. [17] Neurol review Median: in all patients Atypical 60.5%, Delta: electroclinical
3.7 yrs. Ab: 55%, 14.5%, 2 to 5- spectrum with varied
NCS: 29% Hz outcomes, ranging
GSSW:100%, from mild cases to
Asymmetry of those with features
GSSW: 22%, compatible with
Focal spikes: epileptic
17.5% encephalopathy
41

Doege et al. Europ J Ped 2013 Exploratory 10 ILAE1989 36 ± 10 m ND Astatic/ GTC: 70%, ND 60% ND In our patent cohort,
[19] Neurol retrospective study myoclonic- Atypical responded to we found an overlap
astatic Ab: 70%, adjunctive between EMAS and
Tonic use of LTG borderline severe
seizures: myoclonic epilepsy
10% (SME) in two patients.
Itoh Y et al. Brain Dev 2015 Retrospective chart EMAS: 20 ILAE1989 EMAS: EMAS Normal: MS/MAS/AS EMAS: EMAS: 1.5-3- EMAS SE with EDA EDA often seen in
[29] review Symptomatic median: 37 m 19, borderline GTCS 17 Hz GSW in all, favorable unfavorable young children with
epilepsy (SE) SE with EDA: delay: 1, SE (85%), SE with EDA 1 outcome 19 seizure symptomatic epilepsy
with EDA: 21 median 25 m with EDA Atypical ab e2.5-Hz GSW (95%) outcome: 9 were most frequently
Normal 10, sz 12 (60%), in all and caused by flexor-type

European Journal of Paediatric Neurology 36 (2022) 37e50

retarded 11 SE with multifocal ES and rarely by
EDA: GTC 4, accentuation of myoclonic-atonic
GTS 4, GSW 9 seizures.
Atypical ab
sz 8, CPS:1
Larsen J Epilepsia 2015 SLC2A1 study 120 ILAE2006 1e5 yrs. previously Multiple GTC, Ab sz G(P)SW ND ND This study failed to
et al. [58] healthy seizure support that SLC2A1
children types mutation is a cause of
including EMAS without
MAS associated features
such as movement
disorders.
Stenger E Epilepsy Res 2017 Multicenter 50 ILAE1989 and 2010 15e60 m Language delay MS/AS/MAS GTC: 88%, Explosive Clinical Unfavorable Earlier introduction of
et al. [35] retrospective (mean: 50 m) 22% Ab sz:74%, phase BGA: remission: evolution: KD improved long-
survey for EMAS Focal sz: Generalized 54% (27) 34% (17) term seizure effects
undergoing 24%, Status: slowing and and cognitive
ketogenic diet 48% G(P)SW: 100%, outcomes.
focal
(continued on next page)
 Table 2 (continued )

H. Oguni
Authors Publication Year Methods N Inclusion criteria Age at onset Development Main Other EEG findings Favorable Unfavorable Others related to
before onset of seizure type seizure outcome outcome EMAS criteria
epilepsy types

(explosive epileptiform
phase) abnormality:
10%
Wiemer- Epilepsia 2017 Multicenter 30 Uneventful history 1.5e5.6 yrs Uneventful MS/MAS GTC: 47%, ND 47% seizure- MAD is an effective
Kruel A retrospective until epilepsy onset, (mean: history until Atypical Ab free therapy for EMAS.
et al. [34] survey for normal brain MRI, 3.1 yrs) epilepsy onset sz: 17%,
pharmacoresistant GSSW on EEG, typical NCS: 7% (at
EMAS undergoing clinical seizures the time of
MAD MAD
starting)
Eschbach K Epilepsy Res 2018 Cross-sectional 77 / 57 Drop attacks, 2.9 ± 1.3 yrs. Abnormal MS/AS/MAS GTC: 81%, EEG focal Seizure- Abnormal Current epilepsy
et al. [23] retrospective chart absence of brain MRI development (Atypical) features: 39%, free  6 m: development syndromic
review in 2004 and abnormality prior to Ab sz:86%, focal spikes: 44% (23) outcome: 71% classification has
2017 epilepsy: 23% Focal sz: 21% (37) reduced applicability
12%, Status: due to overlapping
21% features, especially
(explosive EMAS vs LGS.
phase)
Johannesen Epilepsia 2018 To characterize the 30 ILAE1989 for EMAS 0.5e7 yrs Normal 5/24, AS:14 Atypical ab 2.5e3.5-Hz Seizure- free: ND 16/31 patients were
KM clinical and EEG diagnosis (mean: mildly (45%), sz: 10 G(P)SW: 25 65% (20) diagnosed with
et al.[33] features of patients 3.7 yrs) impaired 12/ MAS:12 (32%), GTC: (81%) EMAS, but most had
with SLC6A1 24, moderately (39%) 5 (16%) intellectual disability
mutations impaired 4/24, and varying degrees
Severe 1/24, of neurological
speech delay 2/ abnormality before
42

