Case Report: Benign Infantile Seizures Temporally Associated With COVID-19

Marcos García-Howard

Mercedes Herranz-Aguirre

Laura Moreno-Galarraga

María Urretavizcaya-Martínez

Josune Alegría-Echauri

Nerea Gorría-Redondo

Laura Planas-Serra

Agatha Schlüter

Marta Gut+2 authors

^{Department of Pediatrics, CHN, Navarra Health Service Hospital, Pamplona, Spain}

^{Pediatric Infectious Disease Unit, Department of Pediatrics, CHN, Navarra Health Service Hospital, Pamplona, Spain}

^{NavarraBioMed and IdiSNA, Health Research Institute, Pamplona, Spain}

^{Pediatric Respiratory Medicine, Department of Pediatrics, CHN, Navarra Health Service Hospital, Pamplona, Spain}

^{Pediatric Neurology Unit, Department of Pediatrics, CHN, Navarra Health Service Hospital, Pamplona, Spain}

^{Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain}

^{Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain}

^{CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain}

^{Universitat Pompeu Fabra (UPF), Barcelona, Spain}

^{Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain}

Edited by: Christoph Aebi, University Children's Hospital Bern, Switzerland

Reviewed by: Federico Vigevano, Bambino Gesù Children Hospital (IRCCS), Italy; Rudá Alessi, Faculdade de Medicina Do ABC, Brazil

*Correspondence: Sergio Aguilera-Albesa se.arravan@aeliugas

Aurora Pujol tac.llebidi@lojupa

This article was submitted to Pediatric Infectious Diseases, a section of the journal Frontiers in Pediatrics

Edited by: Christoph Aebi, University Children's Hospital Bern, Switzerland

Reviewed by: Federico Vigevano, Bambino Gesù Children Hospital (IRCCS), Italy; Rudá Alessi, Faculdade de Medicina Do ABC, Brazil

Received 2020 May 3; Accepted 2020 Jul 17.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Background: Non-febrile illness seizures may present in previously healthy children as afebrile seizures associated with minor infections, such as mild gastroenteritis or respiratory tract infections, and are linked to a genetic predisposition. For the novel human coronavirus SARS-CoV-2, causing COVID-19, fever, cough, and gastrointestinal complaints are the most common symptoms in children, and a hyperimmune response may be present. No detailed temporally associated neurological complications have been documented in pediatric case series so far.

Case description: We present the case of a 3-months-old girl with non-febrile repeated seizures in a COVID-19 family setting. The infant started with a mild fever and cough that lasted for 2 days. At day 6 from onset, the girl presented with two focal motor seizures with impaired consciousness and awareness. All investigations ruled out signs of meningo-encephalitis or active epilepsy, including normal electroencephalogram and cerebral magnetic resonance imaging. PCR from nasal and throat swabs was positive for SARS-CoV-2. Remarkably, blood ferritin and D-dimer levels were increased. At day 9, the infant presented another afebrile motor seizure, and levetiracetam dose was modified there was a favorable response within 3 months of the follow-up. Much interest has been raised with regards to host genetic determinants to disease severity and susceptibility to COVID-19. We thus performed whole exome sequencing, revealing a pathogenic frameshift mutation in the PRRT2 gene in both the mother and the infant. The mother had presented two late infantile febrile convulsions with normal outcome afterwards.

Discussion: The hyperimmune response described in adult cases with COVID-19 can be seen in infants, even in the absence of respiratory symptoms. Moreover, COVID-19 may present in infants as non-febrile seizures, triggering early onset seizures in infants with a genetic predisposition. In this pandemic situation, precision medicine using massive sequencing can shed light on underlying molecular mechanisms driving the host response to COVID-19.

Keywords: coronavirus, SARS-CoV-2, COVID-19, pediatric COVID-19, non-febrile seizures, afebrile seizures, PRRT2 mutations, benign familial infantile epilepsy

Abstract

Acknowledgments

The authors would like to thank the patient's family for their cooperation and for consenting to the publication of this manuscript. They will also like to thank the enormous effort done by all our hospital and Spanish health workers in the fight against the current COVID-19 pandemic.

