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18
Acute Necrotizing Encephalopathy
of Childhood
Rabporn Suntornlohanakul and E. Ann Yeh
Introduction
Infection- associated encephalopathies are conditions characterized by neurological
dysfunction occurring in the context of infection, primarily viral infection, that can
also be subsumed under general syndromal umbrellas such as acute disseminated
encephalomyelitis, a syndrome occurring primarily in the pediatric age group in
which post- or para- infectious multifocal central nervous system (CNS) magnetic
resonance imaging (MRI) abnormalities are noted. Importantly, however, many
CNS infection- related syndromes with highly specic clinical and radiological ndings have been described in recent years: this higher level of specicity may be important in understanding therapeutic approaches and outcomes. Examples include
acute necrotizing encephalopathy of childhood (ANEC), acute encephalopathy with
biphasic seizures and late reduced diusion, and mild encephalitis/ encephalopathy
with a reversible splenial lesion (Takanashi, 2009). ANEC is of particular interest, in
that its associated MRI scans are characterized by a highly typical pattern, and specic pathogens and genetic abnormalities have been described in association with a
proportion of these cases. In this chapter, following an illustrative case of ANEC, we
will review information on its denitions, epidemiology, pathophysiology, clinical–
radiological manifestations, dierential diagnosis, treatment, and outcomes.
Case
A 10- year- old boy with a history of speech delay was brought to the hospital due to
diculty walking, imbalance, blurred vision, and episodes of confusion and disorientation. Five days prior to admission, he experienced a fever and u- like symptoms. His birth history was unremarkable, and he denied any recent travel or contact
with sick individuals. His neurological exam was signicant for right cranial nerve
VI palsy, nystagmus, dysmetria, and gait ataxia. MRI revealed an expansile high T2/
uid- attenuated inversion recovery lesion of the pons, extending into the medulla,
the midbrain, and bilateral middle cerebellar peduncles (Figure 18.1).
Rabporn Suntornlohanakul and E. Ann Yeh, Acute Necrotizing Encephalopathy of Childhood
Neuropsychiatric Medicine
© Oxford University Press 2024. DOI: 10.1093/ oso/ 9780192870414.003.0019
Infectious Disease and Neurocognition
Figure 18.1 Axial fluid- attenuated inversion recovery imaging showing an expansile
hyperintensity of the pons (arrowheads).
Cerebrospinal uid (CSF) analysis showed a leukocyte count of 5 cells/ μL, a protein level of 27 mg/ dL, and a glucose level of 4.7 mmol/ L. A nasopharyngeal swab
was positive for inuenza B. Other laboratory results were unremarkable. Suspicions
for inuenza- associated CNS abnormalities and a possible diagnosis of ANEC were
raised. Genetic testing for ANEC was sent. He was treated with oseltamivir and received 5 days of intravenous pulse methylprednisolone. Although his clinical status
improved signicantly, he continued to experience residual cognitive and behavioral problems. e follow- up MRI 5 months later showed interval evolution of
the lesions (Figure 18.2). Genetic testing later revealed a pathogenic variant of the
Figure 18.2 Five- month follow- up magnetic resonance imaging (MRI). (a) Axial fluid- attenuated
inversion recovery MRI showing linear T2 hyperintense areas of cavitation in the region of the
claustrum bilaterally (arrowheads). (b) Axial T2 imaging showing interval evolution of the pons
with few cystic areas (arrowheads).
Acute Necrotizing Encephalopathy of Childhood 281
RANBP2 gene, c.1754C>T (p.r585Met). His mother and younger sister were also
found to carry this genetic mutation.
Definitions
e term “acute necrotizing encephalopathy of childhood (ANEC)” was rst
introduced by a Japanese group in 1995 to describe children experiencing acute
neurological symptoms with distinctive radiological and pathological ndings
following inuenza infection (Mizuguchi et al., 1995). Currently, ANEC is dened as a rare neurological condition characterized by the acute onset of impaired
consciousness, neurological decline, seizures, and varying degrees of hepatic
dysfunction, with characteristic MRI ndings including multifocal brain lesions
specically aecting the deep gray matter including the thalami bilaterally and
symmetrically and the brainstem. Given the identication of genetic susceptibility
linked to the RANBP2 mutation in familial and recurrent cases, the term “ANE1”
was introduced to categorize familial or genetic cases (Neilson et al., 2009).
Detailed diagnostic criteria for ANEC and ANE1 are provided in Table 18.1.
