Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis.

Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.

We retrospectively analyzed CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA by mNGS and compared 10-week survival rates among those with and without EBV DNA. Positive CSF-EBV DNA is associated with the increased mortality in HIV-negative CM patients.

Epstein-Barr virus-encoded BART9 and BART15 miRNAs are elevated in exosomes of cerebrospinal fluid from relapsing-remitting multiple sclerosis patients.

Epstein-Barr virus (EBV) infection is approved as the main environmental trigger of multiple sclerosis (MS). In this path, we quantified ebv-miR-BART9-3p and ebv-miR-BART15 in exosomes of cerebrospinal fluid (CSF) of untreated relapsing-remitting MS (RRMS) patients in comparison with the control group. Interestingly, patients displayed significant upregulation of ebv-miR-BART9-3p (18.4-fold) and ebv-miR-BART15 (3.1-fold) expression in CSF exosomes. Moreover, the expression levels of hsa-miR-21-5p and hsa-miR-146a-5p were found to be significantly elevated in the CSF samples obtained from the patient group compared to those obtained from the HC group. The levels of Interferon-gamma (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), transforming growth factor beta (TGF-ß), and tumor necrosis factor-alpha (TNF-α) were observed to be significantly elevated in the serum and CSF exosomes of the patients. The highest increase was observed in TGF-ß (8.5-fold), followed by IL-23 (3.9-fold) in CSF exosomes. These findings are in agreement with the association between EBV infection and inflammatory cytokines induction. Furthermore, the ratios of TGF-ß: TNF-α and TGF-ß: IFN-γ attained values of 4 to 16.4 and 1.3 to 3.6, respectively, in the CSF exosomes of the patients, in comparison to those of the control group. These findings show EBV activity in RRMS patients is different from that of healthy ones. Elevation of ebv-miR-BART9-3p, ebv-miR-BART15, and inflammatory cytokines expression in CSF exosomes in RRMS patients provides a substantial link between EBV activity and the onset of the disease, as well as the transition from EBV infection to MS.

[Primary nasopharyngeal carcinoma with Sjögren's syndrome and positive cerebrospinal fluid Epstein-Barr virus: a case report and literature review].

The study presents an analysis of the diagnostic and treatment protocol for a patient with a first episode of nasopharyngeal carcinoma who also has Sjogren's syndrome and Epstein-Barr Virus (EBV) positive cerebrospinal fluid, as detected through metagenomic next-generation sequencing (mNGS). It reviews existing literature to examine the connections between EBV and various conditions including Sjogren's syndrome, encephalitis or meningitis, and nasopharyngeal carcinoma, emphasizing the importance of EBV positive cerebrospinal fluid. The study focuses on a case from the Eighth Medical Center of the General Hospital of the People's Liberation Army, where a patient was admitted with headaches as the primary symptom on March 3, 2021. This patient had a history of Sjogren's syndrome and was later diagnosed with nasopharyngeal carcinoma. The research involved reviewing both domestic and international databases for cases related to cerebrospinal fluid EBV positive encephalitis or meningitis, and nasopharyngeal carcinoma. It aimed to aggregate data on demographics, initial symptoms, treatment methods, and patient outcomes. Findings suggest that positive cerebrospinal fluid EBV is linked to autoimmune diseases, viral encephalitis or meningitis, and nasopharyngeal carcinoma, albeit infrequently in the context of Sjogren's syndrome. Notably, EBV positive cerebrospinal fluid is commonly associated with recurrent nasopharyngeal carcinoma rather than initial episodes. The study concludes that for patients with an immune condition, exhibiting symptoms like headaches or cranial nerve issues, or in cases where nasopharyngeal carcinoma is suspected, early testing through cerebrospinal fluid mNGS or EBV DNA is recommended. This approach facilitates risk assessment, prognosis determination, and the creation of individualized treatment plans.

Clinical significance of Epstein-Barr virus in the cerebrospinal fluid of immunocompetent patients.

INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.

Clinical characteristics of Epstein-Barr virus infection in the pediatric nervous system.

BACKGROUND: To investigate the clinical characteristics of Epstein-Barr virus (EBV) infection in the pediatric nervous system (NS). METHODS: We retrospectively analyzed the clinical data and follow-up results of 89 children with neurological damage caused by EBV who were hospitalized in the children's hospital of Chongqing Medical University from January 2008 to April 2019. RESULTS: EBV infection of the NS can occur at any time of the year. The highest incidence was seen in the age group of 0-4 years. Fever is the main clinical feature (74/89, 83.1%). The main clinical types were encephalitis/meningoencephalitis (64/89, 71.9%), acute myelitis (2/89, 2.2%), acute disseminated encephalomyelitis (ADEM) (3/89, 3.4%), Guillain-Barré Syndrome (GBS) (15/89, 16.9%), neurological damage caused by EBV-hemophagocytic lymphohistiocytosis (EBV-HLH) (4/89, 4.5%), and NS-post-transplant lymphoproliferative disorder (NS-PTLD) (1/89, 1.1%). Anti-N-methyl-D-aspartate receptor encephalitis was found during the convalescence of EBV encephalitis. EBV encephalitis/meningitis showed no symptoms of tonsillitis, lymph node enlargement, skin rash, hepatosplenomegaly. Acute motor axonal neuropathy is the chief complication in GBS caused by EBV. CONCLUSION: There were significant differences in neurological complications caused by EBV. The prognosis of EBV infection in the NS is generally good. These illnesses are often self-limiting. A few cases may show residual sequelae.

