Brain & Development 31 (2009) 221–227
www.elsevier.com/locate/braindev

Original article

Outcome of acute necrotizing encephalopathy in relation
to treatment with corticosteroids and gammaglobulin
Akihisa Okumura a,*, Masashi Mizuguchi b, Hiroyuki Kidokoro c,d, Manabu Tanaka e,
Sinpei Abe a, Mitsuaki Hosoya f, Hideo Aiba g, Yoshihiro Maegaki h, Hitoshi Yamamoto i,
Takuya Tanabe j, Eiko Noda k, George Imataka l, Hirokazu Kurahashi d,ma

Department of Pediatrics, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8655, Japanc
Department of Pediatrics, Anjo Kosei Hospital, 28 Higashihirokute, Anjo, Aichi 446-8602, Japand
Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japane
Division of Neurology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku, Saitama-city, Saitama 339-8551, Japanf
Department of Pediatrics, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima 960-1295, Japang
Division of Pediatric Neurology, Shizuoka Children’s Hospital, 860 Urushiyama, Shizuoka 420-8660, JapanhDivision of Child Neurology, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japani
Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Japanj
Division of Pediatrics, Hirakata Municipal Hospital, 2-14-1 Kinyahonmachi, Hirakata, Osaka 573-1013, Japank
Department of Pediatrics, Nagoya Daini Red Cross Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya 466-8650, Japanl
Department of Pediatrics, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japanm
Department of Pediatrics, Fukuoka University School of Medicine, 7-5-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japanb

Received 24 October 2007; received in revised form 1 March 2008; accepted 21 March 2008

Abstract
Objective. To examine the relation between outcome and treatment with steroids and gammaglobulin in children with acutenecrotizing encephalopathy. Methods. We retrospectively evaluated the clinical course and outcome of 34 children with acute necrotizing encephalopathy. They were divided into two groups; 17 patients with brainstem lesion and 17 patients without brainstem
lesion. Early steroid use was deﬁned as when steroids were administered within 24 h after the onset. The outcome was judged as
good when a patient had no or mild cognitive impairment and poor when a patient had more severe sequelae, or died. Results.
Among patients without brainstem lesions, the outcome was good in 7 of 12 with early steroid, whereas it was poor in all 5 patients
without early steroid. There was no signiﬁcant diﬀerence in sex, age, and laboratory data between patients with and without earlysteroid. The outcome was not correlated with gammaglobulin treatment. As to patients without brainstem lesions, the outcome was
not correlated with early steroid or gammaglobulin treatment. Conclusions. Steroid within 24 h after the onset was related to better
outcome of children with acute necrotizing encephalopathy without brainstem lesions. Early steroid treatment will be an important
option of the treatment for acute necrotizing encephalopathy.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Acute necrotizing encephalopathy; Outcome; Steroid; Brainstem lesion

1. Introduction*

Corresponding author. Tel.: +81 3 3813 3111; fax: +81 3 5800
1580.
E-mail address: okumura@med.juntendo.ac.jp (A. Okumura).
0387-7604/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2008.03.005

Acute necrotizing encephalopathy (ANE) is awell-deﬁned type of acute encephalopathy described by222

