Case Report: long-term clinical outcomes in RANBP2-associated acute necrotizing encephalopathy

Abstract

Introduction: Acute necrotizing encephalopathy (ANE) is a rare and severe neurological condition primarily affecting children and commonly triggered by viral infections. Morbidity and mortality rates are high. Pathogenic RAN-Binding Protein-2 (RANBP2) variants predispose children to recurrent ANE, known as ANE1, and increase the risk of severe outcomes and early death. Although the pathophysiology of ANE is not fully understood, an inflammation-mediated "cytokine storm" is believed to play a crucial role in central nervous system involvement. Currently, there is no guidance on the optimal duration of immunotherapy.

Case presentation: We present a new pediatric case of RANBP2-associated ANE1, and update one previously published case, detailing their clinical characteristics, treatment strategies, and outcomes. Magnetic resonance imaging revealed lesions characteristic of ANE. In one patient, cerebrospinal fluid (CSF) analysis showed pleocytosis without evidence of bacterial or viral pathogens, and elevated CSF levels of interleukin-6 (IL-6) and IL-8 were consistent with neuroinflammatory response. Both patients experienced rapid neurological decline during ANE attacks. However, both patients were treated with timely immunotherapy, including steroids, plasma exchange, intravenous immunoglobulins, and tocilizumab, with favorable responses.

Conclusion: Recurrent ANE or ANE with a family history of severe neurological events in childhood should raise suspicion for RANBP2-associated ANE1. These cases emphasize the importance of early recognition, prompt immunotherapy initiation, and close monitoring in patients with ANE1. Our cases also contribute to the limited body of knowledge on neuroimaging, treatment, and outcomes in this rare condition, which is of great importance given that the optimal duration of immunotherapy in ANE1 is currently unknown.

Keywords: RANBP2 variant; acute necrotizing encephalopathy; brain MRI; case report; immunomodulation; viral infection.

FIGURE 1

Timelines of clinical events. Timelines illustrate key clinical milestones during and after the first and second admissions for Case 1 at ages 23 and 58 months (4 years, 10 months) (A) and the second and third admissions for Case 2 at ages 30 and 40 months, respectively (B). Clinical events are marked with black circles, immunotherapies with blue circles, and genetic sequencing with green circles.

FIGURE 2

Case 1 MRI and EEG. Case 1 brain MRI at age 23 months demonstrated multiple foci of diffusion restriction on diffusion-weighted imaging (A) with associated hyperintensity on fluid-attenuation inversion recovery (FLAIR) images (B) and microhemorrhages on gradient-echo images (C) in bilateral thalami, prompting concern for acute necrotizing encephalopathy. Continuous video EEG (bipolar montage, sensitivity 15 uV/mm, timebase 30 mm/s) initially showed severe diffuse slowing with delta waveforms. (D) With improvement 1 day after tocilizumab administration (E).

FIGURE 3

Case 2 MRI and EEG. Case 2 brain MRI age 40 months showed recurrent ANE with multiple new foci of diffusion restriction within bilateral basal ganglia, external and internal capsules, thalami, and corpus callosum on diffusion-weighted imaging, consistent with recurrent acute necrotizing encephalopathy (A,B). Follow-up brain MRI at age 4.5 years showed interval resolution of basal ganglia/thalamic abnormalities with persistent pontine encephalomalacia (C). Continuous video EEG (bipolar montage, sensitivity 15 uV/mm, timebase 30 mm/s) showed left hemisphere-onset seizures (D) with status epilepticus (E). Quantitative EEG spectrogram and amplitude-integrated trends (2-h duration) showed frequent left hemisphere-onset seizures progressing to subclinical left hemisphere-onset status epilepticus with secondary generalization (F).