Epilepsia, 53(1):79–86, 2012
doi: 10.1111/j.1528-1167.2011.03311.x

FULL-LENGTH ORIGINAL RESEARCH

Acute encephalopathy in children with Dravet syndrome*Akihisa Okumura, yMitsugu Uematsu, zGeorge Imataka, xManabu Tanaka, {Tohru Okanishi,#Tetsuo Kubota, **Akira Sudo, yyJun Tohyama, zzMegumi Tsuji, xxIori Ohmori, {{Misako Naiki,{{Ayako Hiraiwa-Sofue, ##Hitoshi Sato, ***Shinji Saitoh, and *Toshiaki Shimizu*Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan; yDepartment of Pediatrics, Tohoku University
School of Medicine, Sendai, Japan; zDepartment of Pediatrics, Dokkyo Medical University, Mibu, Japan; xDivision of Neurology,
Saitama Children’s Medical Center, Saitama, Japan; {Department of Pediatrics, Seirei-Mikatahara General Hospital, Hamamatsu,
Japan; #Department of Pediatrics, Anjo Kosei Hospital, Anjo, Japan; **Department of Pediatrics, Sapporo City General Hospital,
Sapporo, Japan; yyDepartment of Pediatrics, Nishi-Niigata Chuo National Hospital, Niigata, Japan; zzDivision of Neurology, ClinicalResearch Institute, Kanagawa Children’s Medical Center, Yokohama, Japan; xxDepartment of Physiology, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; {{Department of Pediatrics, Nagoya
University Graduate School of Medicine, Nagoya, Japan; ##Department of Pediatrics, Kanazawa Medical University School of
Medicine, Uchinada, Japan; and ***Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan

encephalopathy was monthly in seven children and nonein three. The median age at the onset of acute encephalopathy was 44 months (range 8–184 months). All children had status epilepticus followed by coma as theinitial manifestation. Two different distributions of brain
lesions were observed on diffusion-weighted images during the acute phase: cerebral cortex–dominant lesions
with or without deep gray matter involvement and subcortical-dominant lesions. Four children died; nine survived with severe sequelae, and two had moderatesequelae.
Significance: We must be aware that acute encephalopathy is an important complication in children with Dravet
syndrome, and associated with fulminant clinical manifestations and a poor outcome.
KEY WORDS: Dravet syndrome, Acute encephalopathy,
SCN1A, MRI.

SUMMARY
Purpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acuteencephalopathy in children with Dravet syndrome.
Methods: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patientswith clinically diagnosed Dravet syndrome, who had acuteencephalopathy, defined as a condition with decreased
consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with
infectious symptoms.
Key Findings: There were seven boys and eight girls.
A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute

Acute encephalopathy, characterized by noninflammatory
cerebral edema, implies sudden onset of severe central nervous system (CNS) symptoms such as convulsions followedby prolonged consciousness disturbance, and is often preceded by infection (Mizuguchi et al., 2007). In Japan, acuteencephalopathy during influenza, exanthema subitum, andother febrile illnesses has attracted the attention of pediatricneurologists and general pediatricians since the outbreak of
influenza-associated encephalopathy in the winter of 1997/
1998 (Morishima et al., 2002). The occurrence of acuteencephalopathy in children with Dravet syndrome has beenreported sporadically in Japan (Takayanagi et al., 2010). In
addition, we encountered several children with Dravet syndrome who had acute encephalopathy in association with afebrile illness. In addition, similar events have been reported
from the developed countries in Europe, North America,and Oceania (Berkovic et al., 2006; Chipaux et al., 2010;
Tang et al., 2011). Children with Dravet syndrome

Dravet syndrome is an epileptic syndrome characterized
by the following: an onset with prolonged seizures that areoften provoked by fever during early infancy, intractableseizures, repetitive episodes of status epilepticus (SE), and asubsequent decline in cognitive function (Dravet et al.,2005a). Fever sensitivity is an outstanding feature of Dravet
syndrome. SE can be provoked by a febrile illness and may
be followed by severe neurologic sequelae. Most patientswith Dravet syndrome have a mutation in the SCN1A gene,which encodes the voltage-dependent sodium channel(Nav1.1) a subunit (Claes et al., 2001).
Accepted September 14, 2011; Early View publication November 16,
2011.
Address correspondence to Akihisa Okumura, MD, Department of Pediatrics, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan. E-mail okumura@juntendo.ac.jp
Wiley Periodicals, Inc.
ª 2011 International League Against Epilepsy79

80
A. Okumura et al.
complicated by acute encephalopathy were presented in themailing list of the Annual Zao Conference on Pediatric Neurology. These children invariably had fulminant clinicalcourse and poor outcome. The need for research on this
topic was advocated.
We recruited children with Dravet syndrome who hadacute encephalopathy through the mailing list of the Annual
Zao Conference on Pediatric Neurology, to clarify the features of acute encephalopathy in children with Dravet syndrome. We present the results of a retrospective review of
15 patients.