A. Okumura et al. / Brain & Development 31 (2009) 221–227

Mizuguchi et al. [1–3]. The most prominent feature of
ANE is the presence of multiple, symmetric brain lesions
in the bilateral thalami and other speciﬁc brain regions
including periventricular white matter, internal capsule,putamen, upper brain stem tegmentum, and cerebellar
medulla, demonstrated by CT or MRI. The onset of
ANE is triggered by acute febrile diseases, mostly viral,among which inﬂuenza is the most common [2,4]. ANE
is often observed among infants and children, but occasional adult cases have also been reported [1,5,6].
Although ANE is common in Japan and Taiwan [2],several reports on ANE have been made from some
European and American countries [7–9].
ANE is often associated with severe neurologicalsymptoms. Onset of ANE occurs during the earlyfebrile period of viral infection and runs a fulminantcourse with rapid development of coma. The neurological outcome of ANE has been reported to be very
poor. According to Mizuguchi, among 51 children
with ANE, 14 children died, and 20 survived withmoderate or severe neurological deﬁcit [2]. Only 17of them survived with no or mild neurological sequelae[2].
Several authors have suggested that hypercytokinemia is closely related to the development of ANE.
Patients with ANE often have signs of systemic inﬂammatory response syndrome such as shock, multiple
organ failure, and disseminated intravascular coagulation. An association of hemophagocytic syndrome has
been reported [10]. These facts indicate that macrophageactivation and hypercytokinemia will be participated in
the pathogenesis of ANE.
There have been no reports on the treatment against
ANE. We postulated that anti-inﬂammatory treatment
can be eﬀective for ANE, if the development of ANE
is attributable to systemic inﬂammatory response. We
conducted a retrospective study in order to examine
the eﬃcacy of anti-inﬂammatory treatment including
steroids and gammaglobulin.
2. Patients and method
We retrospectively evaluated the clinical course andoutcome of 38 children with ANE recruited from 17
hospitals. We included all patients with ANE who wereserially experienced in each hospital. The diagnosis of
ANE was made on the basis of neuroradiological ﬁndings according to the criteria proposed by Mizuguchi
et al. [2,3]. In this study, we included patients with acuteencephalopathy who had multiple focal lesions whichwere symmetrically distributed in the bilateral thalami
and other brain regions such as the putamina, cerebral
and cerebellar white matter, and brainstem tegmentum[2,3,11]. We excluded the patients with marked metabolic derangement such as elevated lactate, pyruvate,amino acids, or organic acids levels.

We excluded 4 patients from the study, who were critically ill with severe systemic hypotension and/or multiorgan failure on or within a few hours after admission,
because the eﬃcacy of the drug was diﬃcult to evaluate
in these patients. They all died within a few days after
the onset of ANE. Eventually, the remaining 34 patientswere the subject of this study. There were 19 boys and 15
girls. Their median age was 28 months (range, 9–86 months). One patient had a past history of febrile seizure. Five patients had developmental delay before theonset of ANE. None had a prior history of epilepsy.
We assessed the detailed clinical course on the basisof the medical record. The prodromal illness was virologically proven inﬂuenza in 11, respiratory illness in
14, gastrointestinal illness in 5, exanthem subitum in 1
and undetermined due to insuﬃcient information in 3.
Before the onset of ANE, acetaminophene was used in
12 patients and mephenamate in 5. All patients had
severely impaired consciousness and seizure.
Laboratory data were also assessed from the medical
records. In this study, the following values were investigated: platelet counts, aspartate aminotransferase, alanine
aminotransferase,lactatedehydrogenase,creatinine kinase, and protein in cerebrospinal ﬂuid.
Mizuguchi et al. reported that these values may correlate
the outcome of patients with ANE [2,12]. No patients
had elevated serum ammonia levels and pleocytosis in
the cerebrospinal ﬂuid.
We divided the 34 patients into two groups according
to the presence or absence of brainstem lesions on CT
and/or MRI, because the presence of brainstem lesions
is considered to be closely related to poor outcome asreported in previous reports [12]. Brainstem lesion waspresent in 17 patients and was recognized on the ﬁrst
CT in all of them (Fig. 1).
As to the treatment, we paid an attention to steroids
and gammaglobulin. Early steroid use was deﬁned aswhen steroids were administered within 24 h after the
onset of ANE. In our cohort, steroid was used in two regimens: steroid pulse therapy or intravenous dexamethasone. In case with steroid pulse therapy, 30 mg/kg ofmethylprednisolone was administered for 3 days. As to
intravenous dexamethasone, 0.6 mg/kg of dexamethasone was administered in 4 divided doses for 2–4 days.
Gammaglobulin was administered at a dose of 1–2 g/kg.
Antiepileptic drugs were administered in all patients.
We divided the outcome of the patients into twogroups; good and poor outcome. Nine patients had
good outcome. Six of them had no neurological sequelae
and three had mild cognitive impairment (intelligence ordevelopment quotient 50 6 70) without obvious motor
impairment. The other 25 patients had poor outcome.
Ten of them died, 12 had severe cognitive impairment(intelligence or development quotient <30) with marked
motor impairment (all of them could not stand with support), and three had moderate cognitive impairment

A. Okumura et al. / Brain & Development 31 (2009) 221–227

223

Fig. 1. CT ﬁndings. Upper: 21-month-old boy with brainstem lesions. Low density areas are observed in the upper brain stem tegmentum andcerebellar medulla as well as bilateral thalami. Lower: 35-month-old boy without brainstem lesions. Low density areas are present in bilateralthalami, whereas no low density areas are recognized in the brainstem.

