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Acute necrotizing encephalopathy …
- Updated 03.30.2026
- Expires For CME 03.30.2029
Acute necrotizing encephalopathy
Introduction
Overview
Acute necrotizing encephalopathy is a rare, rapidly progressive, and potentially life-threatening encephalopathy that follows an acute febrile illness. Most cases of acute necrotizing encephalopathy are sporadic and nonrecurrent, whereas familial cases have been increasingly recognized. The clinical course is diverse, but the key characteristics of this encephalopathy are the radiographic findings of multiple, symmetrical lesions involving the thalami, tegmentum of the upper brainstem, and other regions. Standardized management protocols are lacking, and tailored treatment plans, along with early diagnosis and timely interventions, are critical for improving outcomes and increasing survival.
Key points
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• Acute necrotizing encephalopathy is considered the outcome of a complex interaction between a viral trigger, immunologic activation, and host genetic susceptibility. | |
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• Despite advances in medicine and technology, acute necrotizing encephalopathy has high mortality and potential for neurologic sequelae. | |
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• There are no guided pharmaceutical treatments, and immunomodulatory therapeutic interventions appear to be the most effective. Prevention, early recognition, and intensive care are essential for a favorable outcome. |
Historical note and terminology
The first case of acute necrotizing encephalopathy was reported in 1979 and was misdiagnosed as Reye syndrome because, at that time, imaging evidence was not sufficient to differentiate this encephalopathy from Reye syndrome. The establishment of acute necrotizing encephalopathy as a new disease came in 1995, when Mizuguchi and colleagues described the first cases of an unrecognized form of acute encephalopathy, prevalent among children in Japan and Taiwan, by reviewing the records of 41 cases (28). The key characteristic of this encephalopathy was the multiple symmetrically distributed necrotic brain lesions. Although initially described exclusively in children from Japan and Taiwan (27), subsequent cases have been reported worldwide, including adult patients, indicating no racial, geographic, or age predilection (17; 09). With time, recurrent or familiar forms of acute necrotizing encephalopathy were attributed to a missense mutation in the nuclear pore-gene RANBP2 (Ran-bindings protein-2) (34). Nowadays, it is becoming clear that most of the acute necrotizing encephalopathy cases may be characterized as a genetic disorder that requires an infectious trigger (33).
Clinical manifestations
Presentation and course
The presentation and clinical course of acute necrotizing encephalopathy can be diverse. The prodromal symptoms can differ depending on the triggering infection, whereas the presenting symptoms vary from mild encephalopathy and seizures to systemic inflammatory response syndrome with shock and multiple organ failure. Most patients with acute necrotizing encephalopathy have a prodromal phase with fever and signs of upper respiratory tract infection (cough, rhinorrhea, pharyngitis, lymphadenopathy), as well as vomiting or diarrhea.
The first signs of encephalopathy appear 0.5 to 3 days after the onset of the antecedent infection. In the acute phase of encephalopathy, the physical findings resemble those of any other type of acute encephalopathy. The incidence of seizures is high in acute necrotizing encephalopathy and can develop at early stages of the encephalopathy. The level of consciousness may fluctuate during the initial few hours but can rapidly deteriorate into coma, usually within 24 hours (27).
Familial and recurrent cases of acute necrotizing encephalopathy due to RANBP2 gene mutations have incomplete penetrance and show considerable clinical diversity among patients (23).
Prognosis and complications
The prognosis may range from complete recovery to permanent neurologic damage and death (28; 33). It is estimated that acute necrotizing encephalopathy has a mortality rate 30% to 40%; most patients will have severe neurologic sequelae, and fewer than 10% will achieve complete recovery. Recovery usually begins around the fifth day of admission and continues for several weeks. Prolonged hospitalization and rehabilitation may be required (50). Although it is unclear what contributes to a more favorable outcome, patients younger than 4 years of age, those with low serum aminotransferase, and those with no involvement of the brainstem are associated with decreased risk of death (27; 04).
In a study of pediatric patients with new-onset acute necrotizing encephalopathy, a severity score (termed ANE-SS) was developed and used to evaluate neurologic outcomes. The ANE-SS score incorporates shock (3 points), brainstem lesions (2 points), age over 48 months (2 points), platelet count below 100,000/μL (1 point), and CSF protein above 60 mg/dl (1 point). Patients were divided into three groups based on their ANE-SS score. The low-risk patients (ANE-SS score 0 to 1 points) had no or mild sequelae. Of the medium-risk patients (ANE-SS score 2 to 4 points), 11% had no or mild sequelae, 22% had moderate sequelae, and 66% had severe sequelae or death. Of the high-risk patients (ANE-SS score 5 to 9 points), 88% had severe sequelae or death, showing a significant correlation between the risk classification and disease outcome (51).