24 the onset of epilepsy.

Routier L Clinical 2019 CGH and WES for 27 ND 1.5e5.6 yrs. Normal ND ND ND ND ND EMAS shows
et al. [26] Genetics EMAS development underlying genetic
before the heterogeneity with
onset of only a few cases
epilepsy linked to mutations in
genes reported in
developmental and
epileptic
encephalopathy.
Tang S et al. Epilepsia 2020 Deep phenotyping 101 ILAE 1989 for EMAS 6e72 months 20/95 pts MAS or AS GTCS(72%), BGA: slow 16/ Seizure-free> There was no MAE is associated
(Median ¼ 34 (21.0%) had

European Journal of Paediatric Neurology 36 (2022) 37e50

[24] and WES for MAE diagnosis (100%) Absence 70 pts (22.8%), 2 yrs: 24/72 statistical with significant
patients months) prior (60%), GSW (100 pts), (33.3%) difference in neurodevelopmental
development MS(69%), GPSW (31 pts), the median impairment. A
delay, 9 pts had TS (19%) Focal age of seizure pathogenic genetic
isolated speech epileptiform onset etiology was
delay activity (7 pts) between identified in 14% of
favorable and pts by WES. MAE is a
unfavorable manifestation of
group. several etiologies
rather than a discrete
syndromic entity.
Hinokuma Epilepsia Open 2020 Genotype and 29 Original definition of 8e60 months Neurological MS/AS/MAS GTC (41%), Generalized or Seizure-free Intractable: EMAS patients had
N et al. phenotype Doose (34 ± 13) signs prior to Tonic bisynchronous 16 (55%) 13 (45%) genetic
[25] correlation and epileptic (38%), (61%), Focal or heterogeneity, and
WES for EMAS seizures 7 pts Absence multifocal HNRNPU and STS
patients (24%) (45%), Focal (18%), No emerged as possible
(10%) epileptic candidate causative
discharges genes.
(21%)
H. Oguni European Journal of Paediatric Neurology 36 (2022) 37e50

can generate ES-causing flexor drop attacks associated with

Abbreviations: MS ¼ myoclonic seizures, MAS ¼ myoclonic-atonic seizures, AS ¼ atonic seizures, EMAS ¼ epilepsy with myoclonic-atonic seizures, yrs. ¼ years, m ¼ months, GSW ¼ generalized spike-waves, G(P)
bidirectional link was

cognitive and seizure

generalized sharp-slow complexes during early childhood, which
seizure outcome. A
failure to respond
treatment and its

are later transformed into focal epilepsy.