(intelligence or development quotient 30 6 50) withvarious degree of motor impairment.
Statistical analyses were performed by means of theMann–Whitney U test for numerical variables and theFisher exact probability test for categorical variables.
A p value <0.05 was considered to be statisticallysigniﬁcant.
3. Results
3.1. Patient characteristics
Patient characteristics in each group were shown in
Table 1. The age, sex, a history of febrile seizure or developmental delay was not signiﬁcantly diﬀerent between
those with and without brainstem lesions. The use of
acetaminophene or mephenamate was not diﬀerent
between the two groups. No laboratory data showed astatistically signiﬁcant diﬀerence between the two groups.

3.2. Patients without brainstem lesions
In this group, outcome was good in 7 patients andpoor in 10. Among 7 patients with good outcome, 6
patients had no sequelae and the other had mild cognitive impairment. Among 10 patients with poor outcome,moderate cognitive impairment was observed in 1,
severe cognitive impairment with marked motor impairment in 7, and death in 2.
Steroid was administered in 14 patients. Early steroid was given to 12 of them. Steroid was used on
the third day in the remaining 2 patients. Steroid
pulse therapy was performed in 3 patients, within
24 h after the onset. Gammaglobulin was administeredin 5 patients.
The relation between therapy and outcome was summarized in Table 2. In 12 patients with early steroid, theoutcome was good in 7 and poor in 5. In contrast, theoutcome was poor in all 5 patients in whom steroid

224

A. Okumura et al. / Brain & Development 31 (2009) 221–227

Table 1
Patient characteristics
With brainstem lesions (n = 17)

Without brainstem lesions (n = 17)

Male:female
Age (months)

7:10
34 (9–86)

12:5
25 (11–67)

NS
NS

Past history
Febrile seizure
Development delay

0
3

1
2

NS
NS

Predromal illness
Inﬂuenza
Respiratory illness
Gastrointestinal illness
Exanthem subitum
Not determined

6
6
2
0
3

5
8
3
1
0

Not done

Antipyretics
Acetaminophene
Mephenamate

3
4

9
1

NS
NS

Laboratory data
Minimum Plt (104/ll)
Maximum AST (IU/l)
Maximum ALT (IU/l)
Maximum LDH (IU/l)
Maximum CK (IU/l)
CSF cell count (/ml)
Protein (mg/dl)

12.7 (0.3–34.7)
397 (56–29,520)
171 (19–16,510)
1160 (472–52,480)
1020 (61–18,630)
1 (0–6)91 (8–1060)

10.5 (3.9–22.1)
427 (71–18,088)
414 (41–12,300)
1386 (315–16,933)
509 (103–53,263)
2 (0–6)59 (9–380)

NS
NS
NS
NS
NS
NS
NS

Plt, platelet counts; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK, creatinine kinase; CSF,
cerebrospinal ﬂuid.

was not administered within 24 h after the onset. Statistical analysis revealed that good outcome was more
often in patients with early steroid use. On the other
hand, the outcome of patients was not correlated withsteroid use, steroid pulse therapy, or gammaglobulin.
Major adverse eﬀects of steroids or gammaglobulin were
not recognized in any patients.
Between patients with and without early steroid, neither sex, age, nor laboratory data showed a signiﬁcantdiﬀerence in any items (Table 3).
Table 2
Therapy and outcome in patients without brainstem lesions
OutcomeSteroid use(n = 14)

No steroid(n = 3)

Good
Poor

7
7

0
3

Good
Poor

Early steroid(n = 12)7
5

No early steroid(n = 5)
0
5

Good
Poor

Steroid pulse(n = 3)2
1

No steroid pulse(n = 14)
5
9

Good
Poor

Gammaglobulin use(n = 5)2
3

No gammaglobulin(n = 12)5
7NS, not signiﬁcant.

NS

p = 0.044

NSNS

3.3. Patients with brainstem lesion
In this group, outcome was good in 2 patients andpoor in 15. Two patients with good outcome had mild
cognitive impairment. Among 15 patients with pooroutcome, moderate cognitive impairment was recognized in 2, severe cognitive impairment with marked
motor impairment in 5, and death in 8.
Steroid was administered in 12 patients. Early steroid
was given to 9 of them. Steroid pulse therapy was performed in 3 patients, within 24 h after the onset in 2of them. Gammaglobulin was administered in 3
patients. Major adverse eﬀects of steroids or gammaglobulin were not seen.
The relation between therapy and outcome was summarized in Table 4. The outcome of patients was notcorrelated with steroid use, early steroid use, steroid
pulse therapy, or gammaglobulin.
4. Discussion
This is the ﬁrst study that revealed the eﬃcacy ofearly steroid against ANE. The outcome of patientstreated with early steroid was better than those without
early steroid, if the patients did not have brainstem
lesions. The results of our study highlighted the importance of early treatment for children with ANE. The
early diagnosis of ANE will not be diﬃcult in mostpatients, because CT or MRI demonstrates characteris-A. Okumura et al. / Brain & Development 31 (2009) 221–227

