ANE has a unique neuroimaging pattern, including changes in the thalamus, medial temporal lobe, pons, and medullary, as well as in the striatum and subcortical peripherals [4]. In 2021, Claudia Lazarte-Rantes et al. [5] first reported a case of ANE associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a pediatric patient in the United States. The 14-month-old boy presented with fever, irritability, left focal seizure, and febrile focal seizure status as the first symptoms, which improved after symptomatic management such as mechanical ventilation, but remained with severe neuropsychiatric symptoms. Clinical studies have found [6] that the onset age of acute necrotic encephalopathy in children peaks between one and three years old, mostly in males, and the main manifestations include fever (100%), seizures (86%), and disturbance of consciousness (100%). MRI revealed increased T2 and T1 signal density in multifocal and symmetric brain lesions (bilateral thalami, 100%) in all patients during the acute phase. Most patients have severe neurological sequelae.
The underlying pathogenesis of ANE is often attributed to immune-mediated mechanisms rather than direct viral cytopathy effects. A strong systemic immune response triggered by a prior infection produces an inflammatory cytokine storm that leads to a breakdown of the blood-brain barrier, followed by edema, pestectomy, and necrosis [7]. Common viruses responsible for this include herpes simplex virus, adenovirus, the novel coronavirus, influenza virus, human rhinovirus, and others [8].
It has been found that acute necrotizing encephalopathy is related to RANBP2 mutation, accompanied by familial inheritance. In 2009, Neilson [9] and others published a landmark paper which reported that many family members suffered from acute necrotizing encephalopathy. They identified a recurrent missense mutation (c.1754C > T: p.Thr585Met, c.1958C > T: p.Thr653Ile, c.1966A > G: p.Ile656Val) in the RANBP2 gene in a large multigenerational family with autosomal-dominant ANE, and concluded that this gene mutation predisposes patients to increased susceptibility to familial ANE with an estimated probability of 40%. This gene is located on chromosome 2q2-11, and RANBP2 mutation is inherited by autosomal dominant inheritance. However, incomplete penetrance has been reported to be 40%. RANBP2 encodes a nuclear porin that plays a role primarily throughout the cell cycle, and mutations in RANBP2 are closely associated with ANE through multiple processes, including mitochondrial function, viral entry, cytokine signaling, immune response, and blood-brain barrier maintenance [7].
Acute necrotizing encephalopathy with RanBP2 mutations has a poor prognosis, and Lee YJ [10] et al. were the first to report familial acute necrotizing encephalopathy with RanBP2 mutations in East Asia, reporting that both female children died. Pongpitakmetha T[11] first reported a previously healthy 29-year-old adult case of COVID-19-associated ANE with RANBP2 mutation, who died within six days after treatment. Due to genetic susceptibility, ANE with RANBP2 mutation can be recurrent [12]. In pediatrics, Forest [13] first reported the case of a 10-year-old girl who was infected with the new coronavirus and experienced necrotizing encephalopathy. In the end the child was diagnosed with a RANBP2 gene mutation, and was admitted to the pediatric intensive care unit (PICU) at the age of two due to fever, flu symptoms and insanity. A brain MRI revealed hyperintensity of external capsules, the cerebellar cortex, hypothalamus, and the pons on fluid attended inversion recovery (FLAIR) sequences with restricted differentiation on differentiation-weighted images (DWI). The final outcome for this child was a vegetative state. Children with ANE should be tested for RANBP2 mutations to determine if they are at risk for recurrent ANE attacks. Our patient in this case was negative for RANBP2 mutations, and has a relatively good prognosis.
The clinical course of ANE can be divided into the prodrome stage, acute encephalopathy stage, and convalescence stage. The prodrome symptoms of ANE is non-specific and varied due to viral infection, including fever, upper respiratory tract infection, chest infection, diarrhea, vomiting, and headache. As ANE progresses, seizures, disturbances of consciousness, and focal neurological deficits may manifest as brain dysfunction. The common clinical manifestations of ANE are seizures, encephalopathy, and dysmotility, which progress rapidly within days, with a fatality rate of up to 30% despite aggressive immunomodulatory therapy. Patients who survive usually have poor neurological outcomes, with less than 10% of survivors recovering completely [7].
Treatment: Early intensive care, supportive therapy (such as seizure treatment and increased intracranial pressure control), antiviral therapy, intravenous corticosteroids, intravenous immunoglobulin(IVIG), and immunomodulators are available treatment options. Steroid administration early in the disease may improve clinical performance by reducing cytokine storms and metabolic dysfunction, as well as relieving inflammation. Khan [14] also reported the case of a 5-week-old infant who received high-dose intravenous methylprednisolone, tozizumab, and intravenous immunoglobulin treatment, showing significant short-term clinical improvement, but with long-term sequelae. However, in this study, the child was treated with low-dose methylprednisolone and high-dose immunoglobulin in the early stage of the disease and showed significant clinical improvement in the short term, but there were still residual paroxysmal convulsions and other neurological sequelae.
This case describes the youngest patient with COVID-19-related necrotizing encephalopathy reported in Asia to date, and the prognosis resulting from SARS-CoV-2 infection is indistinguishable from those resulting from other herpes simplex viruses, adenovirus, neocoronavirus, influenza virus, human rhinovirus, and other infections. Therapeutic aspects, in the present view the early use of corticosteroids, intravenous immunoglobulin, and the use of biological agents according to cytokine examination, are currently good choices to treat this condition.