Acknowledgments

Footnotes

Funding. Whole exome sequencing was carried out thanks to the EASIGenomics COVID-19/ PID1234219 grant to AP and the Illumina Match Funds covid-19 initiative. Pediatric epilepsy studies in our hospital are carried out thanks to Fundación Alicia Koplowitz grant to SA-A.

Footnotes

References

1. Uemura N, Okumura A, Negoro T, Watanabe K. Clinical features of benign convulsions with mild gastroenteritis. Brain Dev. (2002) 24:745–9. 10.1016/S0387-7604(02)00097-9 [] [[PubMed]
2. Durá-Travé T, Yoldi-Petri ME, Molins-Castiella T, Souto-Hernández S, Aguilera-Albesa S. Infantile convulsions with mild gastroenteritis: epidemiological and clinical characteristics and outcome. Rev Neurol. (2010) 5:12–8. 10.33588/rn.5101.2010018 [] [[PubMed]
3. Zhang T, Ma J, Gan X, Xiao N. Are afebrile seizures associated with minor infections a single seizure category? A hospital-based prospective cohort study on outcomes of first afebrile seizure in early childhood. Epilepsia. (2014) 55:1001–8. 10.1111/epi.12651 [] [[PubMed]
4. Conejo Moreno D, Rodríguez Fernández C, Ruíz Ayúcar de la Vega I, Ortiz Madinaveitia S, Hedrera Fernández A, Maldonado, Ruiz E, et al. . Para-infectious seizures: a retrospective multicentre study. An Pediatr. (2016) 85:300–4. 10.1016/j.anpede.2016.01.012 [] [[PubMed]
5. Ma X, Luan S, Zhao Y, Lv X, Zhang R. Clinical characteristics and follow-up of benign convulsions with mild gastroenteritis among children. Medicine. (2019) 98:e14082. 10.1097/MD.0000000000014082 ] [
6. Cha T, Choi YJ, Oh JW, Kim CR, Park DW, Seol IJ, et al. . Respiratory syncytial virus-associated seizures in Korean children, 2011–2016. Korean J Pediatr. (2019) 62:131–7. 10.3345/kjp.2018.07066 ] [
7. St-Jean JR, Jacomy H, Desforges M, Vabret A, Freymuth F, Talbot PJ. Human respiratory coronavirus OC43: genetic stability and neuroinvasion. J Virol. (2004) 78:8824–34. 10.1128/JVI.78.16.8824-8834.2004 ] [
8. Zimmermann P, Curtis N. Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children. Pediatr Infect Dis J. (2020) 39:355–68. 10.1097/INF.0000000000002660 ] [
9. Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM. Neurologic alterations due to respiratory virus infections. Front Cell Neurosci. (2018) 12:386. 10.3389/fncel.2018.00386 ] [
10. Hon KL, Leung CW, Cheng WT, Chan PK, Chu WC, Kwan YW, et al. . Clinical presentations and outcome of severe acute respiratory syndrome in children. Lancet. (2003) 361:1701–3. 10.1016/S0140-6736(03)13364-8 ] [
11. Chiu WK, Cheung PC, Ng KL, Ip PL, Sugunan VK, Luk DC, et al. . Severe acute respiratory syndrome in children: experience in a regional hospital in Hong Kong. Pediatr Crit Care Med. (2003) 4:279–83. 10.1097/01.PCC.0000077079.42302.81 [] [[PubMed]
12. Bitnun A, Allen U, Heurter H, King SM, Opavsky MA, Ford-Jones EL, et al. . Children hospitalized with severe acute respiratory syndrome-related illness in Toronto. Pediatrics. (2003) 112:e261. 10.1542/peds.112.4.e261 [] [[PubMed]
13. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. . A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. (2020) 395:514–23. 10.1016/S0140-6736(20)30154-9 ] [
14. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. . A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. (2020) 382:727–33. 10.1056/NEJMoa2001017 ] [
15. Tan YP, Tan BY, Pan J, Wu J, Zeng SZ, Wei HY. Epidemiologic and clinical characteristics of 10 children with coronavirus disease 2019 in Changsha, China. J Clin Virol. (2020) 127:104353. 10.1016/j.jcv.2020.104353 ] [
