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  • Review Article
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Understanding the long-term neurological effects of SARS-CoV-2 infection

Nature Reviews Neurology (2026)Cite this article

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Abstract

Post-COVID-19 condition (PCC), also known as long COVID, is a heterogeneous condition marked by persistent symptoms following acute SARS-CoV-2 infection. As approximately 6% of people who have experienced acute COVID-19 are estimated to develop PCC, the potential population is vast. Many of the key symptoms of PCC reflect involvement of the nervous system, ranging from cognitive impairment (‘brain fog’), headaches and fatigue to anxiety and depression. This Review summarizes the spectrum of neurological and psychological symptoms that occur following acute SARS-CoV-2 infection, with a particular focus on the international consensus-based core outcome set for PCC. We also explore the proposed underlying mechanisms, including evidence for immune system dysregulation, microvascular dysfunction and volumetric changes on neuroimaging. In addition, we review ongoing and completed large-scale treatment trials. Growing evidence suggests a bidirectional interaction between symptoms traditionally considered neurobiological in origin, such as cognitive deficits and headache, and those within the purview of psychiatry, such as anxiety and depression. PCC represents an opportunity to better understand the long-term consequences of acute infection and improve management strategies and outcomes, not only for people with the condition but also for those with other post-viral syndromes that affect brain health.

Key points

  • Post-COVID-19 condition (PCC) encompasses persistent symptoms including headache, cognitive impairment, fatigue, sleep disturbances, dysautonomia, pain and psychiatric disorders.

  • Systematic reviews and cohort studies highlight variable prevalence of PCC symptoms, and cognitive, sleep and fatigue symptoms often persist for 12–24 months or longer.

  • The proposed pathophysiology of PCC includes viral persistence, immune dysregulation, neuroinflammation, latent herpesvirus reactivation, microvascular injury, gut–brain axis disruption, and structural and functional brain changes.

  • Neurological and psychiatric symptoms substantially impair daily living, employment and health-related quality of life, with some deficits persisting years after infection.

  • Current approaches to PCC management are largely symptomatic and multidisciplinary, including rehabilitation, pacing strategies, cognitive behavioural therapy, pharmacological management for pain and dysautonomia, and sleep interventions. Graded exercise therapy is not recommended.

  • Completed and ongoing trials are exploring pharmacological, immunological and microbiome-targeted interventions, and vaccination remains a key modifiable factor in the reducing risk and severity of PCC.

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Fig. 1: Altered functional connectivity in the brain in PCC.

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References

  1. World Health Organization. WHO Coronavirus (COVID-19) Dashboard (WHO, 2025); https://data.who.int/dashboards/covid19/cases?n=c2025.

  2. Ray, S. T. J. et al. Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study. Lancet Child Adolesc. Health 5, 631–641 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ross Russell AL et al. Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study. Brain Commun. 3, fcab168 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Varatharaj, A. et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 7, 875–882 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chou, S. H. et al. Global incidence of neurological manifestations among patients hospitalized with COVID-19 — a report for the GCS–NeuroCOVID Consortium and the ENERGY Consortium. JAMA Netw. Open 4, e2112131 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Shi, J. et al. Prevalence of and factors associated with long COVID among US adults: a nationwide survey. BMC Public Health 25, 1758 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  7. World Health Organization. Post COVID-19 condition (long COVID). who.int https://www.who.int/news-room/fact-sheets/detail/post-covid-19-condition-%28long-covid%29 (accessed 25 June 2025).

  8. Soriano, J. B., Murthy, S., Marshall, J. C., Relan, P. & Diaz, J. V. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect. Dis. 22, e102–e107 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Munblit, D. et al. A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study. Lancet Respir. Med. 10, 715–724 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adjaye-Gbewonyo D., Vahratian A., Perrine C. G. & Bertolli J. Long COVID in adults: United States, 2022. NCHS Data Brief. 480, 1–8 (2023).

