Received 2022-10-27

Revised 2022-11-15

Accepted 2022-12-14

Role of Epstein-Barr Virus on Cognitive Impairment among Multiple Sclerosis Patients

Elnaz Asadollahzadeh 1, Zahra Ebadi 1, Abdorreza Naser Moghadasi 1

1 Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical, Tehran, Iran

Dear Editor,

Approximately six million people in the United States are affected by neurological diseases (NDs), and their incidence and severity are linked to genetic and environmental factors [1]. Recent studies have implicated human herpesviruses, such as Epstein-Barr virus (EBV), as potentially infectious agents in the etiology of NDs [2, 3]. EBV is a neurotrophic virus that can infect astrocytes, neurons, and
microglia [4]. Furthermore, infected B- and T-cells migrate through areas of the central nervous system, such as the glymphatic system and the nasopharynx, which could impact neuronal cell function [5, 6]. EBV infects B-cells, and there is growing evidence that B-cells play an important role in brain damage in some diseases, e.g., multiple sclerosis (MS) [1]. Demyelinating plaques associated with MS have been found to contain EBV. A high titer of the EBV nuclear antigen (EBNA) or an EBV infection also raises the risk of developing MS in the
future [1].

Additionally, it has been noted that EBV seropositivity in MS is higher than 99% compared to 94% in adults, providing evidence that EBV may have contributed to MS early pathogenesis [7, 8]. B-cells and their activated offspring in the brain produce immunoglobulins and promote the clonal expansion of plasmablasts [9]. These antibodies that attack the myelin-producing glial cells and cause damage are discovered in MS patients' cerebrospinal fluid [9]. Additionally, MS patients frequently have anti-GlialCAM and anti-EBNA1 antibodies [8]. The integrity of the cortical gray matter structures may be impacted, and its atrophy may be accelerated by the B-cell follicles growing in the MS meninges and the presence of dysregulated EBV-infected
B-cells [8, 10]. Previous reports indicated that imaging evidence (e.g., magnetic resonance imaging) of cortical atrophy could appear in the early stages of MS, despite the possibility of a delay between the onset of isolated cortical lesions and atrophy [10]. EBV can prevent B and T lymphocytes from proliferating, which causes neuroinflammation and demyelination when it infects neurons.

Additionally, it accelerates glial cell necrosis and degeneration [11]. Because anti-CD20 monoclonal antibodies are very efficient in treating MS patients, the involvement of B-cells in the onset of MS activity may be increasingly prominent [12]. These incidents support the association between EBV and MS [12]. Compared to the control group, anti-VCA and anti-EBNA-1 titers were considerably greater in MS patients. Higher anti-VCA titers were associated with older age and the female sex, while higher anti-EBNA-1 titers were associated with the male sex [13].

The relationship between exposure to EBV and cognitive performance has been studied, but the results have been mixed. Three tiny samples from a meta-analysis revealed a link between EBV and Alzheimer's disease (AD) [14]. In a recent study, EBV-specific T-cell receptors were found in the cerebral fluid of AD patients, and these receptors were strengthened by the increased antigen-specific clonal growth of CD8+ T-cells in AD [15]. Dickerson et al. evaluated the association between EBV and cognition in two studies involving 521 non-elderly and 229 individuals with schizophrenia, but they could not find a relationship [16]. In research involving 7000 young adults, EBV was also unrelated to cognitive function [17]. The confidence interval in the last two studies was considerable, making it challenging to interpret the findings. Even though the precise mechanism underlying the link between infection and AD is not fully understood, studies have suggested several potential mechanisms. According to some, herpesvirus infection may encourage the development of amyloid plaques in the brain [18]. According to Shim et al. a chronic EBV infection may play a role in the pathogenesis of AD, and an EBV antibody level may be employed as a potential biomarker for determining the likelihood of developing cognitive impairment [19].

It appears that EBV infection and its effect on demyelinating diseases could lead to degenerative processes in MS and cognition. Furthermore, new studies with new methods are needed to support the possibility of elevated EBV antibody titers with cognitive impairment among MS patients.


Conflict of Interest

The authors have no competing interests.

Keywords: Epstein-Barr Virus; Cognitive Impairment; Multiple Sclerosis

Correspondence to:

Abdorreza Naser Moghadasi, Multiple Sclerosis Research Center, Sina Hospital, Hassan Abad Square, Tehran, Iran

Telephone Number: +982166348571

Email Address: [email protected]


  1. Tognasoli APC. Epstein-Barr Virus as a Piece of the Neurodegenerative Disease Mosaic. The University of North Carolina at Greensboro; 2022.
  2. Hagan KA, Munger KL, Ascherio A, Grodstein F. Epidemiology of major neurodegenerative diseases in women: Contribution of the nurses’ health study. Am J Public Health. 2016;106(9):1650-5.
  3. Indari O, Jakhmola S, Pathak DK, Tanwar M, Kandpal M, Mishra A, et al. Comparative Account of Biomolecular Changes Post Epstein Barr Virus Infection of the Neuronal and Glial Cells Using Raman Microspectroscopy. ACS Chem Neurosci. 2022;13(11):1627-37.
  4. Yu F, Lu Y, Li Y, Uchio Y, Pangnguriseng UA, Kartika AV, et al. Epstein–Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity. Cancers. 2020;12(9):2722.
  5. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(4):1089-104.
  6. Fernández-Menéndez S, Fernández-Morán M, Fernández-Vega I, Pérez-Álvarez A, Villafani-Echazú J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. J Neurol Sci. 2016;361:213-9.
  7. Hrastelj J, Robertson NP. A role for the Epstein–Barr virus in multiple sclerosis aetiology? J Neurol. 2022;269(7):3962-3.
  8. Lanz TV, Brewer RC, Ho PP, Moon JS, Jude KM, Fernandez D, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-7.
  9. Robinson WH, Steinman L. Epstein-Barr virus and multiple sclerosis. Science. 2022;375(6578):264-5.
  10. De Stefano N, Matthews P, Filippi M, Agosta F, De Luca M, Bartolozzi M, et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology. 2003;60(7):
  11. Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr virus and neurological diseases. Front Mol Biosci. 2022;8:816098.
  12. Aloisi F, Cross AH. MINI-review of Epstein-Barr virus involvement in multiple sclerosis etiology and pathogenesis. J Neuroimmunol. 2022;371:577935.
  13. Domínguez-Mozo M, Lopez-Lozano L, Pérez-Pérez S, García-Martínez Á, Torrejón M, Arroyo R, et al. Epstein-Barr Virus and multiple sclerosis in a Spanish cohort: A two-years longitudinal study. Front Immunol. 2022;13:991662.
  14. Steel AJ, Eslick GD. Herpes viruses increase the risk of Alzheimer’s disease: a meta-analysis. J Alzheimers Dis. 2015;47(2):351-64.
  15. Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. 2020;577(7790):399-404.
  16. Dickerson F, Stallings C, Origoni A, Katsafanas E, Schweinfurth LA, Savage CL, et al. Association between cytomegalovirus antibody levels and cognitive functioning in non-elderly adults. PLoS One. 2014;9(5):e95510.
  17. Torniainen-Holm M, Suvisaari J, Lindgren M, Härkänen T, Dickerson F, Yolken RH. Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study. Brain Behav Immun. 2018;69:480-5.
  18. Eimer WA, Kumar DKV, Shanmugam NKN, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99(1):
  19. Shim S-M, Cheon HS, Jo C, Koh YH, Song J, Jeon JP. Elevated epstein-barr virus antibody level is associated with cognitive decline in the korean elderly. J Alzheimers Dis. 2017;55(1):293-301.