Diet therapy was

lead to a worse

found between
most effective

CASE 2. ES causing atonic drop attacks in a 4-year-old boy with

outcomes.
focal cortical dysplasia (FCD)

SW ¼ generalized (polyspike- or) spike-waves, GTC ¼ generalized tonic-clonic seizures, Ab sz ¼ absence seizures, sz ¼ seizures, BG ¼ background activity, KD ¼ ketogenic diet, MAD ¼ modified Atkins diet.
The patient developed normally until 2 years and 10 months,
when he started to have head-nodding and drop attacks. He also
delay, seizure
development

EEGs, failure
with seizure

diet therapy
recorded on
persistence:

subsequent

had nocturnal generalized tonic seizures at 3 years of age. He was

respond to
associated

referred to our hospital at age 4, when his daily drop attacks

Factors

global

became frequent and occurred in clusters upon awakening. Inter-

ictal EEG demonstrated frequent intermittent generalized sharp-
Development

slow discharges at times with right frontal predominance. The

Seizure-free

was normal

ictal video-polygraphic examinations revealed that the drop attacks

(57%),

were caused by ES (Fig. 4). Brain MRI revealed right frontal FCD
(47%)

(Fig. 5). ACTH therapy controlled his drop attacks and the gener-
alized epileptic abnormality became localized at the right frontal
Generalized or

(90%), Slowing
of BGA (62%),

seizure types
epileptiform

region. This case also illustrates how a frontal focus can generate ES
of any type
potentially

discharges
multifocal

recorded

causing drop attacks mimicking MAS in EMSs.

(70%)

CASE 3. Atonic seizures in a 7-year and 5-month-old boy with

GLUT1DS
drop attack
GTC (60%),

myoclonic

typical or

absence
atypical

In the family history, one of his paternal cousins had epilepsy,

(30%),

10%)

but the details were unknown. He was born uneventfully at 36

or

weeks. He had a febrile seizure at 10 months of age. He was brought

to our hospital at 1 year and 9 months of age because of slowing in
MS/MAS

psychomotor development and occasional myoclonic jerks. At 2

years and 3 months of age, interictal EEG demonstrated nearly
normal background activity and intermittent generalized SWCs at
epilepsy: 85%
development

2.5e3 Hz. The video-polygraphic examination revealed that his

before the

myoclonic jerks were caused by brief atonic seizures (Fig. 6). He

onset of
Normal

exhibited moderate mental retardation and mild truncal ataxia, and

later developed mild spasticity in both legs at 4 years of age. At 7
years of age, he was diagnosed with GLUT1DS by a CSF/blood
After 2 yrs of

glucose ratio of 0.4 and positive SLC2A1 mutation.

age: 88%

CASE 4. Atonic seizures in an 8-year-old boy with DEE

The patient developed infantile spasms at 5 months of age and
ILAE2017 for EMAS

successfully underwent ACTH therapy. He had chromosomal ab-

normality (14q11.2q12), which included the FOXG1 gene. He
developed febrile status epilepticus twice at 2 years and 6 months
diagnosis

of age and later at 3 years and 1 months of age, after which epileptic
drop attacks continued daily. He was brought to our hospital at 8
years of age when he had severe mental retardation. A long-term
video polygraphic recording captured 3 atonic drop attacks asso-
ciated with brief flattening of ongoing background activity (Fig. 7).
This case illustrated the atonic drop attacks semiologically resem-
166

bling but electroencephalographically different from MAS in EMASs

can be associated with DEE.
retrospective chart

In conclusion, I propose that the mandatory seizure type crite-

rion is changed more precisely to the “presence of either
2021 Multicenter

myoclonic-atonic, atonic or myoclonic-flexor seizures (potentially)

review

causing drop attacks associated with well-organized generalized

SWC” to emphasize the exclusion of MS without falling observed in
patients with MEI and drop attacks of other seizure types often
observed in those with LGS. The spread of digital video-EEG devices
has made recording easier in most specialized hospitals for epilepsy
at least for those with EMASs resistant to appropriate antiseizure
Epilepsia

medications (ASMs).
et al. [31]

1.2. Inclusion of mode of onset and rapid progression to epileptic

Nickels K

encephalopathy in the criteria

An early clinical presentation is characterized typically by an

43
H. Oguni European Journal of Paediatric Neurology 36 (2022) 37e50

Fig. 1. Comparison of the ictal polygraphs among myoclonic-flexor, myoclonic-atonic, and atonic seizures causing drop attacks. The
3 polygraphs show the ictal EEG and associated EMG patterns of the 3 different seizure types observed in typical EMASs cases. Note the well-organized high-amplitude generalized
SWCs causing negative (atonic) and positive (myoclonic) seizures.

