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Infectious Disease and Neurocognition
values, indicating cytotoxic edema (Albayram et al., 2004). e outermost part exhibits high ADC values, which are consistent with vasogenic edema (Albayram et al.,
2004). Furthermore, susceptibility- weighted imaging and gradient- echo images can
assist in identifying hemorrhagic areas within the thalami (Biswas et al., 2018; Goo
et al., 2003). Kwon and colleagues reported an interesting nding in an 18- monthold girl with ANEC associated with rotavirus infection, where arterial spin labeling
perfusion MRI showed decreased perfusion in the thalami and cerebellum on the
second day of admission (Kwon et al., 2019). Other perfusion scan modalities, such
as single- photon emission computed tomography, have shown conicting ndings,
which could be attributable to the dierences in the timing of the images (Hayakawa
et al., 2007; Oki et al., 1995).
Dierential diagnosis
Several conditions can present with clinical manifestations that resemble those associated with ANEC, as the symptoms associated with ANEC are nonspecic. ese
conditions may include meningitis/ encephalitis, seizure disorders, toxic exposures,
metabolic derangements, and hypoxic brain injuries. e clinical course and patient
history are valuable in narrowing the dierential diagnosis. For instance, patients
with Leigh syndrome may exhibit worsening neurological symptoms triggered by
viral infections. However, they typically have a long clinical course with prior delayed
development. Hemophagocytosis lymphohistiocytosis (HLH) is another condition
that may resemble ANEC since it involves immune system activation, leading to systemic cytokine responses and CNS involvement (Janka & Lehmberg, 2013). Because
of this shared mechanism, clinicians oen face challenges in distinguishing between
these two conditions (Akiyoshi et al., 2006; Dai et al., 2016; Radmanesh et al., 2020).
Patients with HLH typically have fever and splenomegaly, along with multiple laboratory abnormalities, including cytopenias, hyperferritinemia, hypobrinogenemia,
and hypertriglyceridemia. Table 18.2 outlines suggested investigations that can be
performed to aid in diagnosis.
Imaging ndings are essential for the diagnosis of ANEC, but it is challenging to
distinguish ANEC from conditions with MRI ndings resembling those of ANEC.
A typical MRI pattern seen in ANEC is shown in Figures 18.4– 18.6. While bilateral thalamic lesions are seen in ANEC, thalamic involvement can be seen in many
other conditions, including myelin oligodendrocyte glycoprotein immunoglobulin
G- associated disease (Figure 18.7). Additionally, ANEC cases, especially those that
are RANBP2- positive (Figures 18.4 and 18.5) typically do not exhibit extensive cor-
tical involvement or brain swelling. erefore, other dierential diagnoses should
be carefully considered, particularly HLH if accompanied by systemic laboratory
abnormalities. In Figure 18.8, we present a proposed clinical approach for patients in
whom a diagnosis of ANEC is suspected.
Acute Necrotizing Encephalopathy of Childhood 289
Table 18.2 Suggested investigations
Metabolic workup • Complete blood count, renal function, hepatic enzyme, ammonia, lactate,
glucose, pH, plasma amino acids, urine organic acids, triglyceride
Inammatory
markers
Toxicology • Urine toxicology screen
Neuroinammatory
disease workup
CSF analysis • Opening and closing pressure
Infectious workup • Serology; bacterial/ mycobacterial, fungal, parasite
Abbreviations: CSF, cerebrospinal uid; Ig, immunoglobulin.
• Erythrocyte sedimentation rate, C- reactive protein, ferritin, antinuclear
antibody, brinogen, lactate dehydrogenase
• Serum cytokines
• Serum myelin oligodendrocyte glycoprotein, AQP4
• Oligoclonal banding and IgG index
• Serum/ CSF for autoimmune encephalitis panel (if indicated)
• CSF cell count and dierential
• Glucose, protein
• CSF polymerase chain reaction studies for infectious agents (viral,
bacterial, fungal)
• Blood cultures
• Nasopharyngeal swab for respiratory virus
• Mycoplasma IgG, IgM
• Stool for enterovirus
Figure 18.4 Axial T2 fluid- attenuated inversion recovery imaging showing increased signal
abnormality within the basal ganglia bilaterally (arrowheads), extending to midbrain (arrow)
in a 7- year- old female with acute necrotizing encephalopathy of childhood found to carry the
RANBP2 mutation.
Infectious Disease and Neurocognition
Figure 18.5 Axial T2 fluid- attenuated inversion recovery imaging showing multiple areas of
abnormal hyperintense signal involving the thalami bilaterally (arrowheads) and the posterior
aspect of internal and external capsules (arrow) in a 4- year- old female with acute necrotizing
encephalopathy of childhood who was found to carry the RANBP2 gene mutation.
Figure 18.6 Axial gradient echo sequences showing hemosiderin staining bilaterally in
the thalami (arrowheads) in a 4- year- old female with acute necrotizing encephalopathy of
childhood associated with influenza A infection (negative for the RANBP2 gene mutation).