Table 18.1 Proposed diagnosis criteria for ANEC and ANE1
Syndrome Criteria for diagnosis
ANEC 1. Acute encephalopathy following viral febrile disease. Rapid deterioration in the
level of consciousness. Convulsions
2. No CSF pleocytosis. An increase in CSF protein is commonly observed
3. Computed tomography or magnetic resonance imaging evidence of symmetric,
multifocal brain lesions. Involvement of the bilateral thalami. Lesions are also
common in the cerebral periventricular white matter, internal capsule, putamen,
upper brainstem tegmentum and cerebellar medulla. No involvement of other CNS
regions
4. Elevation of serum aminotransferases of variable degrees. No increase in blood
ammonia
5. Exclusion of resembling diseases
ANE1 1. Prior episodes of encephalopathy following fever, with or without ndings
of ANEC
2. Family history of ANEC or acute neurologic ndings following fever:
a. Need not be a rst- degree relative; “aected cousins” are common
b. Terms used to describe relatives’ previous episodes: viral encephalitis,
aseptic meningitis, acute disseminated encephalomyelitis, para- infectious
encephalopathy, and “non- classic” or “acute” Leigh syndrome
3. CNS imaging demonstrating additional characteristics lesions in any of the
following structures:
a. Medial temporal lobes, insular cortices, claustra, external capsule
b. Amygdalae, hippocampi, mammillary bodies
c. Spinal cord
Note: criteria from Mizuguchi (1997) and Neilson (2010).
Abbreviations: ANE1, acute necrotizing encephalopathy type 1; ANEC, acute necrotizing encephalopathy of child-
hood; CNS, central nervous system; CSF, cerebrospinal uid.
Infectious Disease and Neurocognition
Epidemiology
e exact global incidence of ANEC remains elusive despite an increasing number of
reported cases worldwide. Notably, a signicant portion of reported cases are from
Asia, particularly Taiwan, China, and Japan. According to a national survey in Japan,
ANEC accounted for 4.1 percent of acute encephalopathy cases between 2007 and
2010 and 2.8 percent in 2014– 2017 (Hoshino et al., 2016; Kasai et al., 2020). Beyond
Asia, limited epidemiological studies have been undertaken. Two longitudinal
studies on inuenza- related neurological symptoms have been published, one in the
United Kingdom and another in Australia. e United Kingdom study (2013– 2015)
examined neurological cases resulting from inuenza infection in both adults and
children (n = 25), with 21 (84 percent) occurring in children. Among these cases,
only four were diagnosed with ANEC (Goenka et al., 2014). In another longitudinal
study of inuenza- associated neurological disease in Australia (2013– 2015), ANEC
accounted for only three (5.6 percent) of 54 cases (Britton et al., 2017). ANEC predominantly aects the pediatric population. In a retrospective single- center study
conducted in China in 2021 that described inuenza- associated encephalopathy
(IAE) and ANEC, a total of 30 ANEC cases were reported with 73.3 percent (22/
30) being under the age of 5 years (Song et al., 2021). No sex predilection has been
reported.
Pathogenesis
Although ANEC can occur in other systemic viral infections, inuenza remains the
most commonly reported pathogen. Due to the common co- occurrence of ANEC
in patients with systemic viral infection, it was initially presumed to be a parainfectious disease. However, no viruses have been isolated from brain biopsies performed in this population, and viral detection in CSF is infrequent (Aksoy et al.,
2021; Chatur et al., 2022; Ito et al., 1999; Mizuguchi et al., 1995). e most widely
accepted proposed mechanism for ANEC is the “cytokine storm,” although the exact
pathogenesis remains to be fully understood. Several studies have demonstrated a
signicant elevation of serum interleukin (IL)- 1 beta, IL- 2, IL- 10, IL- 6, and tumor
necrosis factor alpha (TNF- α) in ANEC cases associated with inuenza and human
herpes virus- 6 (HHV- 6) infection (Ichiyama et al., 2003; Kansagra & Gallentine,
2011). Similarly, an elevation of serum IL- 6 and TNF- α was found in a 4- year- old
girl with ANEC at the time of chikungunya virus infection (Tabarki et al., 2013). e
nding of elevated serum cytokines in ANEC cases, regardless of the pathogen involved, suggests the important role of inammation in the clinical and radiological
manifestations of the disease. Notably, a postmortem histological study revealed extravasation of plasma- like materials surrounding the vessels within thalamic lesions,
reecting a disruption in the blood– brain barrier (Mizuguchi et al., 2002). is is
Acute Necrotizing Encephalopathy of Childhood 283
further supported by a study that noted the development of contrast enhancement
without structural signal abnormalities before the emergence of bilateral thalamic
hypodensity (Yoshida et al., 2013).