    Google Scholar 

  11. Hou, Y. et al. Global prevalence of long COVID, its subtypes, and risk factors: an updated systematic review and meta-analysis. Open Forum Infect. Dis. 12, ofaf533 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Elboraay, T. et al. Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients. BMC Neurol. 25, 250 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Subramanian, A. et al. Symptoms and risk factors for long COVID in non-hospitalized adults. Nat. Med. 28, 1706–1714 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sudre, C. H. et al. Attributes and predictors of long COVID. Nat. Med. 27, 626–631 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thompson, E. J. et al. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat. Commun. 13, 3528 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Burn, E. et al. Venous or arterial thrombosis and deaths among COVID-19 cases: a European network cohort study. Lancet Infect. Dis. 22, 1142–1152 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qureshi, A. I. et al. Acute ischemic stroke and COVID-19: an analysis of 27,676 patients. Stroke 52, 905–912 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nannoni, S., de Groot, R., Bell, S. & Markus, H. S. Stroke in COVID-19: a systematic review and meta-analysis. Int. J. Stroke 16, 137–149 (2021).

    Article  PubMed  Google Scholar 

  19. Zarifkar, P., Peinkhofer, C., Benros, M. E. & Kondziella, D. Frequency of neurological diseases after COVID-19, influenza A/B and bacterial pneumonia. Front. Neurol. 13, 904796 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Garg, R. K., Paliwal, V. K. & Gupta, A. Encephalopathy in patients with COVID-19: a review. J. Med. Virol. 93, 206–222 (2021).

    Article  CAS  PubMed  Google Scholar 

  21. Legriel, S. et al. Outcomes in patients with COVID-19 with acute encephalopathy and coma: an international prospective study. Neurology 100, e2247–e2258 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liotta, E. M. et al. Frequent neurologic manifestations and encephalopathy-associated morbidity in COVID-19 patients. Ann. Clin. Transl. Neurol. 7, 2221–2230 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. O’Mahoney, L. L. et al. The prevalence and long-term health effects of long COVID among hospitalised and non-hospitalised populations: a systematic review and meta-analysis. EClinicalMedicine 55, 101762 (2023).

    Article  PubMed  Google Scholar 

  24. Fernández-de-Las-Peñas, C. et al. Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: a meta-analysis of the current literature. Eur. J. Neurol. 28, 3820–3825 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tana, C. et al. Long COVID headache. J. Headache Pain. 23, 93 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Silva, L. et al. Long-term persistent headache after SARS-CoV-2 infection: a follow-up population-based study. Eur. J. Neurol. 32, e70130 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Uygun, O. et al. Headache characteristics in COVID-19 pandemic — a survey study. J. Headache Pain 21, 121 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Caronna, E. et al. Headache: a striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution. Cephalalgia 40, 1410–1421 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Trigo, J. et al. Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study. J. Headache Pain 21, 94 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Karadaş, Ö et al. Latent class cluster analysis identified hidden headache phenotypes in COVID-19: impact of pulmonary infiltration and IL-6. Neurol. Sci. 42, 1665–1673 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Davis, H. E. et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. eClinicalMedicine 38, 101019 (2021).

    Article  PubMed  Google Scholar 

  32. Larsen, N. W. et al. Characterization of autonomic symptom burden in long COVID: a global survey of 2,314 adults. Front. Neurol. 13, 1012668 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Novak, P. et al. Multisystem involvement in post-acute sequelae of coronavirus disease 19. Ann. Neurol. 91, 367–379 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Larsen, N. W., Stiles, L. E. & Miglis, M. G. Preparing for the long-haul: autonomic complications of COVID-19. Auton. Neurosci. 235, 102841 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sletten, D. M., Suarez, G. A., Low, P. A., Mandrekar, J. & Singer, W. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin. Proc. 87, 1196–1201 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Eastin, E. et al. Evaluating long-term autonomic dysfunction and functional impacts of long COVID: a follow-up study (P1-7.004). Neurology 104, 4290 (2025).

    Article  Google Scholar 

  37. Dani, M. et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin. Med. 21, e63–e67 (2021).

    Article  Google Scholar 

  38. Huang, C. et al. 6-Month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 401, e21–e33 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Merikanto, I. et al. Sleep symptoms are essential features of long-COVID — comparing healthy controls with COVID-19 cases of different severity in the International COVID Sleep Study (ICOSS-II). J. Sleep Res. 32, e13754 (2023).

