Acute necrotizing encephalopathy (ANE) is a fulminant disease of the brain characterized by bilateral thalamic lesions, and is prevalent among children in East Asia. The prognosis of ANE is usually poor with a high mortality rate and neurological sequelae. This study aimed to delineate the clinical characteristics and prognostic factors of ANE.
We retrospectively analyzed clinical data of 399 pediatric patients with encephalitis who were admitted to Samsung Medical Center from December 1998 to March 2011. We enrolled ten patients (11 cases) with ANE and analyzed their demographic, clinical, and neuroimaging data. The location and extent of the brain regions were checked based on fluid-attenuated inversion recovery, T1-, and T2-weighted imaging findings; the presence of contrast enhancement, restricted diffusion, and hemorrhage.
Ten patients were identified, including one patient with two episodes. The median age of onset was 1.5 years (0.4-8.4 years). The mortality rate was 40%, and only 30% of patients survived without neurological sequelae. The definite involvement of the brainstem on brain magnetic resonance imaging was significantly correlated with mortality (
Broad and extensive brainstem involvement suggested the fulminant course of ANE. Early diagnosis of ANE before brainstem involvement, through careful identification of symptoms of brain dysfunction, may be the best way to achieve better neurological outcomes.
Acute necrotizing encephalopathy (ANE) is a novel disease entity proposed by Mizuguchi
There have been a few studies regarding prognostic factors of ANE such as early steroid treatment, magnetic resonance imaging (MRI) findings, or involvement of the brain stem
We reviewed the medical records of 399 pediatric patients (≤18 years old) with encephalitis who were admitted to Samsung Medical Center (Seoul, Korea) from December 1998 to March 2011. This study included patients who diagnosed with ANE based on the criteria proposed by Mizuguchi
In each episode, clinical data were collected based on the retrospective chart review including sex, age, initial clinical manifestations, clinical course, initial laboratory findings, electroencephalography (EEG) findings, causative organism of associated febrile illness, treatment modalities, and outcome.
Neuroimaging was reviewed by a neuroradiologist. The location and extent of signal abnormalities were checked by brain computed tomography (CT) or MRI with fluid-attenuated inversion recovery (FLAIR), T1-, and T2-weighted images. The presence of contrast enhancement in the lesions was also identified. For differentiation of cytotoxic and vasogenic edema of the lesions, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) map images were used. Vasogenic edema (interstitial edema) usually shows high-signal intensity on DWI with an increased ADC map. However, cytotoxic edema (cellular swelling) expresses high-signal intensity on DWI and low-signal intensity on ADC maps. Detection of hemorrhage in the lesion was aided using T2- and T1-weighted images and gradient-echo imaging in patients with MRI. Neuroimaging findings were analyzed by the distribution, pattern and presence of hemorrhage. We paid particular attention to the analysis of the extent and signal intensity of brain stem lesions, the midbrain, pons, and medulla oblongata, for the identification of prognostic factors. The findings of brain stem involvement were as follows: diffuse broad hypointensity on CT, broad hyperintensity on T2-weighted/FLAIR MRI, diffusion restriction (cytotoxic edema) on DWI/ADC, and hemorrhage. The brain stem lesions were divided into three groups (none, mild, and definite) based on extent and signal-intensity as followed: none defined as absent involvement, mild defined as extent of involvement in below 2 lesions among midbrain, pons, and medulla oblongata and subtle signal change without diffusion restriction and hemorrhage, and definite defined as broad extent more than three or marked signal change with diffusion restriction or hemorrhage.
Ethical approval for this retrospective study was provided by the Institutional Review Board of Samsung Seoul Medical Center in Seoul, Korea (SMC 2011-04-104-002).
Data are presented as median and range. Statistical analysis was performed to identify different factors between death and survival groups with the Fisher exact test. And the predictors of mortality in ANE was estimated using multivariate Cox regression and Mann-Whitney test with PASW Statistics 18.0 (SPSS Inc., Chicago, IL, USA). The statistical significance threshold was set at
Of the 399 pediatric patients, we identified ten patients (male:female=6:4) with ANE, including a patient with two episodes (
The clinical characteristics of the patients and the clinical presentations of viral illness are summarized in
The neuroimaging findings are summarized in
Every patient showed symmetric involvement of the thalamus, however, patient 6 showed bilateral but asymmetric (left>right) thalamic involvement (
Cervical spinal cord lesions were observed in patient 2 (
Seven cases (63.6%) had brain stem involvement. We analyzed the extent (the midbrain, pons, and medulla oblongata) and signal-intensity of brain stem lesions. The extent and signal-intensity of brain stem lesions were divided into three groups: absent signal change (none, n=4), subtle signal change (mild, n=3), and broad extent and marked signal change (definite, n=4). The findings of brain stem involvement were as follows: diffuse broad hypointensity on CT, broad hyperintensity on T2-weighted/FLAIR MRI, diffusion restriction (cytotoxic edema) on DWI/ADC, and hemorrhage.
