Shortly after the discovery of human herpesvirus 6 (HHV-6), two distinct variants, HHV-6A and HHV-6B, were identified. In 2012, the International Committee on Taxonomy of Viruses (ICTV) classified HHV-6A and HHV-6B as separate viruses. This review outlines several of the documented epidemiological, biological, and immunological distinctions between HHV-6A and HHV-6B, which support the ICTV classification. The utilization of virus-specific clinical and laboratory assays for distinguishing HHV-6A and HHV-6B is now required for further classification. For clarity in biological and clinical distinctions between HHV-6A and HHV-6B, scientists and physicians are herein urged, where possible, to differentiate carefully between HHV-6A and HHV-6B in all future publications.

The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome.

Objective: To identify differences in the metabolomic profile in the serum of patients with multiple sclerosis (MS) compared to controls and to identify biomarkers of disease severity. Methods: We studied 2 cohorts of patients with MS: a retrospective longitudinal cohort of 238 patients and 74 controls and a prospective cohort of 61 patients and 41 controls with serial serum samples. Patients were stratified into active or stable disease based on 2 years of prospective assessment accounting for presence of clinical relapses or changes in disability measured with the Expanded Disability Status Scale (EDSS). Metabolomic profiling (lipids and amino acids) was performed by ultra-high-performance liquid chromatography coupled to mass spectrometry in serum samples. Data analysis was performed using parametric methods, principal component analysis, and partial least square discriminant analysis for assessing the differences between cases and controls and for subgroups based on disease severity. Results: We identified metabolomics signatures with high accuracy for classifying patients vs controls as well as for classifying patients with medium to high disability (EDSS >3.0). Among them, sphingomyelin and lysophosphatidylethanolamine were the metabolites that showed a more robust pattern in the time series analysis for discriminating between patients and controls. Moreover, levels of hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, 13S-hydroxyoctadecadienoic acid, lysophosphatidylcholines, and lysophosphatidylethanolamines were associated with more severe disease (non-relapse-free or increase in EDSS). Conclusions: We identified metabolomic signatures composed of hormones, lipids, and amino acids associated with MS and with a more severe course.

To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2–138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5–22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85–0.90) was higher than OCB (0.82; 95%CI = 0.79–0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78–0.88) was lower (OCB = 0.92; 95% CI = 0.89–0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

Research from JAMA Neurology — Relapsing-Remitting Multiple Sclerosis and Human Herpesvirus 6 Active Infection

Objective: To evaluate the role of parvovirus B19 (B19), varicella zoster virus (VZV), and human herpes virus 6 (HHV-6) in the aetiopathology of giant cell arteritis (GCA). Methods: Temporal artery biopsy specimens from 57 patients with GCA and 56 controls were investigated. DNA was obtained by biopsy, and quantitative real time polymerase chain reaction assay performed to establish the prevalence and viral load of B19, VZV, and HHV-6. Amplification of the human β-globin gene was used as internal positive control. Results: (a) B19 was detected in 31/57 (54%) patients (median viral load 45.2 (25th–75th centiles 0–180.2) copies/μg DNA) v 21/56 (38%) controls (median viral load 0 (0–66.7) copies/μg of DNA; p = 0.07 for DNA prevalence, p = 0.007 for viral load. Among 31 B19 positive samples, 21 (68%) patients with biopsy proven GCA had >10² B19 copies/μg of DNA v 5/21 (24%) controls; p = 0.001. (b) No significant difference was found for VZV (p = 0.94 for DNA prevalence; p = 0.76 for viral load) and HHV-6 (p = 0.89 for DNA prevalence; p = 0.64 for viral load) in the GCA group compared with controls. Conclusion: B19 may have a role in the aetiopathology of GCA, particularly in those patients with high viral load; no evidence was found for VZV and HHV-6.