In another retrospective study of children with acute necrotizing encephalopathy, several tools were employed, including MRI score, brainstem auditory evoked potential grades, and ANE-SS and modified Rankin scale (mRS), to predict prognosis. Among these, brain MRI appeared more helpful for predicting prognosis in patients with acute necrotizing encephalopathy (08). Another study found a significant and positive correlation between MR imaging score and clinical outcome in patients with acute necrotizing encephalopathy. MRI features awarded points included hemorrhage, cavitation, and location of the lesions in the brainstem and white matter (cerebral, cerebellar, or both) (49).
Biological basis
Etiology and pathogenesis
The pathology of acute necrotizing encephalopathy is characterized by breakdown of the blood-brain barrier, cellular damage, and, typically, the absence of immune cells and infectious agents in the CNS. The etiology and pathogenesis of acute necrotizing encephalopathy remain largely unclear; it is likely that a hyperactive immune response triggered by a viral or other infectious agent causes brain injury and other systemic symptoms. The identified or presumed pathogens responsible for triggering this type of encephalopathy are summarized in Table 1. Among these pathogens, influenza has been the infection most commonly associated with acute necrotizing encephalopathy (13; 15). A nationwide survey in Japan found influenza (41%) and HHV-6 (20.5%) to be more frequently associated with acute necrotizing encephalopathy, whereas no association was found with bacterial infections (13).
Results from a small study, comparing influenza versus non-influenza acute necrotizing encephalopathy cases, suggest that the pathogenesis of acute necrotizing encephalopathy is not dependent on the infectious agent (36).
It is hypothesized that the inflammatory effects triggered by the initial infection generate a “cytokine storm,” with interleukin-6 (IL-6) and TNF-alpha playing central roles. This cytokine cascade damages the CNS vascular endothelium and causes liver dysfunction, acute renal failure, shock, and disseminated intravascular coagulation (01; 30; 16). New insights into acute necrotizing encephalopathy pathogenesis were brought by the discovery of mutations in the genes RANBP2, SCN1A R1575C, and carnitine palmitoyltransferase (CPT) II (41). Furthermore, a correlation is recognized between HLA genotypes and acute necrotizing encephalopathy susceptibility (43).
Table 1. Infectious Triggers of Acute Necrotizing Encephalopathy
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Influenza A (H3N2, H1N1) |
Epidemiology
Acute necrotizing encephalopathy is a rare disease; hence, its epidemiology is largely unknown. Young children seem to be disproportionately affected; however, patients across all age groups and both sexes have been reported (28). Seasonal trends occur mostly in winter and spring (53; 52). Acute necrotizing encephalopathy was initially reported predominantly in Asian countries, and in particular Japan (27; 13). However, additional cases were later reported in Western countries, suggesting that it can occur globally (48; 26; 46). The incidence of acute necrotizing encephalopathy is inferred from studies of influenza-associated encephalopathy (a subgroup of acute necrotizing encephalopathy) because these are the only available large-scale data sources (33). Overall, it is estimated that acute necrotizing encephalopathy accounts for 10% to 20% of influenza-associated encephalopathy cases (35; 44; 45).
Nationwide surveys in Japan rank acute necrotizing encephalopathy among the three leading causes of acute encephalopathy (13; 32). In a large population-based California study of influenza-associated encephalopathy cases, only one adult male among the 2069-patient cohort had acute necrotizing encephalopathy (11). Influenza-associated encephalopathy has not been the focus of US public health surveillance systems until recently (10).
Prevention
The predominance of H1N1 in pediatric cases of acute necrotizing encephalopathy and the low vaccination rates among affected children highlight the importance of seasonal influenza vaccination to protect against influenza and its associated potentially fatal complications (15). This was also demonstrated in a large epidemiological study conducted in Japan, where mass vaccination of school-aged children was associated with a reduction in mortality rate from influenza-associated acute encephalopathy (38).
Differential diagnosis
Confusing conditions
The combination of symptoms, including fever, convulsions, and impaired consciousness in previously healthy children with a preceding viral infection, is common to many acute encephalopathy syndromes. The differential diagnosis between acute necrotizing encephalopathy and encephalopathy due to CNS infection (viral, bacterial, parasitic, or fungal) is based mainly on the CSF findings. In cases of meningoencephalitis, the CSF is typically pleocytic. Also, the imaging findings in meningoencephalitis are usually asymmetric, and brainstem involvement is rare. On MRI, acute disseminated encephalomyelitis typically appears as elliptical to circular patchy lesions that involve the white matter, with asymmetric cortical and subcortical lesions (39). Autoimmune encephalitis usually has a slower clinical course; the brain lesions involve both grey and white matter, and the diagnosis is based on detection of specific autoantibodies (06). Cranial vascular diseases, including central venous or arterial thrombosis, can be detected with contrast-enhanced MRI and MRV/A.
