Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome | Adolescent Medicine | JAMA Neurology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Montalvan  V, Lee  J, Bueso  T, De Toledo  J, Rivas  K.  Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review.   Clin Neurol Neurosurg. 2020;194:105921. doi:10.1016/j.clineuro.2020.105921PubMedGoogle Scholar
Ellul  MA, Benjamin  L, Singh  B,  et al.  Neurological associations of COVID-19.   Lancet Neurol. 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0PubMedGoogle ScholarCrossref
Baig  AM.  Neurological manifestations in COVID-19 caused by SARS-CoV-2.   CNS Neurosci Ther. 2020;26(5):499-501. doi:10.1111/cns.13372PubMedGoogle ScholarCrossref
Paterson  RW, Brown  RL, Benjamin  L,  et al.  The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.   Brain. 2020;143(10):3104-3120. doi:10.1093/brain/awaa240PubMedGoogle ScholarCrossref
Zubair  AS, McAlpine  LS, Gardin  T, Farhadian  S, Kuruvilla  DE, Spudich  S.  Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review.   JAMA Neurol. 2020;77(8):1018-1027. doi:10.1001/jamaneurol.2020.2065PubMedGoogle ScholarCrossref
Koralnik  IJ, Tyler  KL.  COVID-19: A global threat to the nervous system.   Ann Neurol. 2020;88(1):1-11. doi:10.1002/ana.25807PubMedGoogle ScholarCrossref
Aghagoli  G, Gallo Marin  B, Katchur  NJ, Chaves-Sell  F, Asaad  WF, Murphy  SA.  Neurological involvement in COVID-19 and potential mechanisms: a review.   Neurocrit Care. 2020. doi:10.1007/s12028-020-01049-4PubMedGoogle Scholar
Favas  TT, Dev  P, Chaurasia  RN,  et al.  Neurological manifestations of COVID-19: a systematic review and meta-analysis of proportions.   Neurol Sci. 2020;41(12):3437-3470. doi:10.1007/s10072-020-04801-yPubMedGoogle ScholarCrossref
Stafstrom  CE, Jantzie  LL.  COVID-19: neurological considerations in neonates and children.   Children (Basel). 2020;7(9):E133. doi:10.3390/children7090133PubMedGoogle Scholar
Mao  L, Jin  H, Wang  M,  et al.  Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.   JAMA Neurol. 2020;77(6):683-690. doi:10.1001/jamaneurol.2020.1127PubMedGoogle ScholarCrossref
Lechien  JR, Chiesa-Estomba  CM, De Siati  DR,  et al.  Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.   Eur Arch Otorhinolaryngol. 2020;277(8):2251-2261. doi:10.1007/s00405-020-05965-1PubMedGoogle ScholarCrossref
Bénézit  F, Le Turnier  P, Declerck  C,  et al; RAN COVID Study Group.  Utility of hyposmia and hypogeusia for the diagnosis of COVID-19.   Lancet Infect Dis. 2020;20(9):1014-1015. doi:10.1016/S1473-3099(20)30297-8PubMedGoogle ScholarCrossref
Bolay  H, Gül  A, Baykan  B.  COVID-19 is a real headache!   Headache. 2020;60(7):1415-1421. doi:10.1111/head.13856PubMedGoogle ScholarCrossref
Varatharaj  A, Thomas  N, Ellul  MA,  et al; CoroNerve Study Group.  Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study.   Lancet Psychiatry. 2020;7(10):875-882. doi:10.1016/S2215-0366(20)30287-XPubMedGoogle ScholarCrossref
Moriguchi  T, Harii  N, Goto  J,  et al.  A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.   Int J Infect Dis. 2020;94:55-58. doi:10.1016/j.ijid.2020.03.062PubMedGoogle ScholarCrossref
Helms  J, Kremer  S, Merdji  H,  et al.  Neurologic features in severe SARS-CoV-2 infection.   N Engl J Med. 2020;382(23):2268-2270. doi:10.1056/NEJMc2008597PubMedGoogle ScholarCrossref
