Epstein-Barr virus and multiple sclerosis

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.     

The association of multiple sclerosis and Hodgkin's disease: the role of Epstein-Barr virus infection

The aetiology of multiple sclerosis (MS) is still an unresolved question. Several recently reported studies are implicating Epstein-Barr virus (EBV) as one of the key players in MS pathogenesis. We present a 21-year-old male patient with a history of EBV-related infectious mononucleosis in puberty and Hodgkin's disease two years previously treated with irradiation and chemotherapy. The patient presented with spastic paraparesis that resolved promptly on corticosteroid treatment. There were no signs of Hodgkin's disease relapse. In the next three years he had three more bouts of the disease and he was diagnosed with relapse-remitting MS. There is evidence of EBV involvement in MS pathogenesis; the association of MS with EBV-related infectious mononucleosis and Hodgkin's disease being just one of them. Although there are many unanswered questions, it is clear that without EBV seropositivity MS in adults is extremely rare.     

Depression correlated with cellular immunity in systemic immunodeficient Epstein-Barr virus syndrome (SIDES)

We conducted studies on the peripheral blood of 12 depressed patients with previous diagnoses of mood and/or personality disorders. These patients, and other depressives we observed informally, were resistant to infectious mononucleosis during an epidemic of that illness. All 12 had serologic evidence of a chronic or recrudescent viremia caused by the Epstein-Barr virus (EBV), the infectious agent in infectious mononucleosis. Additional evidence that EBV viremia may be causally related to depression was provided by a strong correlation between the intensity of depressive symptoms and the cellular immune response to the EBV infection.     

Multiple Sklerose und Epstein-Barr-Virus

Data from studies of twins and migrants with multiple sclerosis (MS) imply environmental factors in the development of MS. In this respect, increasing evidence indicates that Epstein-Barr virus (EBV) plays a unique role as an infectious risk factor for MS. A nearly 100% seroprevalence of antibodies to EBV in patients with MS, elevated EBV antibody titers years before clinical onset of the disease, and an increased risk for MS after symptomatic primary EBV infection (infectious mononucleosis) suggest an association of MS with a previous infection with EBV. However, the precise mechanisms through which EBV may contribute to MS are still unclear. Currently discussed potential mechanisms are outlined. The notion of a persisting (possibly immunological) change caused during the acute phase of primary EBV infection and subsequently leading to permanently elevated MS risk appears compatible with several aspects of the association found between MS and EBV.     

Quantitative PCR for Epstein-Barr virus DNA and RNA in multiple sclerosis

BACKGROUND: Epstein-Barr virus (EBV) is associated with MS, but it is not clear whether EBV plays a role in the pathogenesis of MS. HYPOTHESIS: We hypothesized that the immune control of EBV might be defective in MS, and that reactivation of EBV might drive the immune response in MS. METHODS: We collected blood from controls and patients with MS, and measured the amounts of EBV DNA and RNA using quantitative PCR. RESULTS: We found that EBV DNA and RNA were frequently detectable in peripheral blood leukocytes from both patients with MS and normal controls. There was no significant difference between patients with MS or controls. Paired samples from a small number of subjects suggest that EBV DNA may increase before and during clinical relapse. CONCLUSIONS: We conclude that the immune control of EBV infection is similar in MS and controls, and that reactivation of EBV may correlate with MS disease activity.     

Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein.