Fig. 2. Ictal polygraph of epileptic (flexor) spasms causing drop attacks. Ictal
polygraph showed sudden-onset triangle EMG discharges (epileptic flexor spasms), which corresponded to diffuse biphasic slow-sharp discharges (more clear after reformatting to
monopolar montage), which differed in morphology from the SWCs in Fig. 1.

44
H. Oguni
Fig. 3. Follow-up sleep EEG at 10 years of age. The patient had frequent intermittent irregular SWCs associated with localized slow waves in the right frontal region since 5 years of
age.
explosive or stormy onset of recurrent GTCS and MASs, whose
seizure frequency peaks within 1 year of epilepsy onset despite
ASMs [22,37]. MASs up to 100 times/day potentially causing injury
developed commonly within 1 month after the onset of GTCS in
otherwise normal developing young children [13,37,49]. This
“stormy onset” leads to a high seizure burden and a negative
cognitive impact on EMASs patients, which is why EMASs is cate-
gorically placed into epileptic encephalopathy (EE) and why pa-
tients undergo aggressive nonpharmacological treatment, such as
ketogenic diet or ACTH therapy as reported in the previous study
[49].
1.3. Importance of normal development and cognition as well as
absence of neurological abnormality before the onset of epilepsy
EMASs itself has long been considered primary generalized or
idiopathic generalized epilepsy, similar to absence epilepsy or ju-
venile myoclonic epilepsy, because patients exhibit normal devel-
opment and are neurologically normal without imaging
abnormality in addition to genetic predisposition (high incidence of
seizures and/or genetic EEG pattern in relatives) [28]. However,
Doose described that 16% of 117 patients with MAE demonstrated
signs of developmental retardation before the onset of epilepsy or
had high-risk factors in their history, although he did not refer to
the degree of developmental retardation [28]. Therefore, the in-
clusion of “mostly” in his criterion has permitted the inclusion of a
significant number of such cases in the genetic EMAS studies [26].
From an etiological point of view, patients with developmental
retardation have developmental brain pathology, potentially
causing DEE such as LGS. In this context, several candidate genes of
EMAS, including SLC6A and SLC2A1, identified in EMAS patients
have remained controversial as responsible genes of EMAS because
most of the investigated patients diagnosed with EMAS exhibited
45
European Journal of Paediatric Neurology 36 (2022) 37e50
possible or significant developmental delay before the onset of
epilepsy [16,20,33]. Most recently, it has been reported that chil-
dren with neuronal ceroid lipofuscinosis type 2 developed MAS at
2e4 years of age and may have been diagnosed with EMASs [50].
However, early language delay existing before the onset of seizures
emphasized as another hallmark of this disease is an important
clinical finding to make a differential diagnosis from EMASs [50,51].
Therefore, caution is needed when diagnosing EMASs in patients
with borderline or mild development delay before the onset of
epilepsy due to concerns over the inclusion of genetic or structural-
metabolic etiologies, as described in the differential diagnosis
section.
1.4. Is the onset age of epilepsy between 6 months and 6 years of
age appropriate?
This age criterion refers to the original criterion proposed by
Doose, who later stated that their series may have included other
ILAE syndromes, mainly MEI and DS, which may have affected the
onset age and seizure type criteria. In his previous 1985 definition,
“repeated febrile or afebrile prolonged or status of unilateral and
generalized tonic-clonic seizures” was a characteristic seizure
pattern of DS and thus removed in the 1992 definition [28,52].
However, the DS elements may have remained at an onset age of
less than 1 year. MEI is characterized by the onset of myoclonic
seizures (MS) at as young as 6 months of age, and its inclusion may
have also affected the lowest onset age of 6 months [53]. In the
subsequent studies of EMAS, the epilepsy onset age was most
frequently between 2 and 5 years of age even though the seizure
type was not specified. Therefore, I propose that the onset age of
epilepsy (mostly afebrile GTCS) and that of MASs are defined
independently, i.e., between 1 and 5 years, and between 2 and 5
years of age, respectively, because GTCS may develop at as young as
H. Oguni
Fig. 4. Ictal polygraph of ES causing drop attacks in a 4-year-old boy with right frontal focal cortical dysplasia. The video-polygraphic examinations revealed drop attacks caused by
spasms at SCM and abdominal muscles and simultaneous atonia at Deltoid, Biceps and paraspinal muscles associated with generalized biphasic sharp-slow discharges morpho-
logically different from the typical SWCs shown in Fig. 1.