Farhadian  S, Glick  LR, Vogels  CBF,  et al.  Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.   BMC Neurol. 2020;20(1):248. doi:10.1186/s12883-020-01812-2PubMedGoogle ScholarCrossref
Etemadifar  M, Salari  M, Murgai  AA, Hajiahmadi  S.  Fulminant encephalitis as a sole manifestation of COVID-19.   Neurol Sci. 2020;41(11):3027-3029. doi:10.1007/s10072-020-04712-yPubMedGoogle ScholarCrossref
Poyiadji  N, Shahin  G, Noujaim  D, Stone  M, Patel  S, Griffith  B.  COVID-19-associated acute hemorrhagic necrotizing encephalopathy: imaging features.   Radiology. 2020;296(2):E119-E120. doi:10.1148/radiol.2020201187PubMedGoogle ScholarCrossref
Delamarre  L, Gollion  C, Grouteau  G,  et al; NeuroICU Research Group.  COVID-19-associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network.   J Neurol Neurosurg Psychiatry. 2020;91(9):1004-1006. doi:10.1136/jnnp-2020-323678PubMedGoogle ScholarCrossref
Hepburn  M, Mullaguri  N, George  P,  et al.  Acute symptomatic seizures in critically ill patients with COVID-19: is there an association?   Neurocrit Care. 2020. doi:10.1007/s12028-020-01006-1PubMedGoogle Scholar
Sohal  S, Mansur  M.  COVID-19 presenting with seizures.   IDCases. 2020;20:e00782. doi:10.1016/j.idcr.2020.e00782PubMedGoogle Scholar
AlKetbi  R, AlNuaimi  D, AlMulla  M,  et al.  Acute myelitis as a neurological complication of Covid-19: a case report and MRI findings.   Radiol Case Rep. 2020;15(9):1591-1595. doi:10.1016/j.radcr.2020.06.001PubMedGoogle ScholarCrossref
Valiuddin  H, Skwirsk  B, Paz-Arabo  P.  Acute transverse myelitis associated with SARS-CoV-2: a case-report.   Brain Behav Immun Health. 2020;5:100091. doi:10.1016/j.bbih.2020.100091PubMedGoogle Scholar
Chakraborty  U, Chandra  A, Ray  AK, Biswas  P.  COVID-19-associated acute transverse myelitis: a rare entity.   BMJ Case Rep. 2020;13(8):e238668. doi:10.1136/bcr-2020-238668PubMedGoogle Scholar
Abu-Rumeileh  S, Abdelhak  A, Foschi  M, Tumani  H, Otto  M.  Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases.   J Neurol. 2020. doi:10.1007/s00415-020-10124-xPubMedGoogle Scholar
Uncini  A, Vallat  JM, Jacobs  BC.  Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic.   J Neurol Neurosurg Psychiatry. 2020;91(10):1105-1110. doi:10.1136/jnnp-2020-324491PubMedGoogle ScholarCrossref
Parauda  SC, Gao  V, Gewirtz  AN,  et al.  Posterior reversible encephalopathy syndrome in patients with COVID-19.   J Neurol Sci. 2020;416:117019. doi:10.1016/j.jns.2020.117019PubMedGoogle Scholar
Dafer  RM, Osteraas  ND, Biller  J.  Acute stroke care in the coronavirus disease 2019 pandemic.   J Stroke Cerebrovasc Dis. 2020;29(7):104881. doi:10.1016/j.jstrokecerebrovasdis.2020.104881PubMedGoogle Scholar
Morassi  M, Bagatto  D, Cobelli  M,  et al.  Stroke in patients with SARS-CoV-2 infection: case series.   J Neurol. 2020;267(8):2185-2192. doi:10.1007/s00415-020-09885-2PubMedGoogle ScholarCrossref
Beyrouti  R, Adams  ME, Benjamin  L,  et al.  Characteristics of ischaemic stroke associated with COVID-19.   J Neurol Neurosurg Psychiatry. 2020;91(8):889-891. doi:10.1136/jnnp-2020-323586PubMedGoogle ScholarCrossref
Hughes  C, Nichols  T, Pike  M, Subbe  C, Elghenzai  S.  Cerebral venous sinus thrombosis as a presentation of COVID-19.   Eur J Case Rep Intern Med. 2020;7(5):001691. doi:10.12890/2020_001691PubMedGoogle Scholar