The Epstein-Barr virus (EBV) causes infectious mononucleosis and is linked to several disparate malignancies. Prior studies on patients with multiple sclerosis (MS) showed that 100% are EBV-seropositive and that their blood contains higher antibody titers than those of controls to both transformation and lytic cycle antigens. We performed three different assays for antibodies in CSF to three major EBV antigens from patients with MS and controls. Among 93 patients with MS, 79 (85%) had CSF that reacted with a 70 kD protein, shown to be the nuclear antigen, EBNA-1, whereas only 11 (13%) of 81 EBV-seropositive controls reacted, p less than 0.001. The CSF of all 14 MS patients, unreactive on immunoblots, contained oligoclonal bands on agarose electrophoresis. Together, the two techniques exhibit 100% sensitivity in the confirmatory diagnosis of MS. We also performed amino acid searches of the Protein Identification Resource sequence database for protein homologies to EBNA. Two pentapeptide identities were found between EBNA-1 and myelin basic protein: QKRPS and PRHRD. None of more than 32,000 other proteins in the database contained both pentapeptides. In healthy EBV-seropositive persons, the EBV-specific, MHC-restricted T lymphocytes keep the EBV-containing B lymphocytes locked in the transformed state. However, in the host genetically susceptible to MS, the same population of lymphocytes might recognize and interact with either of the two identified pentapeptides, inadvertently damaging MBP.     

Epstein-Barr virus neutralizing antibody levels and risk of multiple sclerosis

Previous infection with Epstein-Barr virus (EBV) and infectious mononucleosis are established multiple sclerosis (MS) risk factors, and elevated serum titers of anti-EBV nuclear antigen (anti-EBNA) antibodies in healthy adults are strongly correlated with future MS risk. In this prospective study, we investigated the association between EBV neutralizing antibodies and MS risk. MS risk tended to be higher in individuals with high titers of neutralizing antibodies compared to those with low titers (relative risk [RR] = 2.2, 95% confidence interval [CI] 0.97-5.1). This association was attenuated after adjustment for anti-EBNA1 IgG Ab titers (RR = 1.4, 95% CI 0.5-3.5). This preliminary finding warrants further study in a larger population.     

Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients

OBJECTIVE: To analyze the possible role of human herpesvirus (HHVs) and human endogenous retroviruses (HERVs) infection in multiple sclerosis (MS) pathogenesis. METHODS: A total of 92 cerebrospinal fluid (CSF) samples were collected: 48 from MS patients at the first clinically evident demyelinating event, 23 from patients with other inflammatory neurological diseases (OINDs) and 21 from patients with other non-inflammatory neurological diseases (ONINDs). Total DNA and RNA were isolated, and the prevalences and viral loads of herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, HERV-H and HERV-W in the CSF of MS patients and controls were evaluated using a quantitative real-time polymerase chain reaction assay. RESULTS: (i) For HSV, 1/48 (2.1%, 86 copies/ml of CSF) MS patients and 1/23 (4.3%, 115.2 copies/ml of CSF) OIND patients (a myelitis case) had HSV sequences in the CSF; (ii) for EBV, only 1/48 (2.1%, 72 copies/ml of CSF) MS patients was positive for EBV; (iii) for HHV-6, only 5/48 (10.4%) MS patients had HHV-6 genomes in their CSF (128.1 copies/ml of CSF); (iv) we did not find any positive cases for VZV, CMV, HERV-H and HERV-W among MS patients or controls; (v) no cases of co-infections were found; (vi) the whole prevalence of HHVs was 7/48 (14.6%) for MS patients and 1/44 (2.3%) for controls (p = 0.038). CONCLUSION: The findings described here show that HHV infection is more frequent in the CSF of MS patients than in patients with other neurological diseases; however, only HHV-6 seems to be involved in the pathogenesis of MS in a subset of patients.     

Identification of human herpesviruses 1 to 8 in Tunisian multiple sclerosis patients and healthy blood donors