Treatment
No denitive treatment for ANEC exists, due to the rarity of the syndrome, the heterogeneity of the aected population, and the challenges in conducting high- level
evidence studies. Because there is widespread acceptance that immunopathogenesis
may be driven by a cytokine storm, anti- inammatory therapies have been widely
Figure 18.7 Axial fluid- attenuated inversion recovery imaging showing numerous areas of
high signal intensity involving cortex and subcortical white matter (arrows) in both cerebral
hemispheres, as well as in the thalami bilaterally (arrowheads) in a 5- year- old male who was
positive for myelin oligodendrocyte glycoprotein immunoglobulin G antibodies.
Encephalopathy, seizure, altered mental status.
in the context of influenza or other viral infections
Recommended workup (detailed in Table 18.2)
- Blood for metabolic and inflammatory markers workup
- Toxicology screen
- Infectious workup
- Lumbar puncture
- Neuroinflammatory disease workup
- Neuroimaging (preferrable MRI)
- CSF: normal WBC ± midly elevated protein
- MRI: basal ganglia, pons, thalamic involvement
± hemorrhage
Consider
RANBP2 gene testing
Initiate immunotherapy (detailed in Table 18.3)
- Steroids (IV methylprednisolone)
If no improvement or worsening
- Plasmapheresis and/or IVIG
- IL-6 inhibitors (consider pre-treatment serum IL-6levels)
Antiviral agents (with ID consultation)
- Oseltamivir
- Acyclovir
Consider other dierential diagnoses if any
one of the following is present.
- Multisystemic involvement
- High inflammatory markers
- CSF: prominent pleocytosis
- MRI: deep grey involvement +
cortical/white matter involvement
Figure 18.8 Proposed clinical approach to pediatric patients with symptoms of acute
necrotizing encephalopathy of childhood in the context of influenza infection or other viral
Infectious Disease and Neurocognition
employed. Current treatments are largely based on retrospective studies and case
reports and currently include the use of steroids, intravenous immunoglobulin
(IVIG), plasma exchange (or plasmapheresis; PLEX), and antiviral medications
(Aksoy et al., 2021; Jan et al., 2019; Sun et al., 2022; Wu et al., 2022). Steroids are
generally given in the form of methylprednisolone, although intravenous dexamethasone has also been used in some settings (Wu et al., 2022). No studies have directly
compared these two treatment regimens. A retrospective multicenter study in China
by Li and colleagues found that pediatric patients (n = 36) who received high- dose (≥
20 mg/ kg/ day) methylprednisolone had a signicantly lower mortality rate (9 percent, one out of 11) compared to those who received low- dose methylprednisolone
(< 20 mg/ kg/ day), among whom the mortality rate was 48 percent (12 out of 25) (Li
et al., 2023). In 2008, Okumura and colleagues retrospectively studied outcome in
pediatric ANEC cases (n = 34) who were divided into those with brainstem lesions
and those without (Okumura et al., 2009). e author found that in patients without
brainstem lesions (n = 17), administering steroids within 24 hours aer the onset
was associated with a favorable outcome, dened as no neurological sequelae or
mild cognitive impairment (Okumura et al., 2009). However, the author found no
dierence in outcome in relation to IVIG therapy (Okumura et al., 2009).
PLEX represents another treatment modality that has also been reported in several series (Chatur et al., 2022; Li et al., 2021; Okajima et al., 2022). In a 2022 study
conducted by Chatur and colleagues, the treatment regimen used in the study consisted of steroids in 95 percent (19 out of 20) of the patients, PLEX in 55 percent (11
out of 20), and IVIG in 30 percent (6 out of 20) of the participants (Chatur et al.,
2022). Outcomes in this cohort were good: most patients had no or mild motor disability at 12- month follow- up (Chatur et al., 2022). Table 18.3 summarizes suggested
therapies for ANEC along with common side eects.
Antivirals are usually administered in cases of treatable viral infections, particularly oseltamivir for inuenza infection. In 2021, Erdil and colleagues reported
Table 18.3 Suggested therapies for ANEC with dose and common side eects
Agent Dose Side eects
Methylprednisolone 30 mg/ kg/ dose (maximum 1g)
intravenously once daily for
3– 5 days
Intravenous
immunoglobulin
Plasmapheresis 5– 7 cycle exchanges over 10– 14 days
IL- 6 inhibitors
(tocilizumab)
2 g/ kg intravenously divided over
2– 5 days
(protocol varies)
12 mg/ kg/ dose (body weight < 30 kg)
8 mg/ kg/ dose (body weight ≥ 30 kg)
(maximum 800 mg) intravenously
Hypertension, hyperglycemia,
mood disturbance, gastric
irritation
Fever, chills, headache, myalgias,
nausea
Hypotension, electrolyte
derangement, vascular access
complications
Headache, rash
Acute Necrotizing Encephalopathy of Childhood 293
the use of high- dose oseltamivir (300 mg/ day) as an adjunctive therapy to immunotherapy in an adult case in which signicant clinical recovery occurred (Erdil
et al., 2021).