Methods
We collected patients who met the following criteria
through the mailing list of the Annual Zao Conference on
Pediatric Neurology: clinical diagnosis of Dravet syndrome,a history of acute encephalopathy, and no evidence of direct
CNS infection, such as bacterial meningitis, severe metabolic derangement, or other systemic disorders that could
cause a reduction in consciousness. The mailing list of theAnnual Zao Conference includes >500 pediatric neurologists from all over Japan. In February 2010, the chief author(AO) announced the enrollment of the patients with Dravet
syndrome who had acute encephalopathy within the last
5 years. The chief author provided a structured researchform on the mailing list. The members of the mailing list
were asked to fill out the research form and to send it byemail to the chief author if they had potential subjects. We
did not request the responses from the members who did nothave any potential subjects or would have difficulty participating in this study for any reasons. The 16 potential subjects were reported to the chief author from 14 hospitals
until June 2010. After careful inspection of the chief author,
15 subjects were confirmed to meet the inclusion criteria.
These 15 patients were a subject of this study. The clinicalcourse of patient 11 was presented elsewhere as a casereport (Tsuji et al., 2011). The approximate number of thepatients with Dravet syndrome who were regularly followed
was available from 12 hospitals. According to these data,
acute encephalopathy was observed in 13 of approximately
170 children with Dravet syndrome. The number of patientswith Dravet syndrome in each hospital ranged from 2–56.
The clinical diagnosis of Dravet syndrome was madeaccording to the International League Against Epilepsy(ILAE) classification (Commission on Classification andTerminology of the International League Against Epilepsy,1989). In this study, Dravet syndrome was diagnosed if allof the following characteristics were present: onset in thefirst year of life with hemiclonic or generalized seizures,
frequent seizures provoked by fever, previously normal
development, evolution of generalized spike-wave discharges, refractory to antiepileptic treatment, and subsequent delay in psychomotor development. Children without
myoclonic seizures were included in the Dravet syndrome
Epilepsia, 53(1):79–86, 2012
doi: 10.1111/j.1528-1167.2011.03311.x

classification when they met all the characteristics
described in the preceding. Acute encephalopathy wasdefined principally as a condition characterized bydecreased consciousness with or without other neurologic
findings, such as seizures, involuntary movement, and delirious behavior, lasting for >24 h in children with infectious
symptoms including fever, cough, and diarrhea. However,barbiturate coma or continuous midazolam was administered in several patients. As to these patients, acute encephalopathy was diagnosed when prolonged coma was observed,
even after the discontinuation of these drugs.
This study was approved by the institutional review boardof Juntendo University Fac of Medicine. The patient’s data
were collected anonymously. Neuroimaging data were alsocollected after enrollment. We reviewed the clinical andneuroimaging features of the patients.
The outcomes of the patients were classified into the following four categories: mild sequelae (mild cognitive and/or
motor impairment), moderate sequelae (moderate cognitive
and/or motor impairment), severe sequelae (severe cognitive
and/or motor impairment), and death. The severity of thecognitive impairment was classified according to the intelligence quotient or development quotient as follows: mild,
51–70; moderate, 30–50; and severe, <30. Intelligence quotient or developmental quotient was measured using Tsumori-Inage Developmental Assessment Test, Enjoji Analytical
Development Test, KIDS Infant Development Scale, and Tanaka-Binet Intelligence Scales according to the age of thepatient and the preference of each hospital. A formal assessment was not performed in some patients with apparently
severe cognitive impairment. The severity of the motor
impairment was classified into three groups: mild, if thepatient could walk without support; moderate, if the patient
could sit without support but could not walk without support;
and severe, if the patient could not sit without support.