Members of the human Herpesviridae family are candidates for representing the macroenvironmental factors associated with multiple sclerosis (MS) pathogenesis. To verify the possible role of human herpesviruses (HHVs) as triggering or aggravating factors in relapsing–remitting multiple sclerosis clinical outcome, we studied the prevalence of all eight human herpesviruses in whole blood samples collected from 51 MS patients and from 51 healthy controls. The presence of DNA of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8) was searched by specific nested polymerase chain reaction. HHVs were significantly more prevalent in the blood of MS patients than in those of the controls (P < 10⁻⁴). HSV-1, HSV-2, HCMV and HHV-8 were negative in both MS patients and controls samples. In MS patients, EBV, HHV-7, HHV-6 and VZV were detected in 31.3%, 33.3%, 5.8% and 7.8% of samples, respectively, compared with 3.9%, 9.8%, 1.96% and 1.96%, respectively, of samples from controls. We found a statistically significant difference only for EBV DNA and for HHV-7 DNA prevalence (P < 0.001 and P = 0.03). Although these results indicate lack of apparent association in terms of gender, type of diagnosis, symptoms, disease score and β interferon treatment between EBV or HHV-7 to MS among Tunisian patients, heterogeneity related to genetic polymorphism as well as geographical distribution of the disease and of pathogens may be of significance.     

Severe post-EBV encephalopathy associated with myelin oligodendrocyte glycoprotein-specific immune response

The mechanisms leading to CNS disorders after EBV infections are unclear. We report the case of a patient who developed a severe, but reversible, encephalopathy following an infectious mononucleosis. We detected no EBV DNA in the blood or in the cerebrospinal fluid (CSF) and no EBV-specific antibodies in the CSF. However, we found a potent MOG-specific cellular and humoral immune response. Interestingly, MOG-specific cellular immune response rapidly decreased, paralleling the improvement of clinical condition. In conclusion, this detailed study shows that acute EBV infection can trigger a potent auto-inflammatory response in the CNS, without evidence of an overt infection.     

A case-control study of multiple sclerosis

We conducted a study of 145 persons with multiple sclerosis who had been identified in a 1970 survey and 145 friend controls, to investigate whether the development of MS was associated with exposure to uncommon viruses or an older age at infection with 1 or more common viruses. The most striking finding was a strong positive association for history of infectious mononucleosis (IM), suggesting older age at exposure to Epstein-Barr virus, the most common etiologic agent of IM. We also found significant positive associations for number of different domiciles before adulthood and for visits outside the United States; both would be compatible with an increased likelihood among cases of exposures to uncommon viruses or to multiple strains of a common agent. Cases were younger at menarche, increasing the probability of viral exposure after puberty.     

Trigger, pathogen, or bystander: the complex nexus linking Epstein- Barr virus and multiple sclerosis

A causal role for virus infection in the pathophysiology of multiple sclerosis (MS) has been suggested and widely debated since the landmark epidemiologic studies of Kurtzke revealed a strong environmental determinant to MS susceptibility. Despite multiple efforts, no virus has been unequivocally associated with lesion formation in the brain either by direct isolation or by indirect methods of detection. In many infectious diseases of the central nervous system, oligoclonal IgG bands are the product of a robust and specific humoral response against the causative agent; yet in MS, immunoreactivity to a primary target has been elusive. In the absence of any infectious agent fulfilling Koch's Postulates, new concepts that could plausibly explain the epidemiology of MS have been postulated. The initiation or activation of a nascent autoimmune response in genetically susceptible individuals following exposure to one or more common infectious agents is now a leading hypothesis to explain MS pathogenesis. Epstein-Barr Virus (EBV), a human herpes virus that infects B cells in ~95% of the human population and persists latently in the memory B cell pool throughout life, has received the most attention as a probable candidate; EBV has been implicated as both an environmental trigger and as a direct causative agent of CNS immunopathology. In this review, we will discuss the most salient features of EBV epidemiology, the immunological response to EBV in MS patients and whether EBV infection of the brain is a necessary prerequisite of MS pathology.     

Primary infection with the Epstein‐Barr virus and risk of multiple sclerosis

To determine whether multiple sclerosis (MS) risk increases following primary infection with the Epstein‐Barr virus (EBV), we conducted a nested case‐control study including 305 individuals who developed MS and 610 matched controls selected among the >8 million active‐duty military personnel whose serum has been stored in the Department of Defense Serum Repository. Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls. Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV‐negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow‐up samples seroconverted (exact p value = 0.0008). We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection. ANN NEUROL 2010;67:824–830     

Mononucleosis-associated subacute sclerosing panencephalitis

Summary A thirteen-year-old girl died of subacute sclerosing panencephalitis (SSPE) which occurred as part of a complex encephalitic illness related to acute infectious mononucleosis. The cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) fluorescent antibody (FA) titer was 1:64. Electron microscopic examination revealed 17 nanometer (nm) diameter paramyxovirus-like nucleocapsids in brain sections and 90nm diameter herpes virus-like enveloped particles in negatively stained brain tissue extracts. Indirect FA staining of cerebral cortex sections demonstrated both measles and EBV antigenic material. EBV antigenic material has not previously been demonstrated in brain tissue. The proportion of B lymphocytes among the patient's peripheral blood lymphocytes was significantly increased as compared to normal controls, while the T lymphocyte percentage was normal. It is suggested that defects in cellular immunity associated with infectious mononucleosis may have been responsible for activation of latent measles-like virus. This is the tenth reported case in which two viruses have been associated with SSPE. This is the third instance in the authors' experience in whichacute EBV infection has occurred coincident with the development of SSPE.and the Eunice ShriverSupported in part by NINDS Special Fellowship NSO 1674 (F.H.H.), NIH grants NSO 9675 (J.R.L.) and HDO 4147 (K.E.A.) and training grant NSO 5393 (E.P.R.).Presented in part at the 50th Annual Meeting of the American Association of Neuropathologists, Boston, Mass., June 1974.     

Molecular evidences for a role of HSV-1 in multiple sclerosis clinical acute attack

To verify the possible role of human herpesviruses as triggering or aggravating factors in relapsing-remitting multiple sclerosis (RRMS) clinical acute attack, we studied the prevalence of some herpesviruses in the peripheral blood mononuclear cells (PBMCs) collected from 22 MS patients during an MS relapse and in a stable phase and from 18 healthy controls (HC). DNA belonging to Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), Human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) and Human Herpes virus 6 (HHV-6) has been searched by specific nested polymerase chain reaction (n-PCR). EBV and HHV6 DNA has been detected with high frequency in acute and stable MS and in healthy controls without significant differences. HCMV DNA was observed both in acute and stable MS but not in HC, and, more interestingly, HSV-1 DNA was only found in 13% of acute MS, while both stable MS and healthy controls were negative. On the basis of these results we focused on HSV-1, and to confirm them and to demonstrate that HSV-1 is actively replicating in MS patients during clinical relapse, we searched both messenger RNA (mRNA) and DNA of HSV-1 in the PBMCs of 15 acute MS patients and 15 healthy controls. We found HSV-1 mRNA and DNA in a significant number of acute MS patients but not in the control group. On the whole these data indicate that HSV-1 reactivate in the peripheral blood of MS patients during clinical acute attack and probably play a role in the triggering of MS relapses.     

Symptomatic Epstein-Barr virus infection and multiple sclerosis.

In a case-control study of 214 patients with multiple sclerosis, recall of infectious mononucleosis in subjects seropositive for Epstein-Barr viral capsid antigen was associated with a relative risk of 2.9 (95% CI 1.1 to 7.2). Those who reported having infectious mononucleosis before the age of 18 years had a relative risk of multiple sclerosis of 7.9 (95% CI 1.7 to 37.9). The pathogenesis of multiple sclerosis may involve an age-dependent host response to Epstein-Barr virus infection.     