    Article  PubMed  Google Scholar 

  40. Moura, A. E. F. et al. Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome — a prospective cohort study. BMC Neurol. 22, 417 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Henríquez-Beltrán, M. et al. Sleep and circadian health of critical survivors: a 12-month follow-up study. Crit. Care Med. 52, 1206–1217 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Chinvararak, C. & Chalder, T. Prevalence of sleep disturbances in patients with long COVID assessed by standardised questionnaires and diagnostic criteria: a systematic review and meta-analysis. J. Psychosom. Res. 175, 111535 (2023).

    Article  PubMed  Google Scholar 

  43. Linh, T. T. D. et al. Global prevalence of post-COVID-19 sleep disturbances in adults at different follow-up time points: a systematic review and meta-analysis. Sleep Med. Rev. 71, 101833 (2023).

    Article  PubMed  Google Scholar 

  44. Zhou, J. et al. Pre-existing sleep disturbances and risk of COVID-19: a meta-analysis. eClinicalMedicine 74, 102719 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Punj, M., Schwartz, M., Morris, A., Cheung, J. & Munipalli, B. A survey of sleep quality from a post-COVID clinic. J. Prim. Care Commun. Health 15, 21501319241233205 (2024).

    Article  Google Scholar 

  46. Goldstein, C. A. et al. The possibility of circadian rhythm disruption in long COVID. Brain Behav. Immun. Health 23, 100476 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Global Burden of Disease Long COVID Collaborators. Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA 328, 1604–1615 (2022).

    Article  Google Scholar 

  48. Thaweethai, T. et al. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA 329, 1934–1946 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Peter, R. S. et al. Post-acute sequelae of COVID-19 six to 12 months after infection: population based study. Br. Med. J. 379, e071050 (2022).

    Article  Google Scholar 

  50. Joli, J., Buck, P., Zipfel, S. & Stengel, A. Post-COVID-19 fatigue: a systematic review. Front. Psychiatry 13, 947973 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kedor, C. et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat. Commun. 13, 5104 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Appelman, B. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat. Commun. 15, 17 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Saito, S. et al. Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome. Front. Immunol. 15, 1341843 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jason, L. A., Yoo, S. & Bhatia, S. Patient perceptions of infectious illnesses preceding myalgic encephalomyelitis/chronic fatigue syndrome. Chronic Illn. 18, 901–910 (2022).

    Article  PubMed  Google Scholar 

  55. Nakatomi, Y. et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an (1)(1)C-(R)-PK11195 PET study. J. Nucl. Med. 55, 945–950 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Komaroff, A. L. & Lipkin, W. I. ME/CFS and long COVID share similar symptoms and biological abnormalities: road map to the literature. Front. Med. 10, 1187163 (2023).

    Article  Google Scholar 

  57. McWhirter, L. et al. What is brain fog? J. Neurol. Neurosurg. Psychiatry 94, 321–325 (2023).

    Article  PubMed  Google Scholar 

  58. Xu, E., Xie, Y. & Al-Aly, Z. Long-term neurologic outcomes of COVID-19. Nat. Med. 28, 2406–2415 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Al-Aly, Z. et al. Long COVID science, research and policy. Nat. Med. 30, 2148–2164 (2024).

    Article  CAS  PubMed  Google Scholar 

  60. Al-Aly, Z. & Rosen, C. J. Long COVID and impaired cognition — more evidence and more work to do. N. Engl. J. Med. 390, 858–860 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hampshire, A. et al. Cognition and memory after COVID-19 in a large community sample. N. Engl. J. Med. 390, 806–818 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wood, G. K. et al. Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction. Nat. Med. 31, 245–257 (2025).

    Article  CAS  PubMed  Google Scholar 

  63. Hosp, J. A. et al. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain 144, 1263–1276 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Serrano del Pueblo, V. M. et al. Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects. Brain 147, 3611–3623 (2024).

