Current clinical findings of acute neurological syndromes after SARS-CoV-2 infection

Minjin Wang1,2,3, Jierui Wang1,3, Yan Ren2, Lu Lu1,3, Weixi Xiong1,3, Lifeng Li4, Songtao Xu5, Meng Tang2, Yushang Yuan2, Yi Xie2, Weimin Li6, Lei Chen1,3, Dong Zhou1,3(), Binwu Ying2(), Jinmei Li1,3()

PDF
MedComm ›› 2024, Vol. 5 ›› Issue (3) : e508. DOI: 10.1002/mco2.508
ORIGINAL ARTICLE

Current clinical findings of acute neurological syndromes after SARS-CoV-2 infection

  • Minjin Wang1,2,3, Jierui Wang1,3, Yan Ren2, Lu Lu1,3, Weixi Xiong1,3, Lifeng Li4, Songtao Xu5, Meng Tang2, Yushang Yuan2, Yi Xie2, Weimin Li6, Lei Chen1,3, Dong Zhou1,3(), Binwu Ying2(), Jinmei Li1,3()
Author information +
History +

Abstract

Neuro-COVID, a condition marked by persistent symptoms post-COVID-19 infection, notably affects various organs, with a particular focus on the central nervous system (CNS). Despite scant evidence of SARS-CoV-2 invasion in the CNS, the increasing incidence of Neuro-COVID cases indicates the onset of acute neurological symptoms early in infection. The Omicron variant, distinguished by heightened neurotropism, penetrates the CNS via the olfactory bulb. This direct invasion induces inflammation and neuronal damage, emphasizing the need for vigilance regarding potential neurological complications. Our multicenter study represents a groundbreaking revelation, documenting the definite presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) of a significant proportion of Neuro-COVID patients. Furthermore, notable differences emerged between RNA-CSF-positive and negative patients, encompassing aspects such as blood–brain barrier integrity, extent of neuronal damage, and the activation status of inflammation. Despite inherent limitations, this research provides pivotal insights into the intricate interplay between SARS-CoV-2 and the CNS, underscoring the necessity for ongoing research to fully comprehend the virus's enduring effects on the CNS. The findings underscore the urgency of continuous investigation Neuro-COVID to unravel the complexities of this relationship, and pivotal in addressing the long-term consequences of COVID-19 on neurological health.

Keywords

central nerve injury / Neuro-COVID / neurological syndromes / neurotropic invasion / SARS-CoV-2

Cite this article

Download citation ▾
Minjin Wang, Jierui Wang, Yan Ren, Lu Lu, Weixi Xiong, Lifeng Li, Songtao Xu, Meng Tang, Yushang Yuan, Yi Xie, Weimin Li, Lei Chen, Dong Zhou, Binwu Ying, Jinmei Li. Current clinical findings of acute neurological syndromes after SARS-CoV-2 infection. MedComm, 2024, 5(3): e508 https://doi.org/10.1002/mco2.508