Fig. 5. FLAIR MRI imaging (TR ¼ 3000, TE ¼ 60) and ECD-SPECT findings.
Brain MRI demonstrated huge FCD in the right frontal region, but the patient was
developmentally and neurologically normal before the onset of epilepsy.
1 year of age [30,37,40].
46
European Journal of Paediatric Neurology 36 (2022) 37e50
1.5. Associated seizure types
The most frequent associated seizures were GTCS in 60e100% of
the patients with EMAS [17,18,28,30,37]. GTCS with a brief tonic
component resembling generalized clonic seizures (GCS) or even
brief GCS resembling the repetition of massive myoclonic attacks
was noted [14]. Nocturnal GTCS or GTS may follow after the
cessation of MASs in some cases and are generally resistant to ASMs
[37]. Generalized tonic vibrating seizures with a few clonic com-
ponents were described in the late clinical course in those with an
unfavorable outcome [14,30].
Absence seizures corresponding to runs of generalized irregular
SWCs at 2e3 Hz were observed in 50e80% of the patients [18].
Although Doose himself excluded the presence of atypical absence
seizures in the 1992 definition, subsequent reports described the
presence of atypical absence seizures characterized by runs of <2.5-
Hz generalized SWCs [14]. On the other hand, the typical absence
seizures associated with runs of 3-Hz generalized SWCs were re-
ported in patients with DS or unclassified idiopathic myoclonic
epilepsies [54,55]. Therefore, the absence seizures seen in half of
H. Oguni
Fig. 6. Ictal polygraph of atonic seizures in a 2-year and 3-month-old boy with
GLUT1DS
When he was sitting on the bed, he suddenly dropped his head and recovered quickly.
The ictal polygraph showed generalized SWCs at 2 Hz corresponding to the sudden
brief interruption of ongoing EMG activity in the right trapezius and sternocleido-
mastoid muscles.
patients, typically with myoclonic jerks, facial myoclonia and atonia
(not just loss of awareness) in the diagnostic manual should be
reconsidered whether it is typical or atypical absence seizures.
Nonconvulsive status epilepticus (NCSE), described specifically
as the myoclonic status epilepticus, status of minor seizures, or
minor epileptic status, is characterized by prolonged clouding of
consciousness with random segmental myoclonus associated with
disorganized marked slow background EEG activity with random
SWCs, and was observed in 15e30% of patients with a mostly un-
favorable prognosis [14,17,37,40]. I propose that this seizure type is
Fig. 7. Atonic seizures in an 8-year-old boy with DEE
The polygraph showed the sudden interruption of ongoing EMG activity, which was more clearly visualized on the EEG associated with collapsing of the body forward (the black
arrow indicates the time when the video was captured). Ictal EEG was characterized by generalized flattening of background activity, often associated with epileptic spasms.
47
European Journal of Paediatric Neurology 36 (2022) 37e50
redesignated as atypical absence status with random myoclonic
components based on the forementioned clinical and EEG
characteristics.
1.6. EEG findings
1.6.1. Interictal EEG findings
Although the parietal theta rhythm is described as a character-
istic background EEG pattern affected by genetic predisposition, the
frequency of the background slow wave activity during the explo-
sive phase ranged from diffuse continuous delta and theta rhythms
in patients with mostly unfavorable outcomes to a typical parietal
theta rhythm in those with mostly favorable outcomes [18,35,37].
Although Doose and colleagues stressed the importance of this
parietal rhythm [9,28], whether it is specific to EMASs or also
observed in children with DEE or EE other than EMASs remains
unclear.
The interictal generalized SWCs are always described at 2e3 Hz
in the definitions, but few previous studies referred to the fre-
quency [17,18]. According to our experience with EMAS patients,
the frequency ranged from 1.5 to 2.5 Hz, meeting the definition of
slow SWCs [37](Fig. 8). As mentioned previously, the inclusion of
MEI and DS may have affected the definition of the spike-wave
frequency at 3 Hz. The presence of consistent focal spikes or
generalized SWCs with lateralized features strongly suggests a focal
cerebral pathology, which is against a diagnosis of EMASs.
The interictal EEG findings characterized by diffuse slow back-
ground activity associated with frequent generalized slow SWCs
sufficiently indicate the presence of EE. Further detailed interictal
EEG studies regarding the frequent activation of anomalies with
sequences of slow spike-waves and poly-spike waves in N-REM
sleep are necessary because long-term video-EEG examination is
not always available and the diagnosis of EMASs relies heavily on
history-taking and the interictal EEG findings in outpatient clinical
practice.
H. Oguni European Journal of Paediatric Neurology 36 (2022) 37e50

