Parameters Indicating Development of Influenza-Associated Acute Necrotizing Encephalopathy: Experiences from a Single Center

Abstract

BACKGROUND Influenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE. MATERIAL AND METHODS Acute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared. RESULTS A total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski's sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings. CONCLUSIONS Early clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.

Figure 1

Box and whiskers of specific biochemical serum levels (median+IQR and show all points).

Figure 2

Box and whiskers of specific biochemical CSF levels (median+IQR and show all points).

Figure 3

Mild Encephalopathy with a Reversible Splenial (MERS) lesion: Fever 1 day, with 2 seizures. Axial T2WI (A) and T2WI-FLAIR (B) of MRI shows that the small piece of bright signal (arrow) in splenium of corpus callosum; no abnormality was found in the rest of the parenchyma.

Figure 4

Acute Necrotizing Encephalitis of Childhood (ANE). Fever 1 day, convulsion 3 times. Symmetrical and multifocal involvement were showed in bilateral thalamus and paraventricular (A. T1WI, B. T2WI, C. T2WI-FLAIR) and radial coronal hemisovale center (D) white matter with bilateral thalamus swollen.

Figure 5

Emesia, febris for 5 days, followed by coma, with throat wrap for influenza type B positive (A–C). (A) Axial T2WI MRI showed mildly higher focal signal intensity in the dorsal aspect of pons (arrow), and mildly higher patchy signal intensity in white matter at bilateral temporal lobe (arrow). (B) Axal T2WI MRI indicated symmetric swelling and higher signal intensity in bilateral thalami (arrow), and white matter in external capsule was involved. (C) Axial T1WI MRI indicated mildly lower signal intensity in bilateral thalami (arrow) with slightly higher signal intensity in center (*), involvement of white matter in external capsule (*) was visible; axial ADC map showed more detailed 3-layer structure of bilateral thalami in ANE (arrow).

Figure 6

Comparison of brain vascular innervation area and MRI of IANE.

Figure 7

Diagram of the structural relationship between blood vessels, astrocytes, and AQP-4.