From a neuroimaging and pathology perspective, acute necrotizing encephalopathy should be differentiated from other encephalopathies that can present with bilateral brain lesions in the deep grey matter. These include Leigh syndrome, mitochondrial disorders, glutaric acidemia, methylmalonic acidemia, Wernicke encephalopathy, carbon monoxide poisoning, infantile bilateral striatal necrosis, and other types of encephalopathies that result from severe hypoxia or head trauma. These encephalopathies can be differentiated based on the clinical history and biochemical studies (28).
Diagnostic workup
The diagnosis of acute necrotizing encephalopathy was established using the diagnostic criteria proposed by Mizuguchi and colleagues (28; 27). The diagnosis of acute necrotizing encephalopathy is based on a combination of clinical, laboratory, and neuroimaging findings, as outlined by the Japanese Society of Child Neurology and the International consensus definitions for infection-triggered encephalopathy syndrome (29; 42).
The MRI findings in cases of acute necrotizing encephalopathy are characterized by diffuse brain edema and bilateral symmetric, edematous or necrotic lesions in specific brain regions, including the thalami. On days 1 and 2, the lesions show low T1, high T2, and decreased diffusion. On day 3 and thereafter, the thalamic lesions show a concentric appearance, with a central T1-high lesion indicating hemorrhagic changes. Diffusion-weighted imaging shows increased diffusion (necrosis and perivascular hemorrhage) in the center of the thalamic lesion, restricted diffusion (edema and loosening of neuropil) in the surrounding zone, and increased diffusion (extravasation of plasma) in the periphery. From the second week, there is progressive cerebral atrophy and shrinkage or disappearance of thalamic lesions (29).
Table 2. Diagnostic Criteria of Acute Necrotizing Encephalopathy
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Essential for the acute necrotizing encephalopathy diagnosis is a febrile illness preceding or concurrent with the neurologic manifestation | |
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Clinical | |
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Essential: deterioration of consciousness, lethargy, or personality change lasting more than 24 hours | |
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Common: rapid (hours) reduction of consciousness (with or without seizures) or focal neurologic signs | |
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Brain imaging (CT/MRI) | |
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Essential: symmetric thalamic lesions | |
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Common: periventricular white matter, internal capsule, putamen, brainstem, cerebellum lesions (symmetric, multifocal) | |
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Laboratory findings | |
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Common: Absence of CSF pleocytosis, increased CSF protein, elevated serum transaminase levels with no elevation of serum ammonia levels. | |
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Essential for diagnosing acute necrotizing encephalopathy is the exclusion of other diseases (infectious, metabolic, toxic, autoimmune) | |
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*If all the essential criteria are fulfilled, the diagnosis of acute necrotizing encephalopathy is definite. | |
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Acute necrotizing encephalopathy type 1 is diagnosed if any of the criteria in Table 3 is met. | |
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| |
Table 3. Diagnostic Criteria of Familial or Recurrent Acute Necrotizing Encephalopathy Type 1 (ANE1)
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(1) Familial clustering of encephalopathy following fever, including at least one episode of acute necrotizing encephalopathy | |
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(2) Recurrent encephalopathy following fever, including at least one episode of acute necrotizing encephalopathy | |
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The thalamic lesions appear pathognomonic for acute necrotizing encephalopathy, whereas laboratory findings show considerable variability across patient series (22; 40). Therefore, it was proposed that the aforementioned criteria be revised into major or minor categories. Major criteria would include acute encephalopathy preceded by viral febrile illness, neuroradiologic findings of symmetrical brain lesions involving the bilateral thalami and other regions, and exclusion of other diseases. Minor criteria would include increased CSF protein without pleocytosis and variable elevations of serum aminotransferase levels without hyperammonemia. It has been proposed, and it seems more practical, that a patient with three major criteria and any two minor criteria can be diagnosed with acute necrotizing encephalopathy (22). However, these modifications to the diagnostic criteria have not been fully validated and are not widely used (39).
Acute necrotizing encephalopathy type 1 cases typically develop encephalopathies consistent with acute necrotizing encephalopathy, whereas others lack the characteristic thalamic lesions. Neuroimaging in acute necrotizing encephalopathy type 1 depicts lesions confined to the thalami bilaterally and pons rather than diffuse lesions. In addition, lesions may be seen in the external capsules, claustra, medial temporal lobes, amygdala, and hippocampi (23). CSF examination shows a normal cell count and elevated or normal protein. Serum aminotransferase, lactate dehydrogenase, creatine kinase, and urea nitrogen levels are usually elevated, but there is no hyperammonemia (33).