Epstein-Barr virus-related encephalitis in a young woman: A case report.

Although infectious mononucleosis due to Epstein-Barr virus (EBV) is a common disease among young individuals, central nervous system (CNS) complications are rare. In this report, we describe a case of CNS complications caused by EBV in a previously healthy young woman. She presented to our hospital with a 9-day history of headache and sore throat, followed by the development of fever and facial edema 6 days prior to admission. On Day 2 of admission, she was confused (Glasgow Coma Scale score: 10 points) and had fever, muscle weakness in her right arm and leg, stiff neck, and roving eye movement. We detected EBV in a cerebrospinal fluid (CSF) sample using a polymerase chain reaction (PCR) test. The magnetic resonance imaging of her brain revealed dural enhancement and right parietal and temporal lobe lesions. She was treated with acyclovir and high-dose steroid therapy. She responded well to treatment, recovered without neurologic sequelae, and was discharged home on Day 12. Our experience suggests that PCR detection of EBV DNA in CSF may be useful in diagnosing EBV encephalitis and that prognosis may be associated with an area of the brain that is affected and the time from symptom onset to starting treatment.

Multiple Sclerosis Risk Factors and Pathogenesis.

PURPOSE OF REVIEW: This article summarizes recent advances in the identification of genetic and environmental factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes involved in acute relapses and relapse-independent disability progression. RECENT FINDINGS: The number of single-nucleotide polymorphisms associated with increased risk of MS has increased to more than 200 variants. The evidence for the association of Epstein-Barr virus infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal association has strengthened. Interactions between genetic and environmental factors have been studied more extensively. Dietary factors and changes in the gut microbiota are emerging as possible modulators of the disease risk. Several processes important to MS pathogenesis have been newly investigated or investigated more comprehensively, including the role of B cells, innate immune cells, meningeal inflammation, cortical and gray matter demyelination, and early axonal and neuronal loss. SUMMARY: MS is a complex disease in which the interaction between genetic and environmental factors causes a cascade of events, including activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events manifest as potentially reversible focal neurologic symptoms or progressive nonremitting physical and cognitive disability, or both. Advances in the understanding of the risk factors and pathogenic mechanisms of MS have resulted in improved therapeutic strategies. The results of ongoing or future studies are needed to successfully and fully translate these advances into clinical practice.

Anti-N-methyl-D-aspartate receptor encephalitis associated with reactivated Epstein-Barr virus infection in pediatric patients: Three case reports.

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in children, and its presentation is various. The disease can be triggered by various infections. PATIENT CONCERNS: Case 1 was a 7-year-old female with the presentation of seizure, repeated fever, language disorder, and decreased muscle strength of the right limbs; Case 2 was a 7-year-old male with the manifestation of repeated emesis, headache, involuntary movement, altered personality, seizures, and cognitive impairment; Case 3 was a 2-year-old female with repeated fever, emesis, seizures, coma, and decreased muscle strength of limbs. Anti-NMDAR antibody was identified in cerebrospinal fluid (CSF) in the 3 cases, confirming the diagnosis of anti-NMDAR encephalitis. Pathogenic examinations revealed positive serum Epstein-Barr virus (EBV)-nuclear antigen and EBV-capsid antigen (CA)-IgG antibodies in the 3 cases, as well as positive EBV-early antigen (EA)-IgG antibody in CSF. Case 1 also had positive EBV-CA-IgA antibody; Case 3 also had positive EBV-CA-IgA and EBV-CA-IgG antibodies. DIAGNOSES: Anti-NMDAR antibody and EBV-EA-IgG antibody in CSF were tested positive in the 3 cases. Thus, they were diagnosed as anti-NMDAR encephalitis associated with reactivated EBV infection. INTERVENTIONS: All of the 3 cases received immunoglobulin, corticosteroid, and ganciclovir treatment. Cases 2 and 3 also received antiepileptic drugs due to repeated seizures. In addition, Case 3 also received assistant respiration, plasma exchange, and rituximab. OUTCOMES: The 3 cases were substantially recovered after treatment. Repeat CSF analysis showed decreased titer of the anti-NMDAR antibody. LESSONS: Reactivated EBV infection may trigger anti-NMDAR encephalitis in children, which has not been reported previously. Related possible virology tests should be completed while diagnosing the disease.