References

1 M Monje, A Iwasaki. The neurobiology of long COVID. Neuron. 2022;110(21):3484-3496.
2 T Shimohata. Neuro-COVID-19. Clin Exp Neuroimmunol. 2022;13(1):17-23.
3 L Mao, H Jin, M Wang, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690.
4 G Douaud, S Lee, F Alfaro-Almagro, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604(7907):697-707.
5 IJ Koralnik, KL Tyler. COVID-19: a global threat to the nervous system. Ann Neurol. 2020;88(1):1-11.
6 W Xiong, J Mu, J Guo, et al. New onset neurologic events in people with COVID-19 in 3 regions in China. Neurology. 2020;95(11):e1479-e1487.
7 X Zhao, D Li, W Ruan, et al. Effects of a prolonged booster interval on neutralization of omicron variant. N Engl J Med. 2022;386(9):894-896.
8 L Lu, Q Zhang, J Xiao, et al. COVID-19 vaccine take-up rate and safety in adults with epilepsy: data from a multicenter study in China. Epilepsia. 2022;63(1):244-251.
9 L Lu, L Chen, P Wang, et al. Neurological complications during the Omicron COVID-19 wave in China: a cohort study. Eur J Neurol. 2024;31(1):e16096.
10 A Pilotto, S Masciocchi, I Volonghi, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses. Clin Infect Dis. 2021;73(9):e3019-e3026.
11 AG Laing, A Lorenc, I Del Molino Del Barrio, et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med. 2020;26(10):1623-1635.
12 P Perrin, N Collongues, S Baloglu, et al. Cytokine release syndrome-associated encephalopathy in patients with COVID-19. Eur J Neurol. 2021;28(1):248-258.
13 MM Etter, TA Martins, L Kulsvehagen, et al. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022;13(1):6777.
14 VCS Carneiro, SV Alves-Leon, DJS Sarmento, et al. Herpesvirus and neurological manifestations in patients with severe coronavirus disease. Virol J. 2022;19(1):101.
15 P Büttiker, GB Stefano, S Weissenberger, et al. HIV, HSV, SARS-CoV-2 and ebola share long-term neuropsychiatric sequelae. Neuropsychiatr Dis Treat. 2022;18:2229-2237.
16 K Leuzinger, M Osthoff, S Dr?ger, et al. Comparing immunoassays for SARS-CoV-2 antibody detection in patients with and without laboratory-confirmed SARS-CoV-2 infection. J Clin Microbiol. 2021;59(12):e0138121.
17 M Prudencio, Y Erben, CP Marquez, et al. Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19. Sci Transl Med. 2021;13(602).
18 A Edén, A Grahn, D Bremell, et al. Viral antigen and inflammatory biomarkers in cerebrospinal fluid in patients with COVID-19 infection and neurologic symptoms compared with control participants without infection or neurologic symptoms. JAMA Netw Open. 2022;5(5):e2213253.
19 D Reinhold, V Farztdinov, Y Yan, et al. The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation. J Neuroinflammation. 2023;20(1):30.
20 Y Hou, C Li, C Yoon, et al. Enhanced replication of SARS-CoV-2 Omicron BA.2 in human forebrain and midbrain organoids. Signal Transduct Target Ther. 2022;7(1):381.
21 H Shuai, JF Chan, B Hu, et al. Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron. Nature. 2022;603(7902):693-699.
22 M Khan, M Clijsters, S Choi, et al. Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. Neuron. 2022;110(23):3919-3935. e3916.
23 CY Ho, M Salimian, J Hegert, et al. Postmortem assessment of olfactory tissue degeneration and microvasculopathy in patients with COVID-19. JAMA Neurol. 2022;79(6):544-553.
24 BA Hanson, L Visvabharathy, ZS Orban, et al. Plasma proteomics show altered inflammatory and mitochondrial proteins in patients with neurologic symptoms of post-acute sequelae of SARS-CoV-2 infection. Brain Behav Immun. 2023;114:462-474.
25 A Roczkowsky, D Limonta, JP Fernandes, et al. COVID-19 induces neuroinflammation and suppresses peroxisomes in the brain. Ann Neurol. 2023;94(3):531-546.
26 KL LaRovere, TY Poussaint, CC Young, et al. Changes in distribution of severe neurologic involvement in US pediatric inpatients with COVID-19 or multisystem inflammatory syndrome in children in 2021 vs 2020. JAMA Neurol. 2023;80(1):91-98.
27 PN Ostermann, H Schaal. Human brain organoids to explore SARS-CoV-2-induced effects on the central nervous system. Rev Med Virol. 2023;33(2):e2430.
28 M M?ller, K Borg, C Janson, M Lerm, J Normark, K Niward. Cognitive dysfunction in post-COVID-19 condition: mechanisms, management, and rehabilitation. J Intern Med. 2023;294(5):563-581.
29 Y Kaku, K Okumura, M Padilla-Blanco, et al. Virological characteristics of the SARS-CoV-2 JN.1 variant. Lancet Infect Dis. 2024.
30 R Rubin. As COVID-19 cases surge, here's what to know about JN.1, the latest SARS-CoV-2 “variant of interest.” Jama. 2024.
31 Y Xie, Z Al-Aly. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes Endocrinol. 2022;10(5):311-321.
32 AC Yang, F Kern, PM Losada, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature. 2021;595(7868):565-571.
33 M Heming, X Li, S R?uber, et al. Neurological manifestations of COVID-19 feature T cell exhaustion and dedifferentiated monocytes in cerebrospinal fluid. Immunity. 2021;54(1):164-175. e166.
34 MA Zingaropoli, M Iannetta, L Piermatteo, et al. Neuro-axonal damage and alteration of blood-brain barrier integrity in COVID-19 patients. Cells. 2022;11(16).
35 AL Salvio, RA Fernandes, HFA Ferreira, et al. High levels of NfL, GFAP, TAU, and UCH-L1 as potential predictor biomarkers of severity and lethality in acute COVID-19. Mol Neurobiol. 2023.
36 T Armangue, M Spatola, A Vlagea, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-772.
37 D Liu, PH Lin, HL Li, et al. Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay. J Neurol Neurosurg Psychiatry. 2023;94(8):605-613.
38 H Ari?o, R Ruiz García, B Rioseras, et al. Frequency and referral patterns of neural antibody studies during the COVID-19 pandemic: experience from an autoimmune neurology center. Neurol Neuroimmunol Neuroinflamm. 2023;10(4).
