ESPID REPORTS AND REVIEWS

The Pediatric Infectious Disease Journal Volume 31, Number 7, July 2012 www.pidj.com | 759
Steroids and Childhood Encephalitis
Susanna Esposito, MD, Irene Picciolli, MD, Margherita Semino, MD, and Nicola Principi, MD
G
lucocorticosteroids (GS) have both anti-
inflammatory and immunosuppressive
property,
1
which explains why pediatricians
tend to prescribe them for all pediatric clini-
cal conditions in which it is thought or known
that inflammation and/or autoimmunity are
the main cause of disease signs and symp-
toms. However, such prescriptions are some-
times questionable because the efficacy of
GS has not been demonstrated by controlled
trials, and the risk of adverse events follow-
ing high-dose or prolonged administration
has not been adequately evaluated.
Encephalitis is one of the syndromes
for which GS are frequently used. However,
the importance of this treatment remains
unclear because a diagnosis of encephalitis
covers a range of clinical conditions whose
etiology, pathogenesis, clinical picture and
spontaneous evolution vary. Furthermore, it
has been tested in very few studies involving
children.
2
The aim of this article is to review
what is currently known about the real
impact of GS treatment in children with acute
infectious encephalitis (AIE) and acute dis-
seminated encephalomyelitis (ADEM), the 2
major types of encephalitis.
ACUTE INFECTIOUS
ENCEPHALITIS
The neurological signs and symp-
toms of AIE usually occur within a clinical
picture that is characteristic of the infectious
agent causing central nervous system (CNS)
involvement which, in most cases, can be
found in the CNS, other sites of the body or
biological fluids. Viruses are the most fre-
quently identified. Since the implementation
of vaccination programs that have elimi-
nated or significantly reduced the circulation
of measles, mumps and rubella viruses in
industrialized countries, herpes simplex
virus (HSV, particularly type 1) is the most
frequent cause, followed by virus varicella
zoster (VZV; in countries where VZV vac-
cination coverage is low).
3
However, patho-
gens such as Mycoplasma pneumoniae, Japa-
nese encephalitis virus, enteroviruses and
tickborne encephalitis virus have also been
reported.
3
In addition, some bacteria (mainly
Streptococcus pneumoniae and Neisseria
meningitidis) may cause AIE usually second-
ary to meningitis.
2
GS have a great potency to limit
inammation, and their use could modu-
late the enhanced inflammatory response
observed during serious infections.
3
The
use of GS to treat childhood AIE has never
been studied in controlled trials, and it is not
officially recommended because of concerns
that their immunosuppressive activity may
increase viral replication and spread.
4
How-
ever, this may not be true in the case of HSV
CNS infection, because they only slightly
delay virus clearance and do not limit the
acyclovir-induced inhibition of viral replica-
tion in experimental animals.
5
Moreover, as the CNS signs and
symptoms following HSV infection are not
only due to direct virus-mediated tissue dam-
age but also due to an autoimmune mecha-
nism, it is possible that GS may have a ben-
eficial effect on the evolution of HSV AIE.
Experimental data indicate that they may
attenuate CNS damage by reducing cytokine
and prostaglandin production, and limiting
the nitric oxide concentration induced by
the increased expression of immunological
nitric oxide synthase.
5
Furthermore, in HSV-
infected mice, methylprednisolone signifi-
cantly reduces long-term magnetic resonance
imaging abnormalities,
6
and dexamethasone
restricts neuronal cell death.
7
Similar positive effects have been
found in human studies, although most of
these were retrospective studies of adults. In
general, adults treated with GS plus acyclo-
vir had a better outcome than those receiv-
ing acyclovir alone because they survived
without sequelae or with only minor CNS
damage, and did not experience any major
GS-related adverse events.
8
Positive results
have also been described in pediatric case
reports.
9,10
The optimal timing of GS administra-
tion in HSV AIE has not yet been defined.
However, although GS were prescribed
simultaneously with acyclovir in most pub-
lished cases with a favorable evolution,
810

animal and human data suggest that neuro-
logical signs and symptoms can still improve
if GS are started some days or even more
than 2 weeks after disease onset.
710
No data
in favor of GS use are available from studies
performed in neonates.
Optimal doses and treatment duration
are also unclear and related to the used agent.
Musallam et al
10
used pulsed methylpredni-
solone at a dose 1 g/1.73 m
2
for 3 days, but
high-dose dexamethasone could be adminis-
tered for the same period.
8,9
In conclusion, although they are inter-
esting and encouraging, the available data
are too limited to support an official recom-
mendation for the systematic use of GS in
HSV AIE, and only antiviral therapy can be
universally suggested. The results of a cur-
rently ongoing randomized controlled trial in
Europe should provide information that may
allow a more precise evaluation,
11
but in the
meantime it can be suggested that treatment
with GS may be attempted in cases in which
antiviral therapy does not seem to control the
clinical picture of HSV AIE, and CNS dam-
age is clearly increasing on the basis of clini-
cal findings and neuroimaging.
Similar conclusions can be drawn in
the case of AIE associated with VZV infec-
tion because, once again, the neurological
damage is at least partially attributable to an
immune mechanism that may be reduced by
GS administration. In adults, expert opinion
suggests administering GS in AIE associated
with VZV reactivation, particularly if nuclear
magnetic resonance imaging suggests a
stroke secondary to large vessel vasculitis.
12