    Article  PubMed  Google Scholar 

  65. Becker, J. H. et al. Assessment of cognitive function in patients after COVID-19 infection. JAMA Netw. Open 4, e2130645 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Fanshawe, J. B. et al. Cognitive domains affected post-COVID-19; a systematic review and meta-analysis. Eur. J. Neurol. 32, e16181 (2025).

    Article  PubMed  Google Scholar 

  67. Fernandez-Castaneda, A. et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 185, 2452–68 e16 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pretorius, E. et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with long COVID/post-acute sequelae of COVID-19 (PASC). Cardiovasc. Diabetol. 21, 148 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rensma, S. P. et al. Microvascular dysfunction is associated with worse cognitive performance: the Maastricht Study. Hypertension 75, 237–245 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Douaud, G. et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604, 697–707 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Abrams, R. M. C., Zhou, L. & Shin, S. C. Persistent post-COVID-19 neuromuscular symptoms. Muscle Nerve 68, 350–355 (2023).

    Article  PubMed  Google Scholar 

  72. Premraj, L. et al. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: a meta-analysis. J. Neurol. Sci. 434, 120162 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Taga, A. & Lauria, G. COVID-19 and the peripheral nervous system. A 2-year review from the pandemic to the vaccine era. J. Peripher. Nerv. Syst. 27, 4–30 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Oaklander, A. L. et al. Peripheral neuropathy evaluations of patients with prolonged long COVID. Neurol. Neuroimmunol. Neuroinflamm. 9, e1146 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Falco, P. et al. Small fibre neuropathy frequently underlies the painful long-COVID syndrome. Pain 165, 2002–2010 (2024).

    Article  PubMed  Google Scholar 

  76. Drobinska, N. et al. Small fiber neuropathy in long COVID: a cohort study with multimodal assessment and follow-up. Eur. Neurol. 88, 52–63 (2025).

    Article  CAS  PubMed  Google Scholar 

  77. van der Feltz-Cornelis, C. et al. Prevalence of mental health conditions and brain fog in people with long COVID: a systematic review and meta-analysis. Gen. Hosp. Psychiatry 88, 10–22 (2024).

    Article  PubMed  Google Scholar 

  78. Marchi, M. et al. Psychiatric symptoms in long-COVID patients: a systematic review. Front. Psychiatry 14, 1138389 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Yuan, K. et al. A systematic review and meta-analysis on prevalence of and risk factors associated with depression, anxiety and insomnia in infectious diseases, including COVID-19: a call to action. Mol. Psychiatry 27, 3214–3222 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Taquet, M. et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1,284,437 patients. Lancet Psychiatry 9, 815–827 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Taquet, M. et al. Cognitive and psychiatric symptom trajectories 2–3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK. Lancet Psychiatry 11, 696–708 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Yin, K. et al. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat. Immunol. 25, 218–225 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zakia, H., Pradana, K. & Iskandar, S. Risk factors for psychiatric symptoms in patients with long COVID: a systematic review. PLoS ONE 18, e0284075 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kubota, T., Kuroda, N. & Sone, D. Neuropsychiatric aspects of long COVID: a comprehensive review. Psychiatry Clin. Neurosci. 77, 84–93 (2023).

    Article  PubMed  Google Scholar 

  85. Zeng, N. et al. A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action. Mol. Psychiatry 28, 423–433 (2023).

    Article  CAS  PubMed  Google Scholar 

  86. Wen, J. et al. Trajectories of symptoms in the acute phase of COVID-19 infection and their association with anxiety and depression 2 years after infection. BMC Psychiatry 26, 29 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Huarcaya-Victoria, J. et al. Mental health in COVID-2019 survivors from a general hospital in Peru: sociodemographic, clinical, and inflammatory variable associations. Int. J. Ment. Health Addict. 21, 1264–1285 (2023).

    Article  PubMed  Google Scholar 

  88. Ahmed, G. K. et al. Long term impact of COVID-19 infection on sleep and mental health: a cross-sectional study. Psychiatry Res. 305, 114243 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kappelmann, N., Dantzer, R. & Khandaker, G. M. Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19. Psychoneuroendocrinology 131, 105295 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Couto Amendola, F. et al. A two-year cohort study examining the impact of cytokines and chemokines on cognitive and psychiatric outcomes in long-COVID-19 patients. Brain Behav. Immun. 124, 218–225 (2025).