Majidi  S, Fifi  JT, Ladner  TR,  et al.  Emergent large vessel occlusion stroke during New York City’s COVID-19 outbreak: clinical characteristics and paraclinical findings.   Stroke. 2020;51(9):2656-2663. doi:10.1161/STROKEAHA.120.030397PubMedGoogle ScholarCrossref
Oxley  TJ, Mocco  J, Majidi  S,  et al.  Large-vessel stroke as a presenting feature of Covid-19 in the young.   N Engl J Med. 2020;382(20):e60. doi:10.1056/NEJMc2009787PubMedGoogle Scholar
Dufort  EM, Koumans  EH, Chow  EJ,  et al; New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team.  Multisystem inflammatory syndrome in children in New York State.   N Engl J Med. 2020;383(4):347-358. doi:10.1056/NEJMoa2021756PubMedGoogle ScholarCrossref
Feldstein  LR, Rose  EB, Horwitz  SM,  et al; Overcoming COVID-19 Investigators; CDC COVID-19 Response Team.  Multisystem inflammatory syndrome in U.S. children and adolescents.   N Engl J Med. 2020;383(4):334-346. doi:10.1056/NEJMoa2021680PubMedGoogle ScholarCrossref
Ahmed  M, Advani  S, Moreira  A,  et al.  Multisystem inflammatory syndrome in children: a systematic review.   EClinicalMedicine. 2020;26:100527. doi:10.1016/j.eclinm.2020.100527PubMedGoogle Scholar
Aronoff  SC, Hall  A, Del Vecchio  MT.  The natural history of severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children: a systematic review.   J Pediatric Infect Dis Soc. 2020;9(6):746-751. doi:10.1093/jpids/piaa112PubMedGoogle ScholarCrossref
Kaushik  A, Gupta  S, Sood  M, Sharma  S, Verma  S.  A systematic review of multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection.   Pediatr Infect Dis J. 2020;39(11):e340-e346. doi:10.1097/INF.0000000000002888PubMedGoogle ScholarCrossref
Abrams  JY, Godfred-Cato  SE, Oster  ME,  et al.  Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2: a systematic review.   J Pediatr. 2020;S0022-3476(20)30985-9. doi:10.1016/j.jpeds.2020.08.003PubMedGoogle Scholar
DeBiasi  RL, Song  X, Delaney  M,  et al.  Severe coronavirus disease-2019 in children and young adults in the Washington, DC, metropolitan region.   J Pediatr. 2020;223:199-203.e1. doi:10.1016/j.jpeds.2020.05.007PubMedGoogle ScholarCrossref
Shekerdemian  LS, Mahmood  NR, Wolfe  KK,  et al; International COVID-19 PICU Collaborative.  Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units.   JAMA Pediatr. 2020;174(9):868-873. doi:10.1001/jamapediatrics.2020.1948PubMedGoogle ScholarCrossref
Prata-Barbosa  A, Lima-Setta  F, Santos  GRD,  et al; Brazilian Research Network in Pediatric Intensive Care, (BRnet-PIC).  Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study.   J Pediatr (Rio J). 2020;96(5):582-592. doi:10.1016/j.jped.2020.07.002PubMedGoogle ScholarCrossref
Lindan  CE, Mankad  K, Ram  D,  et al; ASPNR PECOBIG Collaborator Group.  Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.   Lancet Child Adolesc Health. 2020;S2352-4642(20)30362-X. doi:10.1016/S2352-4642(20)30362-XPubMedGoogle Scholar
Lin  JE, Asfour  A, Sewell  TB,  et al.  Neurological issues in children with COVID-19.   Neurosci Lett. 2021;743:135567. doi:10.1016/j.neulet.2020.135567PubMedGoogle Scholar
Panda  PK, Sharawat  IK, Panda  P, Natarajan  V, Bhakat  R, Dawman  L.  Neurological complications of SARS-CoV-2 infection in children: a systematic review and meta-analysis.   J Trop Pediatr. 2020;fmaa070. doi:10.1093/tropej/fmaa070PubMedGoogle Scholar
Centers for Disease Control and Prevention. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). Accessed December 4, 2020.