Results
Demographic data
The demographic data of the patients before the onset ofacute encephalopathy are shown in Table 1. There wereseven boys and eight girls. The onset of Dravet syndrome
ranged from 2–7 months of age. All but one child had a history of SE before the onset of acute encephalopathy. A mutation in the SCN1A gene was present in 9 of the 12 children
in whom a SCN1A mutation was examined, including multiplex ligation-dependent probe amplification: It was a truncation mutation in six children and a missense mutation inthree. Myoclonic seizures were recognized in 14 children.
Cognitive impairment before the onset of acute encephalopathy was absent in three children, mild in three, moderate inseven, and severe in two. The frequency of seizures during
the 3 months before the onset of acute encephalopathy wasmonthly in seven children and none in three. Five children
had histories of one or more episode of SE and three had a81
Dravet Syndrome and Encephalopathy
Table 1. Demographic features
Szs during 3 months before
HistoryCIthe onset of AE
Onset of DS
of status Myoclonic before thePatient Sex (months) SCN1A mutation epilepticus
Sz
onset of AE Frequency Cluster Status
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

M
F
M
F
F
F
M
F
F
F
F
M
M
M
M

6
3
3
4
7
3
2
4
5
6
5
4
4
5
4

IVS 26-2 A>C
L929del fsX934
R568X
K1846fsX1856
IVS4+1G>A
R701X
A1339V
Y145H
V1630L
None
None
None
Not doneNot doneNot done10
Several
3
15
Several03214Frequent
3
2
1
7

No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Moderate
Moderate
Moderate
Moderate
None
None
Mild
Moderate
Mild
Moderate
Moderate
None
SevereSevere
Mild

None
Daily
Monthly
WeeklyMonthly
None
Monthly
WeeklyNone
WeeklyMonthlyMonthly
WeeklyMonthlyMonthly

0
0
0
0
0
0
1
0
0
1
0
0
1
0
0

0
0
0
1
1
0
0
0
0
0
4
2
0
0
4

AED at the onset of AE
VPA, CLB, KBr
VPA, CLB, CZP, KBr, ZNS, LTG
VPA, CZP, KBr
VPA, ZNS, CLB
VPA, CZPVPA, CZP, PB
VPA, ZNS, PB
VPA, CZPVPA, CLB, KBr
VPA, CLB, PB, TPM
VPA, CZP
VPA
VPA, CLB, PRM, SLT, AZA, ESM, CLZ
VPA, ZNS, NZP
VPA, CLB, ZNS

DS, Dravet syndrome; Sz, seizure; CI, cognitive impairment; AE, acute encephalopathy; SE, status epilepticus; VPA, valproate; CLB, clobazam; PB, phenobarbital;
TPM, topiramate; PRM, primidone; SLT, sulthiame; AZA, acetazolamide; ESM, ethosuximide; CLZ, clorazepate; ZNS, zonisamide; NZP, nitrazepam; CZP, clonazepam; KBr, potassium bromide; LTG, lamotrigine.

Table 2. Acute encephalopathy and outcome
Duration of
Onset of AE Prodromal
SE at thePatient (months)
illness
Pathogen onset of AE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

38
153
53
45
13
13
16
27
45
61
15
8
92
184
43

URI
URI
Flu
URI
Subitum
NSFI
Subitum
URI
URI
URI
URI
URI
URI
URI
NSFI

ND
ND
Flu A
ND
HHV-6
ND
ND
ND
ND
ND
ND
RSV
ND
ND
ND

40 min1h
4h
50 min
1h
3h
4h
1.5 h
50 min
2h
2h
1h
1h
1h
5h

OutcomeTreatment for
the initial SEa
DZP
TP (2)DZP (2), PHT, TL, MDZ
DZP, MDZMDZ
DZP, MDZ, PHT, PTB, TP
TL, MDZ (2), PB
DZP, MDZ
DZP, MDZ
MDZ (2), DZP (2)DZP, MDZ, TL
DZP (3), MDZ (3)DZP
DZP (2), MDZ (4)DZP, MDZ, PB, TP

Maximum Neurologic CognitiveMotor
Sz frequency
LOC
sequelae impairment impairment after recovery
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma
Coma

SevereSevereDeath
SevereSevereDeathModerate
SevereModerate
SevereSevereSevereSevereDeath
Death

SevereSevereSevereSevere

None
None

SevereSevereSevereSevere

None
None

Mild
SevereModerate
SevereSevereSevereSevereModerate
SevereNone
SevereSevereSevereMild