All patients underwent EEG during acute encephalopathic periods. Ten cases (10/11, 91%) initially showed abnormal EEG. The EEG revealed diffuse encephalopathic findings characterized by diffuse background slow activity (n=6) or voltage suppression (n=3) on cerebral background rhythm. In addition, regional intermittent slow (n=1) and focal epileptiform activities (n=3) were observed. EEG seizure was recorded in two patients (patient 3 and 10).
Mild elevation of liver transaminases was found in ten cases. The median level of aspartate aminotransferase was 53 U/L (27-209 U/L), and the median level of alanine aminotransferasewas 31 U/L (15-242 U/L). The metabolic tests such as serum amino acid analysis, serum ammonia and lactate/pyruvate level, and urine organic acid analysis were all normal. Lumbar puncture was performed in eight patients (73%); cerebrospinal fluid (CSF) pleocytosis (>5/L) was found in four patients (9-175/µL), and increased CSF protein (>45 mg/dL) was found in five patients (88-246 mg/dL). Pathogens responsible for antecedent infections were identified in 63.6% of cases (7/11) (
The clinical course and management during their hospital admission are summarized in
The overall mortality rate was 40% (4/10). Three patients became brain death within three days from the day of mental status change. The median follow-up duration of six survivors was 3.3 years (range, 1.6-5.6 years). Neurological impairments such as motor deficits, developmental language delay and epilepsy were observed in three of six survivors. Definite involvement of the brain stem in brain imaging exhibited a significant statistical association with mortality (
This study delineated the clinical characteristics, various disease courses and prognosis of ANE patients at a single institution and revealed that definite involvement of the brain stem noted by brain imaging is a significant prognostic factor of ANE.
ANE in childhood is rare. It is a fulminant and life-threatening neurologic disease that usually occurs in healthy children. The reported mortality rates are as high as 30%
There have been many studies to identify prognostic factors associated with ANE. According to previous studies, age, sex, and the presence of causative agent were not significant prognostic factors, which are consistent with the findings in this study
In the present study, definite radiologic involvement of the brain stem was significantly associated with mortality. The relationship between characteristic MRI findings and outcome has also been reported in several previous studies. Kim et al.
There was a patient with cervical spinal cord involvement (
Most cases of ANE are sporadic and do not recur. However, familial and recurrent cases have been reported, and some of them were linked to mutations in RAN-binding protein2 (RANBP2)
This study has a limitation stemming from the rarity of the disease. Patients were treated at a single institution but managed over a long time period, under different clinical situations.
In conclusion, definite involvement of brainstem on brain MRI was associated with the fulminant course of ANE. Early diagnosis and prompt treatment of ANE before brainstem involvement through the close observation of symptoms of brainstem dysfunction in patients with mental status change after a febrile illness may ensure the better neurological outcome.
No potential conflict of interest relevant to this article was reported.
Magnetic resonance imaging findings of a 9-month-old girl (patient 7) who died. (A, B) T2-weighted axial images show increased signal intensity in the thalami and medial temporal lobe. (C, D) Axial gradient-echo images show decreased signal intensity in the thalami and medial temporal lobe indicating hemorrhage. (E, F) Apparent diffusion coefficient images reveal hypointensity in the thalami and medial temporal lobe.
Magnetic resonance imaging findings of a 19-month-old girl (patient 6) who had asymmetric (left dominant) thalamic involvement and recovered completely. (A, B) Initial T2-weighted axial image showing asymmetric increased signal intensity in the thalami (arrows). The dorsal pons (double arrows) was also involved. (C, D) These abnormal signal intensities disappeared on follow-up magnetic resonance images obtained one week after the initial study.
Magnetic resonance imaging findings of a 5-month-old boy (patient 2) who had upper cervical spinal cord involvement. (A) T2-weighted sagittal image shows a high signal intensity lesion in the upper cervical spinal cord (white arrow). (B, C) T2-weighted axial images show increased signal intensity in the thalami (arrows) and cerebellum (double arrows).
The patients' characteristics and antecedent infections
DD, developmental delay; CSF, cerebrospinal fluid; PCR, polymerase chain reaction.
*Same patients with recurrent events. †Nasopharyngeal aspirates. ‡Nasal swab/CSF. §Stool. ∥Respiratory virus PCR. ¶Respiratory virus culture. **H1N1 real time PCR. ††Rotavirus antigen test.
Clinical course and management during admission
ICU, intensive care unit; IVIG, intravenous immunoglobulin; GT, general tonic; CPS, complex partial seizure; GTC, generalized tonic clonic seizure; DLD, developmental language delay; PS, partial seizure.
*Same patients with recurrent events.
Radiological characteristics of 11 Episodes
DWI, diffusion-weighted image; ADC, apparent diffusion coefficient; CT, computed tomography; MRI, magnetic resonance imaging; Th, thalamus; BG, basal ganglia; MD, midbrain; Cbll, cerebellum; Sp, spines; WM, white matter; IC, internal capsule; MO, medulla oblongata; EC, external capsule; HIS, high-intensity signals; LIS, low-intensity signals; GM, gray matter; DLD, developmental language delay.
*Same patients with recurrent events.
Factors associated with increased mortality
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