Venkatesan  A, Tunkel  AR, Bloch  KC,  et al; International Encephalitis Consortium.  Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.   Clin Infect Dis. 2013;57(8):1114-1128. doi:10.1093/cid/cit458PubMedGoogle ScholarCrossref
Sejvar  JJ, Kohl  KS, Bilynsky  R,  et al; Brighton Collaboration Encephalitis Working Group.  Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data.   Vaccine. 2007;25(31):5771-5792. doi:10.1016/j.vaccine.2007.04.060PubMedGoogle ScholarCrossref
Agarwal  S, Conway  J, Nguyen  V,  et al.  Serial Imaging of virus-associated necrotizing disseminated acute leukoencephalopathy (VANDAL) in COVID-19.   AJNR Am J Neuroradiol. 2021;42(2):279-284. doi:10.3174/ajnr.A6898PubMedGoogle ScholarCrossref
Abdel-Mannan  O, Eyre  M, Löbel  U,  et al.  Neurologic and radiographic findings associated with COVID-19 infection in children.   JAMA Neurol. 2020. doi:10.1001/jamaneurol.2020.2687PubMedGoogle Scholar
Lin  J, Lawson  EC, Verma  S, Peterson  RB, Sidhu  R.  Cytotoxic lesion of the corpus callosum in an adolescent with multisystem inflammatory syndrome and SARS-CoV-2 infection.   AJNR Am J Neuroradiol. 2020;41(11):2017-2019. doi:10.3174/ajnr.A6755PubMedGoogle ScholarCrossref
Baig  AM, Khaleeq  A, Ali  U, Syeda  H.  Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms.   ACS Chem Neurosci. 2020;11(7):995-998. doi:10.1021/acschemneuro.0c00122PubMedGoogle ScholarCrossref
Guo  Y, Korteweg  C, McNutt  MA, Gu  J.  Pathogenetic mechanisms of severe acute respiratory syndrome.   Virus Res. 2008;133(1):4-12. doi:10.1016/j.virusres.2007.01.022PubMedGoogle ScholarCrossref
van Riel  D, Verdijk  R, Kuiken  T.  The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system.   J Pathol. 2015;235(2):277-287. doi:10.1002/path.4461PubMedGoogle ScholarCrossref
Netland  J, Meyerholz  DK, Moore  S, Cassell  M, Perlman  S.  Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.   J Virol. 2008;82(15):7264-7275. doi:10.1128/JVI.00737-08PubMedGoogle ScholarCrossref
Matschke  J, Lütgehetmann  M, Hagel  C,  et al.  Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.   Lancet Neurol. 2020;19(11):919-929. doi:10.1016/S1474-4422(20)30308-2PubMedGoogle ScholarCrossref
Buzhdygan  TP, DeOre  BJ, Baldwin-Leclair  A,  et al.  The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier.   bioRxiv. Posted June 15, 2020. doi:10.1101/2020.06.15.150912Google Scholar
Alberti  P, Beretta  S, Piatti  M,  et al.  Guillain-Barré syndrome related to COVID-19 infection.   Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e741. doi:10.1212/NXI.0000000000000741PubMedGoogle Scholar
Dalakas  MC.  Guillain-Barré syndrome: the first documented COVID-19-triggered autoimmune neurologic disease: more to come with myositis in the offing.   Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e781. doi:10.1212/NXI.0000000000000781PubMedGoogle Scholar
Iadecola  C, Anrather  J, Kamel  H.  Effects of COVID-19 on the nervous system.   Cell. 2020;183(1):16-27.e1. doi:10.1016/j.cell.2020.08.028PubMedGoogle ScholarCrossref
Yuki  N, Hartung  HP.  Guillain-Barré syndrome.   N Engl J Med. 2012;366(24):2294-2304. doi:10.1056/NEJMra1114525PubMedGoogle ScholarCrossref