that the epilepsy type is nonspecific for either focal, multifocal or

generalized epilepsy and for etiology. Therefore, I propose that
EMAS is re-designated as genetic generalized epilepsy with MASs,
consistent with the large familial genetic study conducted by Doose
and colleagues [10] and the recent identification of candidate genes
(Table 3).

1.8. Genetic approach

Based on the high incidences of seizures and genetic EEG pat-

Fig. 8. Interictal sleep EEG in a 3-year and 8-month-old boy with EMASs. The interictal
sleep EEG showed generalized slow SWCs at 1.5e2 Hz without focal abnormality.
1.6.2. Ictal EEG
The polygraphic study of MASs showed that the myoclonic
component is associated with a generalized spike or polyspike and
the atonic component is associated with the after going high
voltage slow wave (Fig. 1). However, our most recent computer-
based morphometric study of MS and myoclonic-flexor seizures
in MASs suggested that the depth of positive sharp-component
rather than the height of negative sharp-component or the num-
ber of polyphasic spike components of generalized SWC may have
been a more important neurophysiological marker to generate
MASs [42]. Upon close examination, the muscular myoclonic
contraction and muscular silence on EMG in myoclonic-flexor sei-
zures and MAS, respectively, were time-locked to the positive-
sharp component rather than the following high-voltage slow
waves.
1.7. Is EMAS an appropriate term?
The nomenclature of “epilepsy with myoclonic-atonic seizures”
may result in confusion in its diagnosis. The presence of recurrent
drop attacks in children with epilepsy aged 2e5 years may lead to
an erroneous diagnosis of EMASs for non-experts simply because
the drop attacks themselves are a rare and striking phenomenon in
addition to being a hall mark of EMASs in this age range. Moreover,
the term “epilepsy” may lead to the erroneous idea for non-experts
terns in the relatives of EMAS patients, hereditary factors have been
considered for the etiology of EMAS [28]. Therefore, there have
been many molecular genetic studies on patients with EMAS. Most
were case reports, but a few studies included up to101 cases of
EMAS [24]. These studies revealed many candidate disease-causing
mutations, including SLC2A1, SLC6A1, CHD2, SCN1A, GABRG2,
—————, suggesting the genetic heterogeneity of EMAS
[24,25,56,57]. However, most patients with EMAS carrying muta-
tions had pre-existing intellectual disability [26] and EMAS diag-
nosis remained unclear or might not be justified [58]. In contrast,
Routier et al. investigated patients with EMAS who exhibited
normal development before the onset of epilepsy and identified
disease-causing mutations in 41% including CHD2, KCNT1, KCNA2
and STXBP1, but not SLC2A1 or SLC6A1 (the most frequent EMAS-
causing genes) [26]. These varying results may cause confusion in
searching for the underlying cause of this syndrome in future
studies. The first step is to define EMASs more clearly by evidence-
based electroclinical criteria.
2. Conclusion
EMASs is considered a unique age-dependent genetic epilepsy,
evolving to transient or long-lasting EE. The epileptogenesis of
EMASs peaks within 1 year after the explosive onset of GTCS, MASs
and NCSE resistant to ASMs. In more than two-thirds of patients,
this peak epileptogenesis gradually decreases over the subsequent
2e3 years when the seizures become more easily controlled or
remit spontaneously [37]. At present, the boundary of EMASs
among other myoclonic epilepsies and DEE is not clear when
referring to the original criteria of Doose and most updated ILAE
diagnostic manuals. In addition, the recent genetic studies have