Genetics
In 2009, Neilson and colleagues rst reported genetic associations between familial
and recurrent ANEC cases and a missense mutation in the RANBP2 gene (Neilson
et al., 2009). e RANBP2 gene follows an autosomal dominant inheritance pattern
with incomplete penetrance (Neilson et al., 2003). A study of families carrying this
mutation demonstrated that 40 percent of individuals carrying the mutation developed clinical symptoms associated with ANEC (Neilson et al., 2009). is gene encodes the nuclear pore protein RAN binding protein 2, which plays various roles
during the cell cycle, including facilitating protein transport, cell tracking, and mitochondrial function. However, the exact mechanism by which this mutation leads
to ANEC pathogenesis remains incompletely understood.
ere are similarities in the clinical manifestations of individuals diagnosed with
ANEC who carry the gene mutation and those who do not. In a study by Chatur
and colleagues, no dierences in clinical manifestations were found between individuals carrying the RANBP2 mutation and those without the mutation (Chatur
et al., 2022). e most frequent dierence between the two groups was the presence
of clinical relapses in RANBP2- positive individuals in comparison to no relapses in
RANBP2- negative patients. is highlights the importance of a RANBP2 mutation
in predicting the clinical course in ANEC cases (Chatur et al., 2022). Follow- up in
this study, however, was limited: further studies with longer follow- up are needed to
conrm the association between RANBP2 and clinical course.
Nevertheless, the risk of recurrence in RANBP2- positive individuals has been
conrmed in other studies. Sarigecili and colleagues described nine RANBP2
gene positive patients in whom two of the nine (22 percent) had recurrent events
(Sarigecili et al., 2023). In the study, one patient experienced three attacks in 3
consecutive years, while another had two attacks in 1 year (Sarigecili et al., 2023).
Interestingly, the clinical spectrum associated with RANBP2 mutation may encompass other conditions such as polyneuritis or cranial nerve palsies, which have been
found in family members who also carry the RANBP2 gene mutation (Gika et al.,
2010). e complex and overlapping relationships between the RANBP2 gene muta-
tion, IAE, and ANEC are illustrated in Figure 18.3. Genetic heterogeneity exists for
ANEC as shown in the Neilson et al. study, where four out of 16 familial cases did not
harbor the RANBP2 mutation (Neilson et al., 2009). Other genes have been found
to be associated with ANEC. A signicant association has been observed between
the frequency of alleles DRB1*09:01 and DQB1*03:03 in ANEC patients compared
to controls (Hoshino et al., 2016). ese genotypes are predominantly found within
Japanese populations, potentially explaining the high incidence of ANEC in Japan.
Infectious Disease and Neurocognition
Acute necrotizing encephalopathy
of childhood
RANBP2-positive
mutation
Other neurological
symptoms
Asymptomatic
Figure 18.3 The complex and overlapping relationships between the RANBP2 gene, influenza-
associated encephalopathy, and acute necrotizing encephalopathy of childhood.
Influenza-associated
encephalopathy
Additionally, specic single- nucleotide polymorphisms in the CPTII gene, primarily reported within Asian populations, have also been identied as a risk factor for
the development of ANEC (Shinohara et al., 2011).
Associated pathogens
Influenza
Inuenza is a respiratory virus associated with a range of neurological manifestations, such as febrile seizures and IAE. Both inuenza A and B have been reported
in association with neurological symptoms, but inuenza A appears to be more frequently associated with neurological manifestations (Farooq et al., 2012). In a British
study (2011– 2013) of inuenza- associated neurological manifestations, 84 percent (21/ 25) were attributed to inuenza A (95 percent (20 out of 21) H1N1), while
four cases (16 percent) were linked to inuenza B (Goenka et al., 2014). In a 2- year
Australian longitudinal study evaluating inuenza- associated neurological complications (n = 54), seizures (30 percent, 16 out of 54) and febrile seizures (26 percent,
14 out of 54) were the two most common manifestations, with focal neurological
symptoms being the least prevalent (6 percent, 3/ 54) (Britton et al., 2017). Specic
encephalopathy syndromes associated with inuenza infection include mild encephalitis/ encephalopathy with a reversible splenial lesion, acute encephalopathy
with biphasic seizures and late reduced diusion, and ANEC (Kasai et al., 2020).