Monthly
None
Monthly
None
None
MonthlyMonthly

AE, acute encephalopathy; LOC, loss of consciousness; Sz, seizure; Flu, influenza; URI, upper respiratory tract infection; Subitum, exanthema subitum; NSFI,
nonspecific febrile illness; HHV-6, human herpesvirus 6; RSV, respiratory syncytial virus; DZP, diazepam; MDZ, midazolam; PB, phenobarbital; PHT, phenytoin;
PTB, pentobarbital; TL, thiamylal; TP, thiopental.
a
The AEDs until the cessation of SE are shown according to the order of administration. The numbers in the brackets indicate the number of the doses for eachpatient, when two or more doses were administered.

history of cluster seizures during the 3 months before theonset of acute encephalopathy. All children had been treatedwith antiepileptic drugs (AEDs), such as valproate, benzodiazepines, and bromide.
Acute encephalopathy
The clinical manifestations of the acute encephalopathy
are shown in Table 2. The median age at the onset of acuteencephalopathy was 44 months (range 8–184 months).

Eleven children were younger than 5 years of age, whereas
two were older than 10 years. All children had a febrile illness before the onset of acute encephalopathy. A pathogen
was identified in three children: influenza A in one, humanherpesvirus 6 in one, and respiratory syncytial virus in one.
Rapid antigen test for influenza was negative in the otherfour children.
Neurologic findings of acute encephalopathy were characterized by a fulminant clinical course with SE and severe
Epilepsia, 53(1):79–86, 2012
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82
A. Okumura et al.
loss of consciousness. All children had SE followed bydeep coma as the initial manifestation of acute encephalopathy. The duration of SE ranged from 40 min to 5 h.
Although AEDs were administrated without a delay in amanner similar to that with the previous events with SE in
most patients, seizures were refractory and persisted for
1 h or longer in 12 patients. More than two doses of AEDs
were necessary to control SE in 12. Deep coma was seen
following SE in all patients, even when seizures were controlled with one dose of AEDs. The loss of consciousness
persisted for 2 weeks or longer in 13 children. Seizures
were observed in all children on the first day, in seven on
the second day, and in four on the third day. Thereafter, seizures were observed in only two children during the courseof the acute encephalopathy. Although SE was seen on thefirst day in all patients, it was subsequently seen in only
two children during the course of the acute encephalopathy.
Delirious behavior was not seen in any child. No child had
a biphasic clinical course: that is, an onset with SE, transient recovery of consciousness, and late clustering seizures
with a worsening of consciousness. Despite the severe neurologic symptoms, serious systemic circulatory failure was
not seen during the first few days after onset in any but one
patient (Patient 15), even in those who died later. Vitalsigns such as heart rate, oximetry, blood pressure, and urine
output were continuously monitored in all patients. Mildand transient hypotension was observed in some patients

and was treated appropriately with catecholamine and volume expander.
The laboratory examinations on admission revealed
thrombocytopenia (platelet count <10.0 · 104/ll) in five(33%). Elevated levels of aspartate transaminase (>100
IU/L), alanine transaminase (>80 IU/L), lactate dehydrogenase (>600 IU/L), and creatine kinase (>400 IU/L) were
present in seven (47%), three (20%), seven (47%), and three(20%), respectively. Elevated blood urea nitrogen (>20 mg/dl) and creatinine (>1.0 mg/dl) were seen in three (20%)
and three (20%), respectively. Hypoglycemia (blood glucose <40 mg/dl) was not observed in any child, but hyperglycemia (blood glucose >200 mg/dl) was seen in three(20%). An elevated serum ammonia level was not seen in
any child, whereas metabolic acidosis was present in six
children (40%).
The neuroimaging findings are summarized in Table 3.
Neuroimaging examinations were performed in 12 children
during the first week. Three of them underwent computed
tomography (CT) on the second day of illness, and marked
brain edema was seen in all three. Magnetic resonanceimaging (MRI) was performed in nine children and abnormal findings were seen in seven children. Two different
distributions of brain lesions were observed on diffusionweighted images: cerebral cortex-dominant lesions with orwithout deep gray matter involvement (Fig. 1A–D) andsubcortical-dominant lesions (Fig. 1E,F). Five patients