Table 3
Genetic Generalized Epilepsy with Myoclonic-Atonic, Atonic, or Myoclonic-flexor Seizures (proposing modified criteria).

Overview, Sex, Development and cognition are the same as Table 1.

nset of epilepsy: 1e5 years

Onset of myoclonic-atonic, atonic or myoclonic flexor seizures: 2e5 years
Mode of onset: The explosive or stormy onset of GTCS, myoclonic-atonic, atonic or myoclonic-flexor seizures and/or other seizure types and rapid progression to transient
or long-lasting epileptic encephalopathy
Seizure type
Mandatory seizures: myoclonic-atonic, myoclonic-flexor or atonic seizures (potentially)* causing drop attacks (these 3 seizure types are abbreviated as MASs)
*It should be noted that MASs cause not only dropping on the floor but also head nodding depending on the intensity of the attacks
Associated seizure types: Febrile seizures and GTCS (>2/3 of cases), atypical absence seizures (50%), Atypical absence status with random myoclonic componentsa
(relatively common), Tonic seizures (linked to a higher frequency of cognitive impairment)
EEG
Ictal: MASs are associated with well-organized generalized spike- or polyspike-wave complexes. The atonic component (myoclonic-atonic or atonic type) and massive
myoclonic component (myoclonic-flexor type) are associated with a positive sharp wave component of the generalized spike- or polyspike-wave complex.
Interictal: The background exhibits diffuse slowing of background activity from q to d frequency bands often maximal at the centroparietal area, with generalized slow
spike-waves (2.5<) or polyspike-waves. Consistent focal or lateralized features are absent.
Genetics
Pattern of inheritance and Family history of seizures/epilepsy are the same as Table 1
Known genes
The minority of cases may be explained by variants in SCN1A.
Differential diagnosis:
Atypical benign partial epilepsy of childhood, frontal lobe epilepsy or DEE with ES-induced drop attacks, Lennox-Gastaut syndrome, Dravet syndrome, Myoclonic epilepsy
in infancy, Glucose transporter type 1 deficiency syndrome, Progressive myoclonus epilepsies (especially neuronal ceroid lipofuscinosis type 2)
a
Originally descried as nonconvulsive status epilepticus.

48
H. Oguni
cast a question on the discrete syndromic entity of EMASs which
appears to be a resurgence of 1970s debate about the nosological
independence of EMASs. I propose that the diagnostic criteria of
EMASs are modified as described above according to the accumu-
lated evidence. The electroclinical syndromes will continuously
change with newer electrophysiological and molecular techniques.
Furthermore, individuals diagnosed with the same syndrome may
exhibit different evolutions over time due to multiple variables and
previous diagnoses of electroclinical syndromes require critical re-
evaluation over time.
Declaration of competing interest
There are no conflicts of interest related to this manuscript.
Acknowledgements
I thank all pediatricians and medical staff of the Department of
Pediatrics at Tokyo Women's Medical University who participated
in the examinations and treatment of children with epilepsy with
myoclonic-atonic seizures. I read the journal's position regarding
issues pertaining to ethical publications and confirm that this
report is consistent with those guidelines. Disclosure of Conflict of
Interest: There are no conflicts of interest related to this manu-
script. I am grateful to the patients and their families for their
participation in this study.
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