    Article  CAS  PubMed  Google Scholar 

  91. Teodoro, T., Chen, J., Gelauff, J. & Edwards, M. J. Functional neurological disorder in people with long COVID: a systematic review. Eur. J. Neurol. 30, 1505–1514 (2023).

    Article  PubMed  Google Scholar 

  92. Davenport, T. E. et al. Long COVID is not a functional neurologic disorder. J. Pers. Med. 14, 799 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Van der Feltz-Cornelis, C. M., Moriarty, A. S. & Strain, W. D. Neurological dysfunction in long COVID should not be labelled as functional neurological disorder. Viruses 15, 783 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stein, S. R. et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 612, 758–763 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zuo, W. et al. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China. Lancet Infect. Dis. 24, 845–855 (2024).

    Article  CAS  PubMed  Google Scholar 

  97. Martínez-Mármol, R. et al. SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity. Sci. Adv. 9, eadg2248 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Khan, M. et al. Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients. Neuron 110, 3919–35.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Meinhardt, J. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat. Neurosci. 24, 168–175 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Wong, A. C. et al. Serotonin reduction in post-acute sequelae of viral infection. Cell 186, 4851–67.e20 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Greenhalgh, T., Sivan, M., Perlowski, A. & Nikolich, J. Ž Long COVID: a clinical update. Lancet 404, 707–724 (2024).

    Article  CAS  PubMed  Google Scholar 

  102. Klein, J. et al. Distinguishing features of long COVID identified through immune profiling. Nature 623, 139–148 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dunai, C. et al. Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain. Front. Immunol. 15, 1440324 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Michael, B. D. et al. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nat. Commun. 14, 8487 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Etter, M. M. et al. Severe neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat. Commun. 13, 6777 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Needham, E. J. et al. Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Brain 145, 4097–4107 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Gold, J. E., Okyay, R. A., Licht, W. E. & Hurley, D. J. Investigation of long COVID prevalence and its relationship to Epstein–Barr virus reactivation. Pathogens 10, 763 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Su, Y. et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 185, 881–95.e20 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ruiz-Pablos, M., Paiva, B., Montero-Mateo, R., Garcia, N. & Zabaleta, A. Epstein–Barr virus and the origin of myalgic encephalomyelitis or chronic fatigue syndrome. Front. Immunol. 12, 656797 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Monje, M. & Iwasaki, A. The neurobiology of long COVID. Neuron 110, 3484–3496 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bjornevik, K., Münz, C., Cohen, J. I. & Ascherio, A. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat. Rev. Neurol. 19, 160–171 (2023).

    CAS  PubMed  Google Scholar 

  112. Thakur, K. T. et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain 144, 2696–2708 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Varga, Z. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Leng, A. et al. Pathogenesis underlying neurological manifestations of long COVID syndrome and potential therapeutics. Cells 12, 816 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fogarty, H. et al. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J. Thromb. Haemost. 19, 2546–2553 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pretorius, E. et al. Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc. Diabetol. 20, 172 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Greene, C. et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat. Neurosci. 27, 421–432 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zuo, Y. et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci. Transl. Med. 12, eabd3876 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tung, M. L., Tan, B., Cherian, R. & Chandra, B. Anti-phospholipid syndrome and COVID-19 thrombosis: connecting the dots. Rheumatol. Adv. Pract. 5, rkaa081 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Altmann, D. M., Whettlock, E. M., Liu, S., Arachchillage, D. J. & Boyton, R. J. The immunology of long COVID. Nat. Rev. Immunol. 23, 618–634 (2023).

    Article  CAS  PubMed  Google Scholar 

  121. Liu, Q. et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut 71, 544–552 (2022).

    Article  CAS  PubMed  Google Scholar 

  122. Lau, R. I. et al. A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial. Lancet Infect. Dis. 24, 256–265 (2024).