Table 3. Neuroimaging findings
Acute phase

Recovery phase

Patient

Days after
AE onset

Neuroimaging findings during theacute phase

Days after
AE onset

Neuroimaging findings during
the recovery phase

1
2

6
0

HIA in cerebral cortex, and caudate and lentiform nuclei on DWINo abnormalities on MRI

31
10

Diffuse atrophy on MRIHIA in cerebral cortex and corpus
callosum on DWI4HIA in cerebral cortex, caudate nuclei, thalami,and cerebellum on DWI
Not done
HIA in cerebral cortex and subcortical WM on DWIHIA in cerebral cortex, lentiform nuclei, andthalami on DWIMarked brain edema on CT
No abnormalities on MRI
Marked brain edema on CT
HIA in subcortical WM on DWI
Not doneNot done
HIA in subcortical WM on DWINo abnormalities on MRIHIA in cerebral cortex, thalami, and cerebellum
on DWI
Marked brain edema on CT

3
4
5

0
0

6
7
8
9
10
11
12
13
14

1
0
1
0

15

1

3
1
1

14
34

7
68
13
19
21
21
33

Not done
Diffuse atrophy on MRI
Diffuse atrophy on MRI
Not done
Mild atrophy on MRI
Diffuse atrophy on MRI
Mild atrophy on MRI
Mild atrophy, striatal necrosis on MRI
Diffuse atrophy on MRI
Diffuse atrophy on MRI
Diffuse atrophy on MRI
Not doneNot doneAE, acute encephalopathy; HIA, high intensity areas; WM, white matter; DWI, diffusion-weighted images; CT, computed tomography; MRI, magnetic resonanceimaging.

Epilepsia, 53(1):79–86, 2012
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83
Dravet Syndrome and Encephalopathy

Figure 1.
Diffusion-weighted images. (A, B)
Patient 15, 1 day after the onset ofacute encephalopathy. Abnormalhigh intensities were observed in the
cerebral cortex, thalami, andcerebellar hemispheres. (C) Patient
1, 6 days after the onset of acuteencephalopathy. Abnormal highintensities were seen in the cortex
in the frontotemporal regionbilaterally and the caudate andlentiform nuclei bilaterally.
(D) Patient 5, on the day of onset ofacute encephalopathy. Abnormalhigh intensities were present in thecortex in the temporal-parietaloccipital region bilaterally. Slightly
high intensities were also
recognized in the cortex in thefrontal region bilaterally. (E) Patient
12, 3 days after the onset of acuteencephalopathy. Abnormal highintensities were seen in the entire
subcortical white matter. (F) Patient
9, the day of the onset of acuteencephalopathy. Abnormal highintensities were observed in thesubcortical white matter in thefrontal and mesial occipital regions
bilaterally.
Epilepsia ILAE

A

B

C

D

E

F

(Patients 1, 2, 4, 5, and 14) had cerebral cortex-dominantlesions. In addition to cortical lesions, caudate lesions wereobserved in two children, lentiform nuclei lesions in two,thalamic lesions in three, and cerebellar lesions in two. In
three children, these lesions were present within the first 2
days after the onset. Two patients (Patients 9 and 12) had
subcortical-dominant lesions: One patient had diffusion
abnormalities in the entire subcortical white matter and theother had bilateral frontal lesions. No child with subcortical-dominant lesions had deep gray matter involvement.

Among six children with cerebral cortex–dominant lesions,four had truncation mutations and one had no SCN1A
mutation. SCN1A mutation was not assessed in the othertwo children. As to the two children with subcortical-dominant lesions, one had a missense mutation and the other
had no SCN1A mutation. MRI after recovery from theacute encephalopathy was performed in 11 children.
Marked, diffuse atrophy of the cerebral hemispheres wasobserved in seven children and mild atrophic changes in
the other four.
Epilepsia, 53(1):79–86, 2012
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84
A. Okumura et al.
Regarding treatment, barbiturate coma was administeredin 7 children and continuous midazolam infusion in 12 during the clinical course. Phenobarbital and phenytoin wereused in two and three children, respectively. Artificial ventilation was required in 12 children. Steroid pulse therapy
was performed in eight, steroid other than pulse therapy infour, and intravenous immunoglobulin in five. Selective orsystemic hypothermia was applied in four children.
The outcome in these children was invariably poor
(Table 2). Four children died; nine survived with severe
sequelae and two had moderate sequelae. All but one surviving child had moderate or severe cognitive impairment, andnine had moderate or severe motor impairment. In contrast,
the seizure frequency after recovery was reduced, comparedwith that before the onset of acute encephalopathy in mostsurviving patients. Seven children had no seizures after
recovery and four had monthly seizures. Although no statistical analysis was performed because of the small number ofchildren, the outcome was relatively worse in children witha truncation mutation than in those with a missense mutation. Of six children with truncation mutations, two died andthe other four survived with severe sequelae. Of three children with missense mutations, moderate sequelae were seenin two and severe sequelae in one. Three children without
SCN1A mutations had severe sequelae.

