Abstracts

Rationale: Acute necrotizing encephalopathy (ANE) is a rare disorder characterized by fever, seizures, and altered mental status following a viral infection, without evidence of an infectious encephalitis. Recurrent cases of ANE in families demonstrated mutations in the nuclear pore protein Ran Binding Protein 2 (RANBP2). Adult ANE cases have been reported associated with COVID-19 infection. There has been no reported pediatric case of ANE associated with COVID-19.

Methods: Here, we report a case of recurrent ANE in a pediatric patient with RANBP2 mutation, associated with COVID-19 infection, and treated with aggressive immunotherapy with clinical improvement.

Results: A 24-month-old boy with history of febrile seizures presented with fever, emesis, clinical seizures and encephalopathy. SARS-CoV-2 RNA PCR was positive. Brain magnetic resonance imaging (MRI) showed bilateral symmetrical non-enhancing T2 and fluid attenuated inversion recovery (FLAIR) hyperintensities in the thalami, hippocampi, medial temporal lobes, periaqueductal gray and dorsal midbrain, and external capsules, with small areas of necrotic change in the external capsules, medial temporal lobes, and periaqueductal gray, along with restricted diffusion and microhemorrhages; concerning for ANE (Fig 1A). He received intravenous immunoglobulin (IVIG) 2 g/kg and dexamethasone 1mg/kg daily (rapid taper off by discharge), with clinical improvement to baseline on hospital day (HD) 4 and discharge home HD7.

He again presented at age 30 months with fever, abdominal pain, clinical seizures and encephalopathy. Brain MRI (Fig 1B) showed increased bilateral T2/FLAIR hyperintensities, areas of necrosis with patchy enhancement in the midbrain and pons bilaterally, and new areas of restricted diffusion and microhemorrhages. Continuous video EEG captured left occipital-onset subclinical status epilepticus and multifocal spike waves. Seizures resolved with lorazepam 0.3 mg/kg total, fosphenytoin 30 mg/kg total, valproic acid 40 mg/kg total and maintenance levetiracetam 60 mg/kg/day. Cerebrospinal fluid (CSF) interleukin (IL)-6 and IL-8 were markedly elevated (Table 1).

He was treated with a course of methylprednisolone 30 mg/kg and IVIG 2g/kg starting HD2, and tocilizumab 12 mg/kg HD4 with gradual improvement until new extremity weakness developed HD10. Dexamethasone 0.5 mg/kg daily was started. Repeat MRI showed increased subcortical white matter T2/FLAIR hyperintensities in the left frontal, bilateral parietal, and bilateral temporal lobes (Fig 1C). After 3 plasmapheresis sessions followed by initiation of tocilizumab, IVIG and dexamethasone he regained antigravity extremity movements HD27. Genetic testing demonstrated RANBP2 mutation c.1966A >G previously associated with recurrent ANE.

Conclusions: Patients who present with recurrent ANE should be evaluated for RANBP2 mutation. Cytokine storm plays a major role in ANE pathogenesis, and CSF IL-6 may be elevated. Immunotherapy is the mainstay of ANE treatment, and early IL-6 pathway blockade with tocilizumab may be beneficial.

Funding: Please list any funding that was received in support of this abstract.: No funding sources to report.