    Article  CAS  PubMed  Google Scholar 

  123. Ancona, G. et al. Gut and airway microbiota dysbiosis and their role in COVID-19 and long-COVID. Front. Immunol. 14, 1080043 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cecchetti, G. et al. Cognitive, EEG, and MRI features of COVID-19 survivors: a 10-month study. J. Neurol. 269, 3400–3412 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Petersen, M. et al. Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection. Proc. Natl Acad. Sci. USA 120, e2217232120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Samanci, B. et al. Persistent neurocognitive deficits in long COVID: evidence of structural changes and network abnormalities following mild infection. Cortex 187, 98–110 (2025).

    Article  PubMed  Google Scholar 

  127. Troll, M. et al. Altered corticostriatal connectivity in long-COVID patients is associated with cognitive impairment. Psychol. Med. 55, e49 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Jaywant, A. et al. Cognitive symptoms of post-COVID-19 condition and daily functioning. JAMA Netw. Open 7, e2356098–e2356098 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Cai, M., Xie, Y., Topol, E. J. & Al-Aly, Z. Three-year outcomes of post-acute sequelae of COVID-19. Nat. Med. 30, 1564–1573 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shil, R. S. K. et al. Patients with neurological or psychiatric complications of COVID-19 have worse long-term functional outcomes: COVID-CNS — a multicentre case–control study. Sci. Rep. 15, 3443 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kim, Y., Bae, S., Chang, H. H. & Kim, S. W. Long COVID prevalence and impact on quality of life 2 years after acute COVID-19. Sci. Rep. 13, 11207 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Rodrigues, A. N. et al. Effect of long COVID-19 syndrome on health-related quality of life: a cross-sectional study. Front. Psychol. 15, 1394068 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  133. World Health Organization. WHO Guidelines Approved by the Guidelines Review Committee. Clinical Management of COVID-19: Living Guideline (WHO, 2022).

  134. Kuut, T. A. et al. Efficacy of cognitive-behavioral therapy targeting severe fatigue following coronavirus disease 2019: results of a randomized controlled trial. Clin. Infect. Dis. 77, 687–695 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Berry, C. et al. Resistance exercise therapy after COVID-19 infection: a randomized clinical trial. JAMA Netw. Open 8, e2534304 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Mooren, J. M. et al. Medical rehabilitation of patients with post-COVID-19 syndrome — a comparison of aerobic interval and continuous training. J. Clin. Med. 12, 6739 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Blitshteyn, S. et al. Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PM R 14, 1270–1291 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Rinaldi, L. et al. Long-COVID autonomic syndrome in working age and work ability impairment. Sci. Rep. 14, 11835 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Herring, T. E. et al. Post traumatic stress and sleep disorders in long COVID: patient management and treatment. Life Sci. 357, 123081 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Shil, R. S. K. et al. A clinical approach to the investigation and management of long COVID associated neuropathic pain. Eur. Arch. Psychiatry Clin. Neurosci. 274, 1787–1795 (2024).

    Article  PubMed  Google Scholar 

  141. National Institute for Health and Care Excellence. Neuropathic pain in adults: pharmacological management in non-specialist settings. nice.org.uk https://www.nice.org.uk/guidance/cg173/chapter/Recommendations (2020).

  142. Guttuso, T. Jr., Zhu, J. & Wilding, G. E. Lithium aspartate for long COVID fatigue and cognitive dysfunction: a randomized clinical trial. JAMA Netw. Open 7, e2436874 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  143. McIntyre, R. S. et al. Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial. Brain 147, 849–857 (2024).

    Article  PubMed  Google Scholar 

  144. Geng, L. N. et al. Nirmatrelvir–ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: the STOP-PASC randomized clinical trial. JAMA Intern. Med. 184, 1024–1034 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gaylis, N. B. et al. Reduced cell surface levels of C-C chemokine receptor 5 and immunosuppression in long coronavirus disease 2019 syndrome. Clin. Infect. Dis. 75, 1232–1234 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tanashyan, M. M., Raskurazhev, A. A., Kuznetsova, P. I., Bely, P. A. & Zaslavskaya, K. I. Prospects and possibilities for the treatment of patients with long COVID-19 syndrome. Ter. Arkh. 94, 1285–1293 (2022).