As some studies have shown evidence for elevated serum cytokines and a correlation between disease severity and serum IL- 6 levels, treatments targeting
this cytokine have garnered interest (Aiba et al., 2001). Tocilizumab, a humanized anti- IL- 6 receptor antibody, has been extensively used in the treatment of
many immune- mediated diseases (Kang et al., 2015). Its use has also been described in some case reports of ANEC, with good tolerability and no adverse
effects (Appavu et al., 2021; Ho et al., 2023; Hosie et al., 2023; Koh et al., 2019).
In 2023, Hosie and colleagues described two patients diagnosed with ANEC
who received early add- on tocilizumab treatment (administered within less than
24 hours) with favorable outcomes, despite the presence of severe neurological
manifestations (Hosie et al., 2023).
Outcomes
Early reports of ANEC (1995– 1997) identied generally poor outcomes, with a
mortality rate of approximately one out of four of patients (27 percent, 14 out of
51) (Mizuguchi, 1997). More recently, with greater and likely earlier recognition together with early and aggressive use of immunosuppressive therapies, some groups
have reported lower mortality rates. In 2021, a retrospective study conducted by
Appavu and colleagues on RANBP2 gene mutation- negative ANEC cases (n = 7),
reported a mortality rate of 14 percent (one out of seven) (Appavu et al., 2021). It
is noteworthy that that child in this series who passed away did not receive any immunotherapy, while the others received steroid treatment either alone or in combination with IVIG or tocilizumab. Similarly, Chatur and colleagues reported a
mortality rate of 5 percent (one out of 20) (Chatur et al., 2022). In this study, patients
received early treatment, including steroids, PLEX, and IVIG (Chatur et al., 2022).
No signicant dierences in motor outcomes between patients who tested positive
and negative for the RANBP2 gene mutation were found (Chatur et al., 2022). In the
aforementioned 2023 study of nine RANBP2- positive ANEC patients, as expected,
the two patients with multiple attacks had worse outcomes (Sarigecili et al., 2023).
One patient died at the time of third attack, while another was le with paraplegia
following the second attack (Sarigecili et al., 2023). Factors contributing to the variability in mortality rates and outcomes remain uncertain but may include dierences
between the cohorts, referral patterns, or treatment approaches.
Several studies have attempted to identify factors that predict outcomes of ANEC
patients. Zhu and colleagues found that factors such as the interval (< 1 day) from
prodromal infection to acute encephalopathy, the degree of altered consciousness,
and tracheal intubation were signicantly correlated with severe neurologic sequelae
(Zhu et al., 2021). e presence of brainstem lesions on MRI and the number of
Infectious Disease and Neurocognition
lesions has also been associated with poor outcomes (Chatur et al., 2022; C. G. Lee
et al., 2014; V. W. M. Lee et al., 2023; Zhu et al., 2021).
In 2015, Yamamoto and colleagues developed an acute necrotizing encephalopathy severity score, with scores ranging from 0 to 9 (Yamamoto et al., 2015). e
score incorporates clinical, imaging, and radiological data, assigning 3 points for the
presence of shock, 2 points for age greater than 48 months, 2 points for a brainstem
lesion, 1 point for platelet counts of less than 100,000 μL, and 1 point for CSF protein
concentration greater than 60 mg/ dL (Yamamoto et al., 2015). is score was used
in another 2016 study that supported the correlation with mortality and morbidity
in patients with high scores (Lim et al., 2016). As for longer- term outcomes, Chatur
and colleagues did not nd an association between the initial acute necrotizing encephalopathy severity score and motor outcomes at 12 months (Chatur et al., 2022).
is may be due to relatively good outcomes in this population, with little to no
motor disability seen at 12 months (Chatur et al., 2022).
Finally, poor cognitive outcomes may be seen in ANEC. A case series of children
with a history of ANEC demonstrated impairments in attention in three of three
children at 18 months, 10 years, and 10 years of follow- up respectively (Williams
et al., 2019).
Conclusion
ANEC is an encephalopathy syndrome that is seen primarily in association with
viral infections and which has distinctive clinical– radiological features. Recent research has revealed an interplay between genetic factors, specically the RANBP2
gene, and viral pathogens, although the precise mechanism by which the viral infection induces CNS abnormalities remains unknown. Studies suggest that the clinical
and radiological manifestations may be due to immune mechanisms and a resulting
cytokine storm. Treatment primarily focuses on modulating the immune system
through the use of steroids, IVIG, and PLEX, with novel therapies targeting the cytokine pathway. Outcomes of ANEC are variable, but early treatment and recognition may reduce mortality rates and lead to improved outcomes. Further studies are
needed to determine whether genetics plays a signicant role in determining different outcomes and the extent and degree of any adverse cognitive outcomes.
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