Kreye  J, Reincke  SM, Prüss  H.  Do cross-reactive antibodies cause neuropathology in COVID-19?   Nat Rev Immunol. 2020;20(11):645-646. doi:10.1038/s41577-020-00458-yPubMedGoogle ScholarCrossref
Kowalewski  M, Fina  D, Słomka  A,  et al.  COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review.   Crit Care. 2020;24(1):205. doi:10.1186/s13054-020-02925-3PubMedGoogle ScholarCrossref
Lax  SF, Skok  K, Zechner  P,  et al.  Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series.   Ann Intern Med. 2020;173(5):350-361. doi:10.7326/M20-2566PubMedGoogle ScholarCrossref
Beslow  LA, Linds  AB, Fox  CK,  et al; International Pediatric Stroke Study Group.  Pediatric ischemic stroke: an infrequent complication of SARS-CoV-2.   Ann Neurol. 2020. doi:10.1002/ana.25991PubMedGoogle Scholar
Appavu  B, Deng  D, Dowling  MM,  et al.  Arteritis and large vessel occlusive strokes in children following COVID-19 infection.   Pediatrics. 2020;e2020023440. doi:10.1542/peds.2020-023440PubMedGoogle Scholar
Gulko  E, Overby  P, Ali  S, Mehta  H, Al-Mufti  F, Gomes  W.  Vessel wall enhancement and focal cerebral arteriopathy in a pediatric patient with acute infarct and COVID-19 infection.   AJNR Am J Neuroradiol. 2020;41(12):2348-2350. doi:10.3174/ajnr.A6778PubMedGoogle ScholarCrossref
Mirzaee  SMM, Gonçalves  FG, Mohammadifard  M, Tavakoli  SM, Vossough  A.  Focal cerebral arteriopathy in a pediatric patient with COVID-19.   Radiology. 2020;297(2):E274-E275. doi:10.1148/radiol.2020202197PubMedGoogle ScholarCrossref
Majmundar  N, Ducruet  A, Prakash  T, Nanda  A, Khandelwal  P.  Incidence, pathophysiology, and impact of coronavirus disease 2019 (COVID-19) on acute ischemic stroke.   World Neurosurg. 2020;142:523-525. doi:10.1016/j.wneu.2020.07.158PubMedGoogle ScholarCrossref
Radmanesh  A, Derman  A, Lui  YW,  et al.  COVID-19-associated diffuse leukoencephalopathy and microhemorrhages.   Radiology. 2020;297(1):E223-E227. doi:10.1148/radiol.2020202040PubMedGoogle ScholarCrossref
Rasmussen  C, Niculescu  I, Patel  S, Krishnan  A.  COVID-19 and involvement of the corpus callosum: potential effect of the cytokine storm?   AJNR Am J Neuroradiol. 2020;41(9):1625-1628. doi:10.3174/ajnr.A6680PubMedGoogle Scholar
Moonis  G, Filippi  CG, Kirsch  CFE,  et al.  The spectrum of neuroimaging findings on CT and MRI in adults with coronavirus disease (COVID-19).   AJR Am J Roentgenol. 2020. doi:10.2214/AJR.20.24839PubMedGoogle Scholar
Duong  L, Xu  P, Liu  A.  Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.   Brain Behav Immun. 2020;87:33. doi:10.1016/j.bbi.2020.04.024PubMedGoogle ScholarCrossref
Bernard-Valnet  R, Pizzarotti  B, Anichini  A,  et al.  Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.   Eur J Neurol. 2020;27(9):e43-e44. doi:10.1111/ene.14298PubMedGoogle ScholarCrossref
Ghannam  M, Alshaer  Q, Al-Chalabi  M, Zakarna  L, Robertson  J, Manousakis  G.  Neurological involvement of coronavirus disease 2019: a systematic review.   J Neurol. 2020;267(11):3135-3153. doi:10.1007/s00415-020-09990-2PubMedGoogle ScholarCrossref