Regarding ANEC specically, inuenza accounted for 20 percent (eight out of 41) of
cases in a retrospective study conducted in China (n = 41) and 41 percent (16 out
of 39) in a Japanese national survey of acute encephalopathy (Hoshino et al., 2016;
Acute Necrotizing Encephalopathy of Childhood 285
Zhu et al., 2021). Compared to patients with IAE, two studies have identied that inuenza associated with ANEC is more likely to exhibit elevated liver function tests
(aspartate aminotransferase, alanine transaminase) and CSF pleocytosis (Liu et al.,
2021; Song et al., 2021).
Severe acute respiratory syndrome coronavirus 2 infection
A wide range of neurological symptoms have been reported to be associated with severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2) infection. e symptoms aect both the peripheral nervous system and CNS, with varying degrees of
severity. e mechanism by which SARS- CoV- 2 leads to these diverse neurological
syndromes is unknown. In 2021, Larovere and colleagues studied the neurological manifestations of hospitalized children and adolescents in the United States
with SARS- CoV- 2 or multisystem inammatory syndrome and found that 22 percent (365 out of 1695) of cases had neurologic involvement (Larovere et al., 2021).
Interestingly, no ANEC cases were reported (Larovere et al., 2021). Similar results
were seen in another multinational study of patients in Canada, Iran, and Costa Rica
(Yea et al., 2024).
A small number of reports of RANBP2- positive patients with SARS- CoV- 2 and
ANEC exist. In 2023, Forest and colleagues reported a 10- year- old girl who tested
positive for the RANBP2 mutation and developed ANEC in association with SARSCoV- 2 infection (Forest et al., 2023). is child also had a prior ANEC episode at the
time of an inuenza A infection at 2 years of age (Forest et al., 2023). Intriguingly,
Virhammar and coworkers reported the isolation of SARS- CoV- 2 RNA in the CSF
of an adult patient with ANEC associated with SARS- CoV- 2 symptoms, suggesting
the possibility of neurotropism in the SARS- CoV- 2 virus itself (Virhammar et al.,
2020). In another case report, Bensaidane and colleagues reported an adult case of
ANEC that occurred within 48 hours of receiving the ChAdOx1 nCoV- 19 vaccine
(Bensaidane et al., 2022). Although the individual was found to have abnormalities
in the RANBP2 mutation, the identied variant was due to an intronic change, and
its pathogenic potential was thought to be low (Bensaidane et al., 2022). Other reports of ANEC in relation to SARS- CoV- 2 have not described an association with
RANBP2 gene (Ho et al., 2023; Lazarte- Rantes et al., 2021).
Other associated pathogens
While ANEC has primarily been described in relation to inuenza and SARS- CoV2 infections, other pathogens, primarily viruses, have been documented in ANEC
cases. ese include rotavirus, enterovirus, adenovirus, parainuenza virus, HHV6, human metapneumovirus, adenovirus, respiratory syncytial virus, dengue virus,
herpes simplex virus, and mycoplasma (Abbas et al., 2017; Chatur et al., 2022;
Infectious Disease and Neurocognition
Fan et al., 2022; Huber et al., 2020; Kumar et al., 2021; Otake et al., 2023; Poojari
et al., 2021; Stevanovic et al., 2019; Tabarki et al., 2013). Notably, certain bacterial
pathogens, including Streptococcus pneumoniae, Escherichia coli, and Neisseria
gonorrhoeae, have also been reported (Huber et al., 2020; Wang et al., 2021).
Interestingly, there are no clear dierences in terms of clinical presentation in relation to the dierent pathogens.
Clinical manifestations
e earliest reports of clinical manifestations of ANEC cases were described prior
to knowledge about familial/ genetic cases of ANEC. In these descriptive reports,
aected children presented with prodromal symptoms resembling viral infections,
such as respiratory tract or gastrointestinal symptoms. Following a period of 1–
5 days, neurological symptoms were seen to emerge, including fever, altered consciousness, and seizures (Mizuguchi, 1997; Mizuguchi et al., 1995). Additionally,
various degrees of involvement of other organs were described in these early cohorts, including hemodynamic instability, elevated liver enzyme levels, increased
lactate dehydrogenase concentrations, elevated creatine kinase levels, and thrombocytopenia (Aksoy et al., 2021; Wu et al., 2022; Zhu et al., 2021). e presence of
transaminitis ranged from 12 percent to 77 percent of cases (Aksoy et al., 2021; Jan
et al., 2019; Wu et al., 2022). CSF pleocytosis was reported in 12– 30 percent of cases
in various studies (Chatur et al., 2022; Neilson et al., 2003). Elevation of CSF protein
(> 0.4 g/ L) was found in 55– 83 percent of cases (Aksoy et al., 2021; Chatur et al.,
2022; Fan et al., 2022). One study showed abnormal electroencephalogram results in
all reported cases, although this has not been conrmed in other studies (Fan et al.,
2022). In this study, 83.3 percent (ten out of 12) of patients exhibited diuse slowing
on electroencephalography, while the remaining cases showed asynchronous spike
waves (Fan et al., 2022).