The suggested dose is 6080 mg of predniso-
lone (2 mg/kg/day in children) once daily for
35 days, but no controlled trial supports this
recommendation.
GS do not seem to be effective in AIE
associated with Japanese encephalitis virus
infection,
13
and no conclusive data are avail-
able concerning their effect on in AIE due to
other infectious agents.
ACUTE DISSEMINATED
ENCEPHALOMYELITIS
ADEM is mainly diagnosed in chil-
dren and has an estimated incidence of
0.8/100,000 per year.
2
It is classified as a
demyelinating disease of the CNS and is a
condition that may be regarded as a bridge
linking neurology and the infectious dis-
eases.
2
The clinical features and history of the
disease create difficulties in differential diag-
nosis both with encephalomyelitis caused
ESPID REPORTS AND REVIEWS
From the Department of Maternal and Pediatric Sci-
ences, Universit degli Studi di Milano, Fondazi-
one IRCCS Ca Granda Ospedale Maggiore Poli-
clinico, Milan, Italy.
This review was supported by a grant from the Ital-
ian Ministry of Health (Bando Giovani Ricercatori
2007). The authors have no conflicts of interest to
disclose.
Address for correspondence: Susanna Esposito, MD,
Department of Maternal and Pediatric Sciences,
Universit degli Studi di Milano, Fondazione
IRCCS Ca Granda Ospedale Maggiore Poli-
clinico, Via Commenda 9, 20122 Milano, Italy.
E-mail: susanna.esposito@unimi.it.
Copyright 2012 by Lippincott Williams & Wilkins
ISSN: 0891-3668/12/3107-759
DOI: 10.1097/INF.0b013e31825b129b
2012 Lippincott Williams & Wilkins 760 | www.pidj.com
ESPID Reports and Reviews The Pediatric Infectious Disease Journal Volume 31, Number 7, July 2012
by infectious agents and with noninfectious
inflammatory diseases (other demyelinating
syndromes, vasculitis, nonvasculitic autoim-
mune encephalopathies).
2
Recurrent ADEM
has been described, but in most cases it is a
monophasic inflammatory and demyelinat-
ing disease that usually occurs some days or
weeks after an infection or a vaccination.
2

Although not fully assessed in randomized,
placebo-controlled trials, GS are generally
recommended for children with ADEM,
2

who are usually treated with methylpredni-
solone 1020 mg/kg/day intravenously for
35 days followed by a tapered course of
oral prednisolone. A number of authors have
found that GS are immediately effective in
most cases, leading to a clear improvement
in neurological signs and symptoms after a
few days of administration even in patients
with protracted worsening before the start
of treatment.
14
Only a minority of children
with ADEM seem to be refractory to steroid
therapy and require the addition of immuno-
globulins or the use of plasmapheresis.
15,16
The use of GS to treat ADEM is
strongly suggested by the supposed patho-
genesis of the syndrome itself. It is thought
to be an autoimmune disease for which 2
pathogenic mechanisms have been pro-
posed. The first is suggested by the similar-
ity between the histological features typi-
cally found in biopsy and autopsy samples of
ADEM patients and those found in animals
with experimental autoimmune encephalo-
myelitis due to immunization with myelin
proteins or peptides.
17
As perivenular infil-
trates of T cells and macrophages, associated
with perivenular demyelination, are usually
found in both cases, it has been suggested
that in children with ADEM viral or bacte-
rial epitopes resembling myelin antigens may
activate myelin-reactive T-cell clones as a
result of molecular mimicry, thus inducing
a specific CNS response against the brain
and spinal cord.
18
This pathogenic hypothesis
is further supported by the finding of high-
affinity antibodies directed against myelin-
basic protein, a major component of myelin,
in some patients diagnosed as having ADEM
who had previously received rabies vaccina-
tion.
19
The second hypothesized pathogenic
mechanism in favor of GS administration
is based on the consideration that a neu-
rotropic infectious agent may damage the
CNS and disrupt the blood/brain barrier,
thus leading to a systemic leakage of CNS-
confined autoantigens into the circulation.
This might cause the breakdown of tolerance
and cause the emergence of a self-reactive
and encephalitogenic T-cell response, and the
secretion of cytokines, chemokines or other
soluble factors could perpetuate inflam-
mation over time.
18
There is no evidence in
ADEM that there is a systemic inflammation
that causes the clinical pattern.
In conclusion, unlike AIE, ADEM is a
disease for which the available data seem to
indicate the systematic use of GS. The pos-
sible relationships between ADEM and mul-
tiple sclerosis further support this recommen-
dation, although there is not enough evidence
to conclude that ADEM eventually leads to
multiple sclerosis.
CONCLUSIONS
In conclusion, we do not support the
systematic use of GS in AIE and we suggest
that treatment with GS may be attempted
in cases in which antiviral therapy does not
seem to control the clinical picture of AIE,
and CNS damage is clearly increasing on
the basis of clinical findings and neuroimag-
ing. On the contrary, ADEM is a disease for
which the available data seem to indicate the
systematic use of GS.
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