Morfopoulou  S, Brown  JR, Davies  EG,  et al.  Human coronavirus OC43 associated with fatal encephalitis.   N Engl J Med. 2016;375(5):497-498. doi:10.1056/NEJMc1509458PubMedGoogle ScholarCrossref
Yeh  EA, Collins  A, Cohen  ME, Duffner  PK, Faden  H.  Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis.   Pediatrics. 2004;113(1 pt 1):e73-e76. doi:10.1542/peds.113.1.e73PubMedGoogle Scholar
Shenker  J, Trogen  B, Schroeder  L, Ratner  AJ, Kahn  P.  Multisystem inflammatory syndrome in children associated with status epilepticus.   J Pediatr. 2020;227(Jul):300-301. doi:10.1016/j.jpeds.2020.07.062PubMedGoogle ScholarCrossref
Kim  MG, Stein  AA, Overby  P,  et al.  Fatal cerebral edema in a child with COVID-19.   Pediatr Neurol. 2021;114:77-78. doi:10.1016/j.pediatrneurol.2020.10.005PubMedGoogle ScholarCrossref
Piliero  PJ, Brody  J, Zamani  A, Deresiewicz  RL.  Eastern equine encephalitis presenting as focal neuroradiographic abnormalities: case report and review.   Clin Infect Dis. 1994;18(6):985-988. doi:10.1093/clinids/18.6.985PubMedGoogle ScholarCrossref
Wendell  LC, Potter  NS, Roth  JL, Salloway  SP, Thompson  BB.  Successful management of severe neuroinvasive eastern equine encephalitis.   Neurocrit Care. 2013;19(1):111-115. doi:10.1007/s12028-013-9822-5PubMedGoogle ScholarCrossref
Krishnan  P, Glenn  OA, Samuel  MC,  et al.  Acute fulminant cerebral edema: a newly recognized phenotype in children with suspected encephalitis.   J Pediatric Infect Dis Soc. 2020;piaa063. doi:10.1093/jpids/piaa063PubMedGoogle Scholar
Carter  MJ, Fish  M, Jennings  A,  et al.  Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.   Nat Med. 2020;26(11):1701-1707. doi:10.1038/s41591-020-1054-6PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    3 Comments for this article
    SARS CoV-2 and Neurological complications-our experience and views
    Khichar Shubhakaran, MD()Med, (D.M.) Neurology | Senior Professor and head of department of Neurology, M D M Hospital, Dr. S.N Medical College, Jodhpur (Rajasthan) India-342001
    We are also seeing various complications like GBS, pseudotumorcerebri, precipitation of stroke, seizures etc, but do not have the access to antiganglioside antibodies, all those who can afford to get it done we should try for that and get it documented for academic and research purpose in this pandemic of modern time of advanced technology. The gangliosides are particularly abundant in the brain and in the nervous system; they participate in maintenance and repair of neuronal cells, memory formation and synaptic transmission (1). So we have to be watchful in this regard towards impairment of these neurological functions i.e. new autoimmune disorder like GBS, multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMO-SD), chronic inflammatory demyelinating neuropathy (CIDP), etc. and precipitation of neurodegenerative and cognitive disorders in acute, convalescent and post recovery follow up. Of course the pediatric population is less affected, but as in the case of neurons, the SARS-CoV-2 may affect the growth and development of pediatric population.