Management
A number of treatments have been used for acute necrotizing encephalopathy; however, there is no approved medication, no randomized controlled trial, and no evidence-based guidelines to support any specific approach. Interventions used in most cases include intensive and supportive care, empiric treatments (antiviral agents), and immunomodulatory therapies (02). Given the presumed pathogenesis of acute necrotizing encephalopathy, immunomodulatory approaches seem to hold the biggest potential. Among the immunomodulatory treatments commonly used are glucocorticoids, intravenous immunoglobulins, and plasma exchange (37; 05; 25). Glucocorticoid treatment is the most frequently used, but doses and courses vary widely across studies (37; 22; 24). Pulse-dose steroid therapy (30 mg/kg of methylprednisolone for 3 days or intravenous dexamethasone 0.6 mg/kg in four divided doses for 2 to 4 days) early in the course of the disease has been associated with improved outcomes (37; 02). In clinical practice, methylprednisolone is generally administered in combination with IVIG in an attempt to further reduce neuroinflammation, although the exact role of IVIG in the treatment of acute necrotizing encephalopathy is unclear (20; 05).
Corticosteroid use has been associated with improved outcomes in acute necrotizing encephalopathy type 1 cases, the acute necrotizing encephalopathy subtype with a genetic substrate and a relapsing course. This favorable effect has been associated not only with steroid anti-inflammatory effects but also with their protective effects on mitochondria, allowing for neuroprotection and synaptic plasticity (03). On the contrary, immunoglobulins or plasmapheresis have not been associated with any therapeutic benefit in cases of acute necrotizing encephalopathy type 1 (23).
Given the pathophysiology of acute necrotizing encephalopathy, there has been increased interest in treatments blocking downstream cytokine activation. Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, has been shown to be effective when administered early (18 to 32 hours after the onset of encephalopathy) and when serum IL-6 levels are not significantly elevated (18; 12; 14).
A recent retrospective study including pediatric patients supports the use of a severity-based immunotherapy approach to optimize outcomes (07). In low- to medium-risk patients (ANE-SS < 5), methylprednisolone doses of both 20 and 30 mg/kg/day significantly reduced mortality. In high-risk patients (ANE-SS ≥ 5), only the higher doses of 30 mg/kg/day methylprednisolone provided additional survival benefit. In addition, in the high-risk group, the combination of high-dose methylprednisolone (30 mg/kg/day) with tocilizumab significantly improved survival (83.3% survival rate as compared to 100% mortality in the low methylprednisolone group) (07). In the same study, plasma exchange did not have a significant therapeutic impact across all risk groups (07).
Therapeutic hypothermia has been shown to protect against the damaging effects of post-ischemic inflammation through different mechanisms, including anti-cytokine effects by reducing the levels of proinflammatory cytokines such as IL-6 and TNF-alpha (21). Immediate hypothermia has been used for patients with CPT II variant, which is thought to reduce the mitochondrial energy failure in many tissues, including the brain capillary endothelium (19). There are case reports of children with influenza-induced acute necrotizing encephalopathy, successfully treated with anti-inflammatory agents in combination with hypothermia (31; 47).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Aspasia Katragkou MD
Dr. Katragkou of Goryeb Children's Hospital has no relevant financial relationships to disclose.
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Katia Camille Halabi MD
Dr. Halabi of Goryeb Children's Hospital has no relevant financial relationships to disclose.
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Desiree-Anne Ramsaran MD
Dr. Ramsaran of The Brooklyn Hospital Center has no relevant financial relationships to disclose.
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Editor
-
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.
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Patient Profile
- Age range of presentation
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- 0 to 65+ years
- Sex preponderance
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- No sex preponderance
- Heredity
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- Autosomal incomplete dominant inheritance
ICD & OMIM codes
- ICD-10
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- Acute necrotizing hemorrhagic encephalopathy, unspecified: G04.30
- Postinfectious acute necrotizing hemorrhagic encephalopathy: G04.31
- Postimmunization acute necrotizing hemorrhagic encephalopathy: G04.32
- Other acute necrotizing hemorrhagic encephalopathy: G04.39
- ICD-11
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- Encephalopathy, not elsewhere classified: 8E47
- OMIM
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- Encephalitis, acute, infection-induced, susceptibility to, 12; IIAE12: # 620461
- Encephalopathy, acute, infection-induced, susceptibility to, 3; IIAE3: # 608033
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May. 12, 2026
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Epilepsy & Seizures
Self-limited (familial) infantile epilepsy
May. 08, 2026
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General Child Neurology
Developmental delay in children: evaluation and management
Apr. 29, 2026
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General Child Neurology
Neonatal opioid withdrawal syndrome
Apr. 29, 2026
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General Child Neurology
Guillain-Barre syndrome in children
Apr. 24, 2026
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Neuropharmacology & Neurotherapeutics
Nusinersen
Apr. 23, 2026