    CAS  PubMed  Google Scholar 

  147. Putilina, M. V., Teplova, N. V., Bairova, K. I., Petrikeeva, A. E. & Shabalina, N. I. The result of prospective randomized study CITADEL — the efficacy and safety of drug cytoflavin in postcovid rehabilitation. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 121, 45–51 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Tosato, M. et al. Effects of l-arginine plus vitamin c supplementation on physical performance, endothelial function, and persistent fatigue in adults with long COVID: a single-blind randomized controlled trial. Nutrients 14, 4984 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Achleitner, M. et al. Clinical improvement of long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis. Mol. Psychiatry 28, 2872–2877 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Novak, P. Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report. eNeurologicalSci 21, 100276 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bonilla, H. et al. Therapeutic trials for long COVID-19: a call to action from the interventions taskforce of the RECOVER initiative. Front. Immunol. 14, 1129459 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Preview : Journal Type Where are the long COVID trials? Lancet Infect. Dis. 23, 879 (2023).

  153. Ledford, H. Long-COVID treatments: why the world is still waiting. Nature 608, 258–260 (2022).

    Article  CAS  PubMed  Google Scholar 

  154. Notarte, K. I. et al. Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: a systematic review. EClinicalMedicine 53, 101624 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Ayoubkhani, D. et al. Trajectory of long covid symptoms after COVID-19 vaccination: community based cohort study. Br. Med. J. 377, e069676 (2022).

    Article  Google Scholar 

  156. Mizrahi, B. et al. Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study. Br. Med. J. 380, e072529 (2023).

    Article  Google Scholar 

  157. Ellul, M. A. et al. Neurological associations of COVID-19. Lancet Neurol. 19, 767–783 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Taquet, M. et al. Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med. 18, e1003773 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Romero-Duarte, Á et al. Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicentre 6-month follow-up study. BMC Med. 19, 129 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Huang, L. et al. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir. Med. 10, 863–876 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Pazukhina, E. et al. Prevalence and risk factors of post-COVID-19 condition in adults and children at 6 and 12 months after hospital discharge: a prospective, cohort study in Moscow (StopCOVID). BMC Med. 20, 244 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Perlis, R. H. et al. Prevalence and Correlates of Long COVID Symptoms Among US Adults. JAMA Netw. Open 5, e2238804 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Whitaker, M. et al. Persistent COVID-19 symptoms in a community study of 606,434 people in England. Nat. Commun. 13, 1957 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhao, Y. et al. The phenotype and prediction of long-term physical, mental and cognitive COVID-19 sequelae 20 months after recovery, a community-based cohort study in China. Mol. Psychiatry 28, 1793–1801 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Tok, P. S. K. et al. Post COVID-19 condition among adults in Malaysia following the Omicron wave: a prospective cohort study. PLoS ONE 19, e0296488 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cai, J. et al. A one-year follow-up study of systematic impact of long COVID symptoms among patients post SARS-CoV-2 omicron variants infection in Shanghai, China. Emerg. Microbes Infect. 12, 2220578 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Leisman, D. E. et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med. 8, 1233–1244 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Verde, F. et al. Serum neurofilament light chain levels in Covid-19 patients without major neurological manifestations. J. Neurol. 269, 5691–5701 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. The Brain Infection and Inflammation Group, Liverpool Interdisciplinary Neuroscience Centre (LINC), Clinical Infection, Microbiology, and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

    Rachael Matthews, Ali Alam & Benedict D. Michael

  2. Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK

    Rachael Matthews & Benedict D. Michael

  3. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Ed Bullmore

  4. NIHR Health Protection Research Unit (HPRU) for Emerging and Zoonotic Infection, University of Liverpool, Liverpool, UK

    Benedict D. Michael

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R.M., A.A. and B.D.M. researched data for the article. All authors contributed substantially to discussion of the content. R.M. and A.A. wrote the article. E.B. and B.D.M. reviewed and/or edited the manuscript before submission.

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Matthews, R., Alam, A., Bullmore, E. et al. Understanding the long-term neurological effects of SARS-CoV-2 infection. Nat Rev Neurol (2026). https://doi.org/10.1038/s41582-026-01205-y

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