key: cord-328680-zdwep5b2
authors: Burr, Tyler; Barton, Christopher; Doll, Elizabeth; Lakhotia, Arpita; Sweeney, Michael
title: NMDA-receptor encephalitis associated with COVID-19 infection in a toddler
date: 2020-10-09
journal: Pediatr Neurol
DOI: 10.1016/j.pediatrneurol.2020.10.002
sha: 
doc_id: 328680
cord_uid: zdwep5b2

nan

Anti-NMDA receptor (NMDAR) encephalitis is characterized by mood and behavior changes, seizures, abnormal movements, autonomic instability, and encephalopathy. It occurs most commonly in young adults. A paraneoplastic association has been made with ovarian teratoma, though this is rare in children 1 . More recently, cases of anti-NMDAR encephalitis following viral infections have been reported, including herpes simplex virus (HSV), Japanese encephalitis virus (JEV), and now the 2019 novel coronavirus (SARS-CoV-2) 2-5 . We present the first pediatric case of SARS-CoV-2-associated anti-NMDAR Encephalitis.

We report a 23-month-old female who developed fever, fussiness, poor sleep, constipation, and decreased oral intake in July 2020. She was fully vaccinated and did not have a personal or family history of frequent infections. A week after onset of symptoms, she presented to the emergency department where she was noted to be dehydrated and febrile to 100.9°F. She appeared fussy, was not interacting with care givers, was no longer talking, and had nearly constant kicking and thrashing movements of her arms and legs. Screening SARS-CoV-2 PCR resulted positive. Two days after admission, she had several seizures, treated acutely with lorazepam and levetiracetam. CSF analysis demonstrated a glucose of 56mg/dL (serum 105mg/dL), total protein 25 mg/dL, 7 WBC/µL (89% lymphocytes, 11% monocytes), 2 RBC/µL. Multiplex nested polymerase chain reaction analysis on CSF was negative for Escherichia coli, Streptococcus pneumoniae, Streptococcus agalactiae, Haemophilus influenzae, Neisseria meningitidis, Listeria monocytogenes, enterovirus, human parechovirus, herpes simplex virus 1 and 2, varicella zoster virus, cytomegalovirus, human herpesvirus 6, and Cryptococcus neoformans/gattii. SARS-CoV-2 PCR from the CSF was negative. CSF Oligoclonal Bands and IgG index were not obtained. Serum CRP and ESR were normal. MRI of the brain with and without contrast was normal.

Two weeks into the disease course, despite resolution of fever, she continued to have worsening encephalopathy and persistent hyperkinetic movements of the arms, legs and head. Intravenous methylprednisolone (30mg/kg/day) was administered for 5 days. Autoantibody testing demonstrated NMDAR-IgG positivity in the serum (1:640) and CSF (1:40). Repeat serum SARS-CoV-2 PCR remained positive and anti-SARS-Cov2 IgG resulted positive. Tetanus antibodies and Pneumococcal IgG 23 indicated normal response to previous immunizations. EBV, CMV, Mycoplasma and Bartonella serologies were negative. Due to persistent encephalopathy, poor sleep, hyperkinetic movements and mood lability, IVIG (2gm/kg) was administered. Over the following week, abnormal movements and encephalopathy gradually resolved and she was back to her previous baseline 2 weeks after being discharged from the hospital.

Anti-NMDAR encephalitis is a known autoimmune or paraneoplastic condition. While it has been linked to prior viral infections, such as herpes simplex virus infection, and in the setting of tumors, most commonly ovarian teratomas, there may be no identified provoking factors. A recent observational study showed that patients with a history of anti-NMDAR encephalitis, but no history of HSV encephalitis, were more likely to be seropositive for anti-HSV-1 IgG (49% seropositivity vs 21% in agematched controls). Antibody evidence of previous EBV or CMV infections were not significantly different between the two groups 6 . This suggests an increased risk of anti-NMDAR encephalitis following HSV-1 infection, even without clinically evident viral encephalitis. Additional mechanisms of indirect pathogenesis, such as molecular mimicry in which a viral epitope is structurally similar to an NMDAR epitope, may be explanatory. A similar indirect pathogenesis may exist in patients with coronaviruses such as SARS-CoV-2.

A post-infectious inflammatory condition following acute SARS-CoV-2, termed multisystem inflammatory syndrome in children (MIS-C), has been described. MIS-C typically presents 4-6 weeks after acute SARS-CoV-2 infection. A prospective and retrospective surveillance of children in the United States with MIS-C related to SARS-CoV-2 reported infrequent nervous system involvement 7 . Increased autoantibody production in children with MIS-C has been described 8 .

There have been two cases of anti-NMDAR encephalitis associated with SARS-CoV-2 in adults reported 5, 9 . Both patients showed significant recovery following immunotherapy with steroids and IVIG. At the time of publication, the authors are unaware of other cases of anti-NMDAR encephalitis with recent SARS-CoV-2 infection in pediatric populations. As the understanding of both the neurological and non-neurological manifestations of SARS-CoV-2 in children are evolving, we report a child with SARS-CoV-2-associated anti-NMDAR encephalitis.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Japanese encephalitis-induced anti-N-methyl-d-aspartate receptor encephalitis: A hospital-based prospective study

Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases

Anti-N-methyl-D-aspartate receptor encephalitis associated with reactivated Epstein-Barr virus infection in pediatric patients: Three case reports

Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report

Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection

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The immunology of multisystem inflammatory syndrome in children with COVID-19

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