Discussion
Our study revealed that acute encephalopathy can be an
important complication of Dravet syndrome. A catastrophic
clinical course is the outstanding feature of acute encephalopathy in children with Dravet syndrome. Some authors
have recently reported children with Dravet syndrome
accompanied by acute encephalopathy (Chipaux et al.,2010; Takayanagi et al., 2010; Tang et al., 2011). The clinical course of these patients is characterized by severe SE,
followed by massive neurologic regression and marked
brain atrophy. These features are similar to those in ourpatients. Sakauchi et al. (2011) conducted a questionnaire
survey on the causes and prevalence of deaths related to
Dravet syndrome. They reported that acute encephalopathy
with SE was the cause of mortality in 21 (36%) of 59
patients who died. Berkovic et al. (2006) found de novo
mutations of SCN1A in 11 of 14 children with alleged vaccine encephalopathy. These patients may have had acuteencephalopathy, like our patients. Moreover, Kobayashi
et al. (2010) performed a mutational analysis of SCN1A in
15 children with various types of acute encephalopathy.
A missense SCN1A mutation was detected in a patient witha history of acute encephalitis with refractory, repetitive
partial seizures. These facts suggest that Dravet syndromeor SCN1A mutation may be a genetic predisposition of acuteencephalopathy induced by infection.
We considered the catastrophic neurologic conditions in
our patients as acute encephalopathy rather than severe SE,
Epilepsia, 53(1):79–86, 2012
doi: 10.1111/j.1528-1167.2011.03311.x

although it is well known that pyrexia can cause SE leading
to severe neurologic sequelae or even death in children with
Dravet syndrome (Oguni et al., 2001; Dravet et al., 2005a).
The SE triggered by fever in children with Dravet syndrome
is not usually followed by severe neurologic deterioration(Oguni et al., 2001; Dravet et al., 2005a,b). Postictal motor
deficit may be observed in some patients after SE, but motor
function usually recovers within a few hours. In contrast,
our patients were characterized by severe neurologic deterioration and marked brain lesions on MRI. These neuroimaging abnormalities are distinct from those reported in Dravet
syndrome including temporal sclerosis, nonspecific atrophic changes, and increased intensities in the white matter(Oguni et al., 2001; Dravet et al., 2005b; Siegler et al.,2005; Striano et al., 2007). Hypoxic ischemic damage inassociation with systemic circulatory failure may explain
the widespread brain lesions. However, serious hypoxia
and/or systemic circulatory failure were not observed in any
but one patient during the first few days. On the other hand,
SE and prolonged impairment of consciousness are coreneurologic symptoms of acute encephalopathy induced by
infectious diseases (Togashi et al., 2004; Nagao et al.,2008; Wada et al., 2009). Diffusion abnormalities on MRI
are often observed in children with acute encephalopathy,
even without serious hypoxia or systemic circulatory failure(Takanashi et al., 2006; Okumura et al., 2009). On the basisof these observations, we considered that the SE in ourpatients will be derived from acute encephalopathy in itself
from the start of seizures, not from epilepsy.
We found two different patterns of diffusion abnormalities on MRI in our cohort: reduced diffusion in the cortex
and deep gray matter and that in the subcortical white matter. The distribution of the diffusion abnormalities was
unique in patients with cortical and deep gray matter
involvement. Thalamic involvement is a remarkable featureof acute necrotizing encephalopathy (Mizuguchi, 1997).
However, diffusion abnormalities of the cortex have notbeen reported in children with acute necrotizing encephalopathy. Studies of scn1a mRNA expression in mice haveshown that scn1a mRNA is highly expressed in the thalami,
deep cerebral nuclei, pons, medulla, and spinal cord (Ogiwara et al., 2007). The involvement of the caudate nuclei andputamen may be explained by high expression of the mutant
SCN1A. Reduced diffusion in the subcortical white matter
was observed in two of our patients. The distribution of diffusion abnormalities resembled that of acute encephalopathy with biphasic seizures and late reduced diffusion(AESD), proposed by Takanashi et al. (2006; Takanashi,2009). However, biphasic clinical course, that is an
outstanding feature of AESD, was not recognized in any ofour patients. The different clinical manifestations despite
similar MRI findings are difficult to explain at present.
The precise incidence of acute encephalopathy amongchildren with Dravet syndrome is not easy to determine. In
our study, 13 of approximate 170 children with Dravet