    Just as Intravenous immunoglobulins (IVIg) and plasmapharesis are useful in the treatment of GBS with antiganglioside antibodies, the trial of IVIg and monoclonal antibodies in other neurological complications with SARS-CoV-2 along with monitoring of antiganglioside antibodies may prove to be a game changer, as it has been claimed to be effective in general treatment of COVID-19 (2).
    1. Cutillo G, Saariaho A-H, Meri S. Physiology of gangliosides and the role of antiganglioside antibodies in human diseases. Cell Mol Immunol 2020;17:313–22.doi:10.1038/s41423-020-0388-9
    2. Alan A. Nguyen, Saddiq B. Habiballah, Craig D. Platt, Raif S. Geha, Janet S. Chou, and Douglas R. McDonald. Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution! Clin Immunol. 2020 Jul; 216: 108459. doi: 10.1016/j.clim.2020.108459
    Hyper-inflammatory state in Covid-19 might induce cells to abandon mitochondrial oxidative phosphorylation in favor of cytosolic aerobic gly
    Calixto Machado, MD, PhD, FAAN | Institute of Neurology and Neurosurgery, Havana, Cuba
    I read with interest the paper by LaRovere et al. to comprehend the variety and severity of neurologic involvement among children and adolescents with COVID-19 (1).
    Several papers of life-threatening neurologic involvement have appeared about children and adolescent patients developing multisystem inflammatory syndrome (MIS-C), which is a fairly infrequent, hyperinflammatory, severe disease, temporally linked with SARS-CoV-2 infection, apparently post-infectious (2). 
    These authors concluded that COVID-19 or MIS-C had neurologic involvement, although mostly transient symptoms. Though brain infarcts were found in MRI studies, these authors found, in several patients, T2 hyperintensity, leptomeningeal enhancement, and reduced diffusivity within the bilateral frontal lobes,
    basal ganglia, and thalami, with no focal lesions (1).
    This publication appears when several authors have also reported reversible encephalopathy bilateral thalamic lesions after SARS-CoV-2 infection. the most characteristic MRI feature included symmetric, multifocal lesions with invariable thalamic involvement, showing T2-weighted fluid-attenuated inversion recovery hyperintense signal, and reduced diffusivity (3).
    I have recently discussed that the hyper-inflammatory state of immune cells during the cytokine storm in Covid-19 might cause a dramatic change in metabolism, inducing cells to abandon mitochondrial oxidative phosphorylation for ATP production, in favor of cytosolic aerobic glycolysis, which is an inefficient way to generate ATP. This might explain disturbances in water diffusion within tissue, detected by MRI-ADC, due to a cytotoxic edema. Afterwards, improvement of the patient’s inflammatory syndrome surely helped to recover mitochondrial oxidative phosphorylation, explaining reversible and transient symptoms. Whether it was indeed the hyper-inflammatory state that led to abandonment of mitochondrial oxidative phosphorylation, needs further research on this topic (4).  
    The pathogenesis of MIS-C is unknown, and a postinfectious immunological etiology has been hypothesized but not proven. SARS–CoV-2 antibodies arise in the second week after infection, but their presence does not indicate resolution of infection. Therefore, current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment (1,3).
    Nonetheless, virus invasion into the central nervous system through olfactory nerve invasion, cellular invasion, and trans-synaptic transmission, provide the routes for SARS-CoV-2 to vastly invade infratentorial and supratentorial structures. Viral dissemination through neural pathways, retrograde or antegrade, is facilitated by proteins called dinein and kinesin, which can be targets of viruses, hence, possible direct virus infection can also be an important pathogenic contributing factor (4).  
    1. LaRovere K, Riggs B, Poussaint T. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol. JAMA Neurol. Published online March 05, 2021. doi:10.1001/jamaneurol.2021.0504.
    2. Abdel-Haq N, Asmar BI, Deza Leon MP, et al. SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment. Eur J Pediatr. 2021, doi: 10.1007/s00431-021-03935-1.