39 F Graus, MJ Titulaer, R Balu, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
40 J Dalmau, F Graus. Antibody-Mediated Encephalitis. N Engl J Med. 2018;378(9):840-851.
41 EP Flanagan, MD Geschwind, AS Lopez-Chiriboga, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.
42 X Ren, W Wen, X Fan, et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell. 2021;184(7):1895-1913. e1819.
43 M Schwarz, D Torre, D Lozano-Ojalvo, et al. Rapid, scalable assessment of SARS-CoV-2 cellular immunity by whole-blood PCR. Nat Biotechnol. 2022;40(11):1680-1689.
44 B Ning, Z Huang, BM Youngquist, et al. Liposome-mediated detection of SARS-CoV-2 RNA-positive extracellular vesicles in plasma. Nat Nanotechnol. 2021;16(9):1039-1044.
45 L Jiao, Y Yang, W Yu, et al. The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys. Signal Transduct Target Ther. 2021;6(1):169.
46 XH Yao, T Luo, Y Shi, et al. A cohort autopsy study defines COVID-19 systemic pathogenesis. Cell Res. 2021;31(8):836-846.
47 X Nie, L Qian, R Sun, et al. Multi-organ proteomic landscape of COVID-19 autopsies. Cell. 2021;184(3):775-791. e714.
48 SR Stein, SC Ramelli, A Grazioli, et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. 2022;612(7941):758-763.
49 S Jarius, F Pache, P K?rtvelyessy, et al. Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients. J Neuroinflammation. 2022;19(1):19.
50 B Neumann, ML Schmidbauer, K Dimitriadis, et al. Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms. J Neurol Sci. 2020;418:117090.
51 M Bellon, C Schweblin, N Lambeng, et al. Cerebrospinal fluid features in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) positive patients. Clin Infect Dis. 2021;73(9):e3102-e3105.
52 S Krasemann, U Haferkamp, S Pfefferle, et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022;17(2):307-320.
53 RA Bull, TN Adikari, JM Ferguson, et al. Analytical validity of nanopore sequencing for rapid SARS-CoV-2 genome analysis. Nat Commun. 2020;11(1):6272.
54 J Mertens, J Coppens, K Loens, et al. Monitoring the SARS-CoV-2 pandemic: screening algorithm with single nucleotide polymorphism detection for the rapid identification of established and emerging variants. Clin Microbiol Infect. 2022;28(1):124-129.
55 MA Ellul, L Benjamin, B Singh, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783.
56 A Varatharaj, N Thomas, MA Ellul, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020;7(10):875-882.
57 E Xu, Y Xie, Z Al-Aly. Long-term neurologic outcomes of COVID-19. Nat Med. 2022;28(11):2406-2415.
58 M Taquet, JR Geddes, M Husain, S Luciano, PJ Harrison. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416-427.
59 L Bauer, BM Laksono, FMS de Vrij, SA Kushner, O Harschnitz, D van Riel. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci. 2022;45(5):358-368.
60 EF Balcom, A Nath, C Power. Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease. Brain. 2021;144(12):3576-3588.
61 AK Pr?bstel, L Schirmer. SARS-CoV-2-specific neuropathology: fact or fiction? Trends Neurosci. 2021;44(12):933-935.
62 M Boldrini, PD Canoll, RS Klein. How COVID-19 affects the brain. JAMA Psychiatry. 2021;78(6):682-683.
63 LT Nolen, SS Mukerji, NI Mejia. Post-acute neurological consequences of COVID-19: an unequal burden. Nat Med. 2022;28(1):20-23.
64 FL Fontes-Dantas, GG Fernandes, EG Gutman, et al. SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice. Cell Rep. 2023;42(3):112189.
65 MJ Peluso, HM Sans, CA Forman, et al. Plasma markers of neurologic injury and inflammation in people with self-reported neurologic postacute sequelae of SARS-CoV-2 infection. Neurol Neuroimmunol Neuroinflamm. 2022;9(5).
66 F Lersy, I Benotmane, J Helms, et al. Cerebrospinal fluid features in patients with coronavirus disease 2019 and neurological manifestations: correlation with brain magnetic resonance imaging findings in 58 patients. J Infect Dis. 2021;223(4):600-609.
67 M Guasp, G Mu?oz-Sánchez, E Martínez-Hernández, et al. CSF biomarkers in COVID-19 associated encephalopathy and encephalitis predict long-term outcome. Front Immunol. 2022;13:866153.
68 N Kanberg, J Simrén, A Edén, et al. Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. EBioMedicine. 2021;70:103512.
69 F Verde, I Milone, I Bulgarelli, et al. Serum neurofilament light chain levels in Covid-19 patients without major neurological manifestations. J Neurol. 2022;269(11):5691-5701.
70 D Plantone, S Locci, L Bergantini, et al. Brain neuronal and glial damage during acute COVID-19 infection in absence of clinical neurological manifestations. J Neurol Neurosurg Psychiatry. 2022;93(12):1343-1348.
71 N Kanberg, A Grahn, E Stentoft, et al. COVID-19 recovery: consistent absence of cerebrospinal fluid biomarker abnormalities in patients with neurocognitive post-COVID complications. J Infect Dis. 2023.
72 L Devlin, GY Gombolay. Cerebrospinal fluid cytokines in COVID-19: a review and meta-analysis. J Neurol. 2023;270(11):5155-5161.
73 R Gondim, EAG de Arruda, R Neto, et al. Cytokines, chemokines, and cells growth factors in patients with mild to moderate SARS-CoV-2 infection: a case-control study. J Med Virol. 2023;95(8):e29044.
74 Y Kase, I Sonn, M Goto, R Murakami, T Sato, H Okano. The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: analysis using 2D and 3D cultures. Exp Neurol. 2023;363:114379.
75 F Ceban, S Ling, LMW Lui, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135.
76 HE Davis, L McCorkell, JM Vogel, EJ Topol. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146.
PDF

Accesses

Citations

Detail

Sections
Recommended

/