225

Table 3Comparison between the patients with or without early steroid
Early steroid (n = 12)

No early steroid (n = 5)

Male:female
Age (months)

9:3
26.5 (11–58)

3:2
15 (11–67)

NS
NS

Laboratory data
Minimum Plt (104/ll)
Maximum AST (IU/l)
Maximum ALT (IU/l)
Maximum LDH (IU/l)
Maximum CK (IU/l)
CSF protein (mg/dl)

10.5 (3.9–22.1)
395 (71–18088)
321 (41–10472)
1220 (315–16933)
642 (103–8400)
57 (9–299)

9.9 (4.9–13.0)775 (95–11480)
940 (54–12300)
1681 (710–7501)
481 (218–53263)
94 (37–380)

NS
NS
NS
NS
NS
NS

Outcome
Good
Poor

7
5

0
5

p = 0.044

Plt, platelet counts; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK, creatinine kinase; CSF,
cerebrospinal ﬂuid.

tic thalamic lesions from the early stage of the illness. In
fact, brain lesions were clearly observed on the CTwithin a few hours after the patients became comatose.
Therefore, early steroid treatment will be practical inchildren with ANE.
We consider that hypercytokinemia and hyperpermeability of both the blood–brain barrier and the capillary
walls of the brain will be closely related to the pathogenesis of ANE, and that early steroid therapy will be eﬀective in these conditions. There have been several reports
on cytokine levels in children with inﬂuenza-associatedencephalopathy including ANE and other subtypes ofacute encephalopathy [4,13,14]. Ichiyama et al. measured serum cytokine levels of a patient with ANE due
to inﬂuenza A [4]. Serum levels of interleukin-6, tumor
necrosis factor-alpha and soluble tumor necrosis factor
receptor 1 were highly elevated. Akiyoshi et al. reported
a girl with ANE associated with hemophagocytic syndrome [15]. Serum and cerebrospinal ﬂuid interleukin6 and tumor necrosis factor-alpha were markedly elevated in this patient. Concurrent ANE and macrophage
Table 4
Therapy and outcome in patients with brainstem lesion
OutcomeSteroid use (n = 12)

No steroid (n = 5)

Good
Poor

0
12

2
3

Good
Poor

Early steroid (n = 9)0
9No early steroid (n = 8)
2
6

NS

Good
Poor

Steroid pulse (n = 3)0
3

No steroid pulse (n = 14)
2
12

NS

No gammaglobulin (n = 14)

Good
Poor

Gammaglobulinuse (n = 3)0
3NS, not signiﬁcant.

2
12

NS

activation syndrome had been reported in a patient withjuvenile idiopathic arthritis [16]. Histopathological studies of the brain have revealed severe brain edema andperivascular plasma exudation in ANE [2,3]. Thalamic
lesions of ANE showed perivascular diapedesis of erythrocytes that suggests a severe injury of intracerebral
blood vessels [17]. It is accepted that steroids suppress
the pro-inﬂammatory process including increased cytokine levels and hyperpermeability of the vessels. It isrational that steroids can improve the outcome of
ANE, if they are used during the appropriate period.
In this study, the eﬃcacy was not clearly diﬀerent
between methylprednisolone pulse therapy and intravenous dexamethasone. There have been several studies
that revealed beneﬁcial eﬀects of these regimens forinﬂammatory diseases in the central nervous system.
Methylprednisolone pulse therapy against inﬂuenzaassociated encephalopathy was described in the tentative
guideline proposed by the Research Organization forInﬂuenza Encephalopathy Researchers in Japan in
1999. Thereafter, methylprednisolone pulse therapy
has been widely applied to children with inﬂuenza-associated encephalopathy. A recent questionnaire survey
revealed the eﬃcacy of methylprednisolone pulse therapy against inﬂuenza-associated encephalopathy,
although the subtypes of acute encephalopathy were
not determined in these patients [18]. Dexamethasone
was often used as an adjunctive treatment in children
with acute bacterial meningitis. Several studies andmeta-analyses showed that dexamethasone signiﬁcantly
reduces rates of mortality, severe hearing loss, and neurological sequelae in patients with bacterial meningitis[19]. Lebel et al. demonstrated that the patients withbacterial meningitis treated with dexamethasone became
afebrile earlier and were less likely to acquire moderateor severe bilateral sensorineural hearing loss, as compared with those who received placebo [20]. Odio et al.
reported that intravenous dexamethasone reduced the226