85
Dravet Syndrome and Encephalopathy
syndrome had acute encephalopathy. Although this result
can be largely overestimated, the incidence of acute encephalopathy among children with Dravet syndrome will be
more frequent than that among general children. It is estimated that acute encephalopathy develops in 500–1,000
among 17 million children every year in Japan. These facts
indicate that children with Dravet syndrome will be at anincreased risk for acute encephalopathy.
It is remarkable that the seizure frequency before theonset of acute encephalopathy was relatively low in a majority of our patients. Three children had no seizures and sevenhad monthly seizures during the 3 months before the onsetof encephalopathy. Given the refractory nature of Dravet
syndrome, antiepileptic drug treatment was appropriate in
our patients because of lower seizure frequency. We must
be aware that acute encephalopathy can develop in children
with Dravet syndrome unexpectedly, even if the seizures arewell controlled by AEDs.
The neuroimaging findings and the severity of thesequelae in our children may be related to the type of
SCN1A mutation, although statistical analyses could not
be performed because of the small sample size. Children
with truncation SCN1A mutations tended to have cerebral
cortex–dominant lesions and a poor outcome. Those withno mutation or a missense mutation tended to have subcortical-dominant lesions with a relatively favorable outcome.
This suggests that children with a truncation SCN1A mutation may develop more severe acute encephalopathy.
There is an ongoing controversy on the genotype–phenotype correlation of SCN1A mutations. Further studies withmore patients are necessary to clarify the relationshipbetween the type of SCN1A mutation and the severity ofacute encephalopathy.
Recent genetic studies have revealed that the mutation in
the PCDH19 gene encoding protocadherin 19 is present insome female patients with Dravet syndrome (Depienne
et al., 2009; Marini et al., 2010). The patients with Dravet
syndrome with PCDH19 mutations share most of the hallmark features of Dravet syndrome with SCN1A mutation
including early onset, seizures provoked by fever, frequentSE, and stagnation of development (De Jonghe, 2011). The
relation between acute encephalopathy and PCDH19 mutation will be a subject of future studies.
Fever-induced refractory epileptic encephalopathy inschool-aged children (FIRES) is a recently proposed clinicalentity (Nabbout et al., 2011). Acute phase of FIRES is characterized by seizures rapidly aggravating into SE a few days
to 1 week after febrile illness. Severe seizures and poor outcome are similar between FIRES and acute encephalopathy
in children with Dravet syndrome. However, there are somedifferences between these two conditions. Onset in mostchildren with FIRES is after fever had disappeared, whereas
onset of encephalopathy is usually associated with fever inchildren with Dravet syndrome. Although repeated seizures
up to 100 per day are common in children with FIRES, along seizure refractory against AEDs is characteristic inacute encephalopathy in children with Dravet syndrome.
FIRES usually occurs in previously healthy children, but adelay in psychomotor development is not uncommon priorto acute encephalopathy in children with Dravet syndrome.
Therefore, these two clinical entities will be distinguishable.
In conclusion, we reviewed the clinical and neuroimaging
features of acute encephalopathy in 15 children with Dravet
syndrome. The acute encephalopathy was characterized byfulminant manifestations with SE and subsequent deepcoma. Diffusion-weighted images revealed two different
patterns of brain lesions: cerebral cortical–dominant lesions
and subcortical-dominant lesions. The outcome was mostly
poor, with death or severe neurologic sequelae.

Acknowledgments
This study is supported by the grants from the Ministry of Health,Labour, and Welfare of Japan (H21-Shinkou-Ippan-010 and H22-NanjiIppan-049), and the grants from the Ministry of Education, Culture, Sports,
Science and Technology of Japan (20249053 and 23591518).

Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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