    3. Princiotta Cariddi L, Tabaee Damavandi P, Carimati F, et al. Reversible Encephalopathy Syndrome (PRES) in a COVID-19 patient. J Neurol. 2020, doi: 10.1007/s00415-020-10001-7.
    4. Machado C. Reader response: Encephalopathy and bil
    More Confirmation of Possible MEEN.
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Interesting study confirming a significant prevalence of neurological complications of post COVID-19 neuropathology. This may also support the syndrome of MEEN (Mass Epidemic Encephalopathic Nightmare). This also justifies further research, and promotes the more urgent need to vaccine the population, instead of herd immunity for COVID. Thank you, and stay safe, Gary Joseph Ordog, MD.
    Views 34,252
    Citations 0
    Original Investigation
    March 5, 2021

    Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

    Author Affiliations
    • 1Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts
    • 2Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
    • 3Department of Radiology, Boston Children’s Hospital, Boston, Massachusetts
    • 4Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts
    • 5Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern, Children’s Health Medical Center Dallas
    • 6Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill
    • 7Pediatric Critical Care Division, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla
    • 8Division of Pediatric Critical Care Medicine, Department of Pediatrics, New York University Grossman School of Medicine, New York
    • 9Division of Infectious Diseases, Department of Pediatrics, Department of Microbiology, University of Mississippi Medical Center, Jackson
    • 10Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida
    • 11Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
    • 12Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora
    • 13Department of Pediatrics, Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, New Jersey
    • 14Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis
    • 15Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington, Seattle
    • 16Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia
    • 17Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, New Jersey
    • 18Division of Pediatric Critical Care Medicine, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
    • 19Pediatric Critical Care Division, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston
    • 20Department of Pediatrics, Penn State Hershey Children’s Hospital, Pennsylvania State University College of Medicine, Hershey
    • 21Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock
    • 22Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
    • 23Department of Pediatrics, University of Cincinnati, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
    • 24COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 25Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 26Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
    • 27Division of Critical Care, Yale University School of Medicine, New Haven, Connecticut
    • 28Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio
    • 29Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham
    • 30Division of Critical Care, Connecticut Children’s, Hartford, Connecticut
    • 31Division of Pediatric Infectious Diseases, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, Missouri
    • 32Division of Pediatric Critical Care, Department of Pediatrics, State University of New York Downstate Health Sciences University, Brooklyn
    • 33Section of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Houston
    • 34Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
    • 35Miller Children’s and Women’s Hospital of Long Beach, Long Beach, California
    • 36Division of Critical Care Medicine, Akron Children’s Hospital, Akron, Ohio
    • 37Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
    • 38Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital, Brooklyn, New York
    • 39Division of Critical Care Medicine, University of California, San Francisco, Benioff Children's Hospital, Oakland
    • 40Division of Critical Care, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri
    • 41Division of Pediatric Critical Care, University of Minnesota Masonic Children’s Hospital, Minneapolis
    • 42Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa
    • 43Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston
    • 44Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
    • 45Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mott Children’s Hospital and University of Michigan, Ann Arbor
    • 46Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, Massachusetts
    JAMA Neurol. Published online March 5, 2021. doi:10.1001/jamaneurol.2021.0504
    Key Points

    Question  What is the extent of neurologic involvement in US hospitalized children and adolescents with coronavirus disease 2019 (COVID-19)?

    Findings  In this study of 1695 patients 21 years or younger hospitalized for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Forty-three patients (12%) developed COVID-19–related life-threatening neurologic disorders, 11 (26%) died, and 17 (40%) survived with new neurologic sequelae.

    Meaning  In this study, COVID-19–related neurologic involvement was common in hospitalized children and adolescents and mostly transient.


    Importance  Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear.

    Objective  To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19.

    Setting, Design, and Participants  Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features.

    Exposures  Severe acute respiratory syndrome coronavirus 2.

    Main Outcomes and Measures  Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge.

    Results  Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died.

    Conclusions and Relevance  In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.