A. Okumura et al. / Brain & Development 31 (2009) 221–227

risk for neurological and/or audiological sequelae by
1:3.8 [21]. These results indicate that both methylprednisolone pulse therapy and intravenous steroid are eﬀective for hypercytokinemia-mediated brain injuries.
However, the eﬃcacy of these two regimens has notbeen compared. Further studies are necessary in orderto clarify which treatment is more beneﬁcial for children
with ANE.
There may be a concern about selection bias ofpatients treated with early steroid. However, there wasno signiﬁcant diﬀerence in laboratory data on admission
between those treated with early steroid and no early steroid. This indicates that the diﬀerence of the severity of
ANE will be small, if present, between those who treatedwith early steroid or not. We do consider that the diﬀerence of outcome in patients without brainstem lesions
will not be attributable to selection bias of the patients.
The eﬃcacy of steroid was not obvious in children
with brainstem lesions, even if the drugs were usedwithin 24 h after the onset. The diﬀerence in eﬃcacy ofsteroids cannot be attributable to the severity of the illness, because no signiﬁcant diﬀerence in patient characteristics was present between those with and without
brainstem lesions. In addition, there were no signiﬁcantdiﬀerences in the laboratory data that can be correlatedwith the outcome of various types of acute encephalopathies. Therefore, we consider that brainstem lesions, inthemselves, are quite harmful and can be a marker ofadverse outcome. Fatal outcome is not uncommon inchildren with brainstem encephalitis due to enterovirus
71 [22,23]. The patients were characterized by sudden
cardiopulmonary collapse, neurogenic pulmonary
edema, and extensive damage to the medulla and pons.
Therefore, poor outcome will be inevitable in patientswith ANE with brainstem lesions. However, there isan anecdotal report that may indicate the eﬃcacy ofvery early steroids for patients with brainstem lesions.
Uematsu et al. reported a 7-month-old girl with ANEwith brainstem lesions preceded by bacterial meningitis[24]. In this patient, intravenous dexamethasone wasused one day before the appearance of ANE lesions
for the treatment against bacterial meningitis. Thispatient was reported to have no developmental delay
at 17 month of age. Thus, we consider that there is apossibility that steroid or other anti-inﬂammatory treatment may be eﬀective, if they are administered earlier
and more intensely. The outcome of patients with brainstem lesion treated with very early steroid pulse therapy
should be investigated, before we gave up steroid for
ANE with brainstem lesion.
There may be other therapeutic choices, if hypercytokinemia is closely related to the development of ANE.
Cyclosporine or other immunosuppressive agents canbe drugs of choice. However, the eﬃcacy and safety ofthese drugs for acute encephalopathy have not yet been
established. It is well known that cyclosporine may

cause posterior reversible encephalopathy [25,26]. In thisstudy, we could not assess the eﬃcacy of these drugs,
because they were not administered in any of ourpatients. The use of immunosuppressive drugs will bea subject of future studies.
The limitation of this study is a relatively small number of the patients and a retrospective design. In order toobtain ﬁrm evidence of therapeutic eﬀects, randomized
control trials with a large number of the patients aredesirable. However, the incidence of ANE is considered
to be low, although it is more frequently observed inJapan or eastern Asia than in the European countries
or the North America. In fact, the number of children
with ANE was approximately 1 per 3–5 years in the hospitals participating in this study, although they are tertiary referral hospitals where seriously ill children arecollected. Therefore, randomized control trials will bequite diﬃcult.
In conclusion, the results of this study strongly suggested the eﬃcacy of early steroid treatment for children
with ANE without brainstem lesions. However, no beneﬁcial eﬀects were observed in those with brainstem
lesions. Early steroid treatment will be an important
option of the treatment for ANE, although further studies are necessary in order to determine the optimal regimen of steroid use.

Acknowledgements
This study was supported by the Grant from the Ministry of Education, Culture, Sports, Science and Technology (17209037).
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