[Cerebrospinal fluid findings in chronic active Epstein-Barr virus infection with central nervous system involvement].

As chronic active Epstein-Barr virus (EBV) infection (CAEBV) progresses, EBV-infected tumor cells invade the central nervous system (CNS). To establish a diagnostic procedure for CNS invasion, we retrospectively analyzed cerebrospinal fluid (CSF) obtained from eight patients. Two patients presented with consciousness disturbance and were diagnosed with CNS invasion based on scan and autopsy results, respectively. The remaining six patients were diagnosed without CNS invasion by clinical findings and scans. In the two patients with CNS invasion, the number of mononuclear cells and the protein concentration were increased, whereas the CSF to serum glucose ratio and the adenosine deaminase concentration were raised. In one of the two patients, however, bacterial meningitis could not be excluded. Cytological examination of CSF demonstrated class 1-3. Notably, the CSF EBV-DNA load was positive in all patients, independent of CNS invasion diagnosis, and the CSF load correlated with that of the peripheral blood. Taken together, this indicates that CSF may lack the specific markers of CNS invasion in CAEBV patients. The CSF EBV-DNA load and the cytological analysis did not reflect CNS invasion; therefore, new biomarkers need to be established.

Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia.

The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.

Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome.

Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3 years.

EBNA1 antigen-specific CD8+ T cells in cerebrospinal fluid of patients with multiple sclerosis.

Epidemiological data suggests that Epstein-Barr virus may be involved in the pathogenesis of Multiple Sclerosis (MS). We aimed to determine the frequency of CD8+ T cells specific for one EBNA1-derived epitope (HPVGEADYFEY) in cerebrospinal fluid (CSF) and blood of patients with MS and other inflammatory neurological diseases (OIND). The frequency of specific CD8+ T cells was assessed by HLA-class-I-binding pentamers restricted to HLA-B35. The frequency of HPVGEADYFEY-specific CD8+ T cells did neither differ significantly in blood nor CSF in MS compared to OIND, but was consistently higher in CSF compared to blood regardless of diagnosis.

A study on viral CNS inflammation beyond herpes encephalitis.

The early diagnosis of herpes simplex virus encephalitis (HSVE) enables induction of antiviral therapy in this potentially life-threatening disease. The study aimed to determine clinical findings including cerebrospinal fluid (CSF) data and MRI imaging in HSVE patients and to identify features distinguishing HSVE from encephalitis of other viral etiologies. We retrospectively reviewed consecutive patients who were diagnosed with viral encephalitis between 2000 and 2014 at the University Hospital Halle. Forty-nine patients with viral encephalitis were identified. A viral etiology could be confirmed by PCR or antibody testing in 22/49 (44.9 %) of patients (15 (30.6 %) HSV, 5 (10.2 %) VZV, 2 (4.1 %) EBV). In HSVE, typical findings were focal slowing in electroencephalophy (EEG) (80 %, p = 0.021) and presence of cortical (86.7 %, p = 0.030) lesions in MRI. Restricted diffusion was particularly helpful in detection of early signal abnormalities in HSVE (p = 0.014). In 27/49 (55.1 %) of patients, no causative agent could be elucidated. In these patients, 15/27 (55.6 %) experienced a rather "benign" disease course with no MRI pathology despite initially HSVE mimicking clinical picture. However, CSF was significantly different showing a higher amount of granulocytes and activated lymphocytes. The remaining 12/27 (44.4 %) patients developed MRI changes consistent with encephalitis, in 4 of these patients, disease course was fatal. Beside PCR-based serology as standard procedure, MRI including diffusion-weighted images and EEG represent additional tools in early HSVE diagnosis. CSF cytology might be particularly supportive in differentiating likely benign forms of encephalitis.

Virological testing of cerebrospinal fluid in children aged less than 14 years with a suspected central nervous system infection: A retrospective study on 304 consecutive children from January 2012 to May 2015.

OBJECTIVE: The study aimed to describe the prevalence of HSV DNA, VZV DNA, Enterovirus RNA, Parechovirus RNA, CMV DNA, EBV DNA, adenovirus DNA, HHV-6 DNA, HHV-7 DNA, HHV-8 DNA and Parvovirus B19DNA in children aged less 14 years with a suspected viral infection of the central nervous system in a clinical practice setting. METHODS: Between January 2012 and May 2015, cerebrospinal fluids from 304 children were tested with an in-house real-time PCR method. RESULTS: A positive PCR was detected in 64 subjects (21%): the mean number of tests performed in patients who showed a viral infection was 7.5, significantly higher (p = 0.001) with respect to that reported in negative samples (6.4). Enterovirus is the leading virus detected: 12 out of the 37 positive children reported were newborns (85.7% of all the newborns with a positive result). The second most frequently identified virus was HHV-7 (5 positive PCR out of 105 samples tested, 4.8%, if we excluded a child with a concomitant S. pneumoniae isolated), a prevalence significantly higher with respect to VZV (p = 0.02) and to CMV (p = 0.04). HHV-6 was the third most commonly identified aetiology (4.2%). All children were immunocompetent. SIGNIFICANCE: Only a minority of children had a specific viral aetiology identified: the rate of HHV-7 positivity suggests a routine testing of these viruses within the diagnostic algorithm in immunocompetent paediatric patients. This approach could help to define the clinical role of this herpesvirus.