Selective association of multiple sclerosis with infectious mononucleosis

Previous studies have suggested an association between multiple sclerosis (MS) and infectious mononucleosis (IM) but data on the exact strength of this association or its selectivity have been conflicting. In this study we have evaluated the association between MS and a variety of common childhood infections and afflictions in a large population-based case-control study involving 2,877 MS cases and 2,673 controls in the Netherlands. We examined the frequency of different common infections and afflictions before the age of 25 and the age at which they occurred, using a self-administered questionnaire.The Odds ratios (ORs) for the occurrence of a variety of clinically manifest common childhood infections including rubella, measles, chicken pox and mumps before the age of 25 for MS cases versus controls ranged between 1.14 and 1.42, values similar to those for irrelevant probe variables used to reveal recall bias. In contrast, the OR for clinically manifest IM in MS cases versus controls, corrected for demographic variables, was 2.22 (95% confidence interval 1.73 - 2.86; P < 0.001). The average age of onset of IM in the population of MS cases (16.5 years) did not differ from controls (16.8 years). Our data confirm previous much smaller studies to show that the risk for MS is significantly enhanced by prior IM, and extend those previous data by showing that this association is far stronger than with other common childhood infections or afflictions.     

The significance of Epstein—Barr virus seropositivity in multiple sclerosis patients?

The objective of this study was to evaluate and investigate the significance of the previously found 100% seropositivity toward Epstein–Barr virus (EBV) found in multiple sclerosis (MS) patients in contrast to healthy controls. Using a commercially available ELISA-test (Biotest), which differentiates infections with EBV into previous infections, primary infections, reactivated infections and no previous infection, we found 137 of 138 MS patients and 124 of 138 healthy controls seropositive. A primary infection in 4 of the 124 EBV seropositive healthy controls in contrast to no primary infections in the MS EBV seropositive group was significant ( P =0.049652, Fishers exact test). This may be suggestive of a lack of primary infections in MS patients, and thus strengthens the idea that MS patients are infected with EBV before development of MS. Further studies are in progress to analyse whether EBV infection is a prerequisite for the development of this disease.     

Association between clinical disease activity and Epstein-Barr virus reactivation in MS

OBJECTIVE: To assess the potential significance of Epstein-Barr virus (EBV) reactivation in disease activity in MS patients. METHODS: The prevalence of antibodies against herpes simplex virus type 1 (HSV-1), HSV-2, EBV, and cytomegalovirus was determined in a group of 108 MS patients and in 163 healthy control subjects. Sera were analyzed using combinations of novel assay systems employing highly purified viral and recombinant antigens. In addition, PCR for the detection of EBV DNA was performed in serial samples. RESULTS: In contrast to the control populations, antibodies against EBV were present in 100% of MS patients. Among the tested human herpesviruses, this high extent of seropositivity was only found for EBV. Primary infection was found exclusively in the control group (3.7%), whereas serologic evidence of EBV reactivation was seen in MS patients (13. 9%) as well as control subjects (17.2%). There was no temporal coincidence between EBV reactivation and disease activity in MS patients. However, in 19 patients followed monthly for 1 year, active viral replication as measured by increased immunoglobulin (Ig) M and IgA responses to EBV early antigens (p54 + p138) and positive serum DNA was seen in 72.7% of patients with exacerbations during the study period and in none of the patients with clinically stable disease. CONCLUSIONS: The results demonstrate an association between EBV reactivation and disease activity in MS patients over time, and suggest that EBV might play an indirect role in MS as an activator of the underlying disease process.     

What advice do patients with infectious mononucleosis report being given by their general practitioner?

OBJECTIVE: The aim of this study was to describe the advice that patients with acute infectious mononucleosis recall having been given by their general practitioner (GP; family or primary care doctor). METHODS: Individuals with a recent diagnosis of infectious mononucleosis were recruited for a randomised controlled trial assessing the effectiveness of a brief educational intervention on recovery. All participants were asked at their initial assessment what advice that they had been given by their GP. They were not given any prompts and were free to give several responses. Responses were grouped into various themes. RESULTS: Seventy-one patients took part. Of these, 11 (15%) recalled being given no specific advice. Of the remaining 60 participants, 70% recalled being given advice to rest, or to "take it easy", usually without any qualification; 10% recalled being given dietary advice, and 17% advice on simple symptom management. CONCLUSION: The majority of individuals with recent onset infectious mononucleosis recall being given advice to rest by their GPs. This finding is discussed in relation to evidence suggesting that rest may be unhelpful.