It is not clear if the clinical syndrome in RANBP2- positive children with ANEC
(or ANE1) diers from those who are RANBP2 negative. As noted above, outside of
increased risk for recurrence, few dierences between those with ANEC who were
RANBP2 positive and RANBP2 negative were seen in one study (Chatur et al., 2022).
In 2023, Sarigecili and colleagues described nine pediatric patients with ANEC, all
of whom tested positive for the RANBP2 gene (Sarigecili et al., 2023). Among these
patients, four out of nine had a history of previous attacks with a similar phenotype.
Encephalopathy occurred in all cases, with seizures occurring in 44 percent (four
out of nine) of patients, ataxia in 11 percent (one out of nine), and monoplegia in
11 percent (one out of nine) (Sarigecili et al., 2023).
e visual pathway may be aected in this population. In the Sarigecili et al. series, 33 percent (three out of nine) of patients experienced acute vision problems
including blurred vision and visual loss (Sarigecili et al., 2023). Similarly, Chew and
Ngu’s report of three RANBP2- positive siblings in a Malaysian family demonstrated
Acute Necrotizing Encephalopathy of Childhood 287
two with visual symptoms, including one with blurred vision and impaired color vision and another with visual loss (Chew & Ngu, 2020). Of note, regarding laboratory
investigations, the majority of patients in RANBP2- positive cases do not appear to
have hepatic involvement, as indicated by normal liver enzyme levels in 78 percent
(seven out of nine) of the RANBP2- positive cases reported by Sarigecili et al. (2023).
Radiographic findings
e initial 1995 case series rst describing ANEC, a time when MRI was less widely
available, demonstrated imaging ndings including multiple hypodense lesions in a
symmetrical pattern on computed tomography scans of the brain, with the common
unifying feature of bilateral thalamic lesions (Mizuguchi et al., 1995). Notably, this
was an imaging- based description based on pattern recognition. Bilateral involvement of the thalami has remained a distinctive feature of ANEC. However, other
areas of focal involvement have been described, including the periventricular white
matter, brainstem, basal ganglia, cerebral cortex and subcortex, and cerebellum
(Wong et al., 2006; Zhu et al., 2021). It is important to note that results of genetic
testing were not reported in the patients described in these cases.
In the acute stage, the aected areas appear hypointense on T1- weighted imaging and hyperintense on T2/ uid- attenuated inversion recovery- weighted MRI
sequences. Hemorrhage, cavitation, and contrast enhancement may also be seen
(Wong et al., 2006). e imaging features are dynamic: early scans may be within
normal limits, with progression to marked swelling of the thalami over the course
of a 24- hour period (Yoshida et al., 2013). Notably, the study by Chatur and colleagues found that the presence of hemorrhagic lesions on MRI was associated
with inuenza A infection and were not limited to those who were positive for the
RANBP2 gene mutation (Chatur et al., 2022). Furthermore, no dierences in imaging regarding the degree of thalamic swelling, thalamic hemorrhage, or the extent
of diusion restriction between patients with positive RANBP2 and those without
were seen in this study (Chatur et al., 2022). In another study, Neilson and colleagues
found that in familial cases (ANE1), other CNS structures were frequently involved,
specically the external capsule, claustrum, limbic structures, or temporal lobes
(Neilson et al., 2009).
Other MRI modalities have elucidated other features, including metabolic changes
and the evolution of acute brain changes in ANEC. Magnetic resonance spectroscopy
of lesions has shown high choline and inverted lactate peaks. Diusion- weighted
MRI has revealed the specic nding of a trilaminar pattern in the thalamus during
the acute stage, specically showing a center core in the thalamus with a higher apparent diusion coecient (ADC) than the normal parenchyma (Albayram et al.,
2004). e high ADC core in the thalamus is correlated with the presence of subacute
hemorrhagic lesions observed on the follow- up MRI (Albayram et al., 2004). e
periphery of the core displays very low ADC and high diusion- weighted imaging