A case of Epstein-Barr encephalitis with some curiosities.

We present the magnetic resonance imaging findings of an eight-year-old boy with Epstein-Barr virus (EBV) encephalitis, with special attention to lesion neuroanatomic distribution, diffusion-weighted images, and proton magnetic resonance spectroscopy (MRS). T2 and FLAIR-weighted images showed bilateral and symmetric basal nuclei lesions, with diffusion facilitation. MRS of the lesions demonstrated elevated lactate/lipid and excitatory neurotransmitters. The purpose of this report is to alert to this imagiologic pattern of EBV infection, and in particular to the fact that facilitated diffusion does occur on EBV encephalitis.

Proven Epstein-Barr encephalitis with negative EBV-DNA load in cerebrospinal fluid after allogeneic hematopoietic stem cell transplantation in a child with acute lymphoblastic leukemia.

We report a case of EBV encephalitis in a seven-yr-old child with Ph+ ALL. Two months after an allogeneic HSCT from his HLA mismatched mother, the patient showed an altered sensorium, generalized seizures, and a left hemiparesis. Brain MRI demonstrated multiple lesions highly suggestive for viral encephalitis. Blood and CSF PCR analyses were negative for the most common viruses involved in immunocompromised patients including EBV. A cerebral biopsy was performed, which showed intense gliosis and perivascular lymphocytic cuffing. PCR analysis performed on brain tissue was positive only for the EBV genome, while extensive investigations for other viral infections were negative. The patient's neurological symptoms rapidly worsened and he died two months later. This case report suggests that in patients presenting neurological and radiological signs of encephalitis after an HSCT, an EBV involvement should be considered, even in the absence of CSF and blood PCR virus detection.

Utility of quantitative EBV DNA measurements in cerebrospinal fluid for diagnosis and monitoring of treatment of central nervous system EBV-associated post-transplant lymphoproliferative disorder after allogenic hematopoietic stem cell transplantation.

BACKGROUND: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) after hematopoietic stem cell transplantation (HSCT) is a rare but life- threatening condition. Despite routine EBV DNA-emia monitoring in blood, central nervous system involvement of the disease is still associated with diagnostic difficulties and poor outcome. CASE REPORT: We describe a 17-year-old female patient with severe aplastic anemia who developed central nervous system EBV-associated PTLD after matched unrelated allo-HSCT. EBV DNA concentration in cerebrospinal fluid was initially tested due to central nervous system-related symptoms. The sample was found to be highly EBV DNA-positive. Using quantitative real-time polymerase chain reaction (PCR) measurements, therapy efficiency was monitored until complete remission of the EBV-associated PTLD. CONCLUSIONS: The case report illustrates the high utility of quantitative real-time PCR EBV measurements in cerebrospinal fluid for rapid diagnosis and therapy monitoring of central nervous system EBV-associated PTLDs after allo-HSCT.

Quantitative detection of epstein-barr virus DNA in cerebrospinal fluid and blood samples of patients with relapsing-remitting multiple sclerosis.

The presence of Epstein-Barr Virus (EBV) DNA in cerebrospinal fluid (CSF) and peripheral blood (PB) samples collected from 55 patients with clinical and radiologically-active relapsing-remitting MS (RRMS) and 51 subjects with other neurological diseases was determined using standardized commercially available kits for viral nucleic acid extraction and quantitative EBV DNA detection. Both cell-free and cell-associated CSF and PB fractions were analyzed, to distinguish latent from lytic EBV infection. EBV DNA was detected in 5.5% and 18.2% of cell-free and cell-associated CSF fractions of patients with RRMS as compared to 7.8% and 7.8% of controls; plasma and peripheral blood mononuclear cells (PBMC) positivity rates were 7.3% and 47.3% versus 5.8% and 31.4%, respectively. No significant difference in median EBV viral loads of positive samples was found between RRMS and control patients in all tested samples. Absence of statistically significant differences in EBV positivity rates between RRMS and control patients, despite the use of highly sensitive standardized methods, points to the lack of association between EBV and MS disease activity.

Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings.

BACKGROUND: Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS. METHODS: The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated. RESULTS: Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs). CONCLUSION: The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS.