key: cord-0951382-3q6xtm60 authors: Yavuz, Pınar; Demir, Osman Oguz; Ozsurekci, Yasemin; Ozen, Seza; Anlar, Banu; Haliloglu, Goknur title: New-onset ocular myasthenia after multisystem inflammatory syndrome in children date: 2022-02-26 journal: J Pediatr DOI: 10.1016/j.jpeds.2022.02.046 sha: dcadf8a600b5125463a18dc4f23c4a85f85a9e50 doc_id: 951382 cord_uid: 3q6xtm60 nan Neurologic complications of SARS-CoV-2 infection in children including headache, altered mental status, encephalopathy, seizures, coma, encephalitis, demyelinating disorders, and aseptic meningitis have been-described (1, 2) . Various mechanisms of involvement are hypothesized including direct viral injury to neural cells, vascular endothelial, and inflammatory injury (3) . Autoimmunity and development of autoantibodies also is postulated Myasthenia gravis (MG) is an autoimmune disease, involving dysfunction of the neuromuscular junction with clinical phenotypes ranging from isolated ocular to generalized weakness with bulbar and respiratory involvement. Juvenile MG accounts for 10-15% of all autoimmune myasthenias. , ocular MG is defined when symptoms are limited to the levator palpebrae superioris, orbicularis oculi, and extraocular muscles, J o u r n a l P r e -p r o o f accounting for 10-35% of juvenile MG (4, 5) . MG is triggered by both genetic and environmental causes including infections, autoimmune diseases, and rheumatic diseases (6) . a single pediatric patient with transient MG has been reported after MIS-C (7) . MIS-C is defined as a novel entity within 2-6 weeks of initial SARS-CoV-2 exposure, and is characterized by an uncontrolled inflammatory response with multiorgan failure (8) . Utilization of proteomics, RNA sequencing, autoantibody arrays, B-and T-lymphocyte repertoire analysis have characterized factors contributing to hyperinflammation and vascular injury (9, 10) . Evidence has shown a strong autoimmune signature with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens and enhanced neutrophil responses tied to T-cell receptor repertoire with speculation of pathogenesis as a superantigen-driven pathogenic process (9). We present a child with severe MIS-C and weakness who developed ocular MG 11 weeks after onset of SARS-CoV-2 infection. Parental informed consent was taken to publish the case and facial photographs. A 6-year-old girl with previously diagnosed asthma presented with fever for 4 days, rash for 2 days, and abdominal pain 3-weeks after a positive nasopharyngeal RT-PCR test for SARS-CoV-2 performed because of a 2-day history of cough. She had been followed without any medication at that time. Her family history was unremarkable except for paternal coronary artery disease. She was admitted in poor general condition J o u r n a l P r e -p r o o f with tachycardia (160 beats/min) and fever (39.1°C). She had bilateral non-suppurative conjunctivitis, periorbital edema and erythema, erythematous maculopapular rash on her neck, trunk and extremities (Figure 1a-c) . Extensive laboratory evaluation revealed WBC: 6.7x10 3 /µL (normal 5-13x10 3 /µL), lymphocyte: 0.67x10 3 /µL (normal 1-5x10 3 Echocardiography revealed tricuspid and mitral insufficiency and pericardial effusion. Oral intake was stopped due to abdominal pain and rebound tenderness. IV fluids, empiric broad spectrum antibiotic, anticoagulant and anti-inflammatory therapy were administered: ceftriaxone, amikacin and ornidazole, favipiravir, anakinra, IV immunoglobulin (2 g/kg), methylprednisolone (2 mg/kg/day), and enoxaparin sodium (0.5 mg/kg/dose). On hospital day 2, she developed persistent hypotension and respiratory distress and thus was intubated and plasma exchange was performed. Accumulating data support immune-mediated injury to multiple organ systems following SARS-CoV-2 infection. In children, the involvement of central and peripheral nervous system of MIS-C includes a wide range of manifestations including muscle weakness, paresthesia, headache, meningismus/meningitis and encephalopathy (11) . However, long-term follow-up is required to assess for neurologic complications of (7). Although she responded initially to pyridostigmine, corticosteroid and methotrexate were given due to suboptimal response, and there was complete resolution of the symptoms one month after discharge. Anti-AChR Ab and SARS-CoV-2 antibody tests were negative, leading to slow discontinuation of pyridostigmine and corticosteroids. Time lag between severe MIS-C and new-onset ocular MG was 8 weeks in our patient, who had a favorable response to pyridostigmine treatment, requiring no additional pharmacotherapy. She was symptom-free at 4-month follow-up visit although serum Anti-ACHR Ab was still positive. Prepubertal MG is more prevalent in males and usually is seronegative. We speculate that an exaggerated IFN pathway response may be a risk factor for the development of autoantibodies such as those directed against AChR in our case. New-onset MG following hepatitis B and C, herpes simplex, HIV, varicellazoster, West Nile and Zika virus infections have been reported (17) (18) (19) . As in our patient, MG occurring following SARS-CoV-2 infection is also possible. Although there is no documented direct link between any specific preceding infection and MG, suggested mechanisms for this temporal association can be epitope homology/molecular mimicry between surface proteins of the virus and the acetylcholine receptor, epitope spreading, bystander activation, immortalization of infected B lymphoctes, loss of immunologic self-tolerance, and drug-induced exacerbation (15, 19, 20) . There has been a mild increase in serum CK level in our patient on hospital day 3 of MIS-C admission, correlating with highest serum IL-6 level. Within 3 days her serum CK level returned to normal. This slight increase may be due to various mechanisms such as muscle inflammation during the disease course (21) . Prolonged ICU stay, use of corticosteroids, electrophysiologic findings, course of the weakness and total recovery were compatible with ICU-AW, which should be separately evaluated in children with Our case highlights the association of SARS-CoV-2 infection with MIS-C and MG as an autoimmune complication and cautions need for prolonged observation. 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