16. Shen KL, Yang YH, Jiang RM, Wang TY, Zhao DC, Jiang Y, et al. . Updated diagnosis, treatment and prevention of COVID-19 in children: experts' consensus statement (condensed version of the second edition). World J Pediatr. (2020) 16:232–9. 10.1007/s12519-020-00362-4 ] [
17. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. (2020) 58:712–3. 10.1016/j.jemermed.2020.04.006 [[PubMed][Google Scholar]
18. CDC COVID-19 response team. Coronavirus disease 2019 in children—United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. (2020) 69:422–6. 10.15585/mmwr.mm6914e4 ] [
19. Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, et al. . PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. (2012) 90:152–60. 10.1016/j.ajhg.2011.12.003 ] [
20. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. (2020). 10.1001/jama.2020.2648. [Epub ahead of print]. [] [[PubMed]
21. Tagarro A, Epalza C, Santos M, Sanz-Santaeufemia FJ, Otheo E, Moraleda C, et al. . Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain. JAMA Pediatr. (2020) e201346. 10.1001/jamapediatrics.2020.1346. [Epub ahead of print]. ] [
22. Castagnoli R, Votto M, Licari A, Brambilla I, Bruno R, Perlini S, et al. . Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents. A systematic review. JAMA Pediatr. (2020). 10.1001/jamapediatrics.2020.1467. [Epub ahead of print]. [] [[PubMed]
23. Zerr DM, Blume HK, Berg AT, Del Beccaro MA, Gospe SM, Jr, Allpress AL, et al. . Non-febrile illness seizures: a unique seizure category?Epilepsia. (2005) 46:952–5. 10.1111/j.1528-1167.2005.65204.x [] [[PubMed]
24. Casanova JL, Su HC. A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection. Cell. (2020) 181:1194–1199. 10.1016/j.cell.2020.05.016 ] [
25. The COVID-19 Host Genetics Initiative . The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur J Human Genet. (2020) 28:715–8. 10.1038/s41431-020-0636-6 ] [
26. Pant DC, Dorboz I, Schluter A, Fourcade S, Launay N, Joya J, et al. . Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest. (2019) 129:1240–56. 10.1172/JCI123959 ] [
27. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. . Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. (2020) ciaa248. 10.2139/ssrn.3541136. [Epub ahead of print]. ] [
28. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395:1033–4. 10.1016/S0140-6736(20)30628-0 ] [
29. Sturrock BR, Chevassut TJ. Chloroquine and COVID-19—a potential game changer?Clin Med. (2020) 20:278–1. 10.7861/clinmed.2020-0129 ] [
30. White NJ. The treatment of malaria. N Engl J Med. (1996) 335:800–6. 10.1056/NEJM199609123351107 [] [[PubMed]
31. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J Antimicrob Agents. (2020) 55:105923 10.1016/j.ijantimicag.2020.105923 ] [
32. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. . Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. (2005) 2:69. 10.1186/1743-422X-2-69 ] [
33. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. . In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. (2020) ciaa237. 10.1093/cid/ciaa237. [Epub ahead of print]. ] [
34. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. (2020) 105949 10.1016/j.ijantimicag.2020.105949. [Epub ahead of print]. ] [[Google Scholar]
35. Alexander PE, Debono VB, Mammen MJ, Iorio A, Aryal K, Berg D, et al. . COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine. J Clin Epidemiol. (2020) 123:120–6. 10.1016/j.jclinepi.2020.04.016 ] [