key: cord-0915832-e6e30ku7
authors: Khan, Mariha; Bhattarai, Samhita; Boyce, Thomas G.; Hayek, Reyaad A.; Zhadanov, Sergey I.; Hooper, Elisabeth E.; Fernandez, Edward G.; Koehn, Monica A.
title: Acute Necrotizing Encephalopathy Associated with Coronavirus Disease 2019 in an Infant
date: 2022-04-18
journal: J Pediatr
DOI: 10.1016/j.jpeds.2022.04.031
sha: 48d6bb5f6a4f7ba66ec6df88efbbeccab37ec248
doc_id: 915832
cord_uid: e6e30ku7

A 5-week-old infant born at term was diagnosed with acute necrotizing encephalopathy associated with SARS-CoV-2 as evidenced by clinical presentation, neuroimaging, and cerebrospinal fluid studies. Our patient was treated with high dose intravenous methylprednisolone, tocilizumab and intravenous immunoglobulin with significant short-term clinical improvement but long-term sequelae.

multiple reports of neurologic involvement in patients, primarily adults, with coronavirus-19 disease (COVID-19) have been reported; these include encephalopathy, anosmia, ageusia, peripheral neuropathy, plexopathy, seizure, meningitis, and stroke. 1 In addition, cases of acute necrotizing encephalopathy (ANE) have been reported in severe COVID-19 infection in adults and one in the pediatric population. 2, 3 ANE was originally described in 1995 as a complication of viral respiratory tract infection in pediatric patients of Japanese descent, with RNA viruses implicated in the majority of cases. 4 The hallmark of ANE is multiple necrotic brain lesions showing a symmetric distribution. We present a case of ANE as the initial presentation of SARS-CoV-2 infection in aninfant.

A previously healthy, 5-week-old female infant born at 39 weeks gestation was brought to medical attention after 3 days of decreased oral intake, with irritability, progressive lethargy, and episodic bilateral lower extremity stiffening. There was no history of fever, respiratory or Based on clinical presentation, neuroimaging, and CSF findings, a diagnosis of acute necrotizing encephalitis associated with SARS-CoV-2 was made. Given the severity of generalized rigidity, encephalopathy, and the concern for poor neurologic outcome, the patient was treated with intravenous tocilizumab 12mg/kg once, high dose methylprednisolone 30 mg/kg for 5 days, and intravenous immunoglobulin (IVIG) 2 gm/kg. No significant adverse reaction occurred. To characterize initial tremors with increased tone, video electroencephalogram monitoring was initiated immediately on admission and was performed for 48 hours. This showed poor interhemispheric synchrony and poor regional and state specific patterns for age but no evidence of seizures.

Minimal respiratory support was provided transiently with 2L of 21% fraction of inspired oxygen for comfort, but intubation was not required. Sedation with dexmedetomidine improved dystonic posturing, rigidity, and irritability. With decreased posturing and irritability, dexmedetomidine sedation was weaned over 5 days, following which oral clonidine was initiated.

The neurologic status and rigidity improved steadily. On day 8 of hospitalization, she was transferred to the pediatric medical-surgical unit, where she tolerated oral feedings well.

Multimodality therapies were associated with improved range of motion in the lower extremities, and oral clonidine was transitioned to gabapentin. Repeat brain MRI ( Figure 1C , 1D) on hospital day 9 showed near complete resolution of brain edema in the insula and temporal regions. Diffusion signal abnormality persisted but now was confined to the thalami and left caudate head, with more apparent intrinsic T1 signal shortening in the dorsomedial thalamic nuclei implying necrosis. The patient was discharged to home on hospital day 20.

At the patient's 8-month follow up she was not able to sit independently without support, and neck support was poorly sustained. Muscle tone was increased without any clonus. At 12month follow up, the patient continued to have poor head and truncal support, spastic quadriparesis, and asymmetric tonic neck reflex. Overall, the patient had a developmental age of 3 months with features consistent with cerebral palsy.

Although the respiratory tract is the primary target of SARS-CoV-2 infection, neurologic consequences of infection have been recognized, and neurologic symptoms contribute significantly to morbidity in adult patients. 5 Our patient with ANE as a manifestation of SARS-CoV-2 infection in a young infant presented with profound encephalopathy, rigidity, and dystonia. She also had typical features of ANE on MRI of the brain including symmetric involvement of the thalami, caudate heads, internal capsules, and temporal lobes with areas of necrosis and probable hemorrhage. 2 J o u r n a l P r e -p r o o f ANE is a rare parainfectious, rapidly progressive condition often resulting in devastating neurologic sequelae. ANE is usually triggered by a preceding viral infection, with influenza A and B, varicella, and human herpes virus 6 most commonly associated ANE. 6 ANE is not believed to be due to a direct viral infection of the central nervous system, but rather a manifestation of an immune-mediated process with increased pro-inflammatory cytokines, especially interleukin 6 (IL-6). 6 PCR analysis on the cerebrospinal fluid in patients with ANE usually fails to detect viral nucleic acid. As in our patient, CSF protein typically is elevated, but pleocytosis is absent. Common clinical manifestations of ANE are seizures, encephalopathy, and motor deficits, with rapid progression over a few days and a case-fatality rate as high as 30% despite aggressive immune-modulatory therapy. Patients who survive generally have a poor neurologic outcome. 6 Most cases of ANE are sporadic and nonrecurrent; however, familial cases associated with a RANBP2 missense mutation on chromosome 2q11-13, termed ANE-1, is inherited in an autosomal dominant pattern with variable penetrance. The exact underlying pathophysiology is unknown, but it has been postulated that the neurologic injury in ANE-1 is due to changes in permeability of vessel walls due to high circulating levels of cytokines in these patients. 6 Children with ANE should be tested for the presence of a mutation in RANBP2 to determine whether they are at risk for recurrent episodes of ANE.

A dysregulated host immune response is a widely recognized mechanism of excessive systemic inflammation in patients hospitalized with COVID-19 and multiorgan inflammatory syndrome (MIS) can be associated with adverse clinical outcomes including brain injury. 7 Upregulated cytokine response has been implicated in ANE in severe viral infection with increased blood IL-6 levels correlating strongly with poor outcome. 8 In addition, case studies in J o u r n a l P r e -p r o o f 7 children with ANE due to influenza have shown clinical and radiologic improvement after a single dose of tocilizumab, a monoclonal antibody targeting the IL-6 receptor. 9 It is impossible to determine with certainty whether our patient's initial improvement was due to corticosteroid, IVIG, tocilizumab, some combination of these agents, or the natural history of the disease. Further delineation of effective treatments for this condition would require randomized trials, which are not practical given its rarity. MRI remains crucial in prompt recognition of this rare complication allowing for supportive care and possibly effective specific therapy with a goal of improved neurologic outcome. 

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: imaging features

Acute necrotizing encephalopathy associated with SARS-CoV-2 exposure in a pediatric patient

Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions

A comprehensive literature review on the clinical presentation and management of the pandemic coronavirus disease 2019 (COVID-19)

Acute necrotizing encephalopathy: an underrecognized clinicoradiologic disorder

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Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy

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