Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus (EBV) was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with Single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for EBV serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045), and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years vs 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases

Miljöfaktorers betydelse för multipel skleros

Background Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. It usually strikes during young adulthood, and 2.5 million individuals are estimated to have the disease worldwide. The causes of MS are not known, but several factors have been shown to be associated with the risk of the disease, including certain genes, vitamin D, smoking and Epstein- Barr virus infection. Little is known about how/if these factors interact. Methods Study I: The risk of MS by month of birth was investigated using MS cases from the Swedish MS registry and using general population controls. Studies II–V: We identified MS cases who had donated blood prior to disease onset, and MS cases whose mothers had donated blood during pregnancy, by cross-linking a database of MS cases, and a database of mothers of MS cases, to two local biobank cohorts. One of them consisted of blood samples collected during early pregnancy, and one with samples collected during health controls. Levels of 25(OH)D (25-hydroxyvitamin D), RBP (retinol binding protein, a surrogate marker for vitamin A), CRP (C- reactive protein), cotinine (a nicotine metabolite) and anti Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibodies were measured in cases and matched controls. The risk of MS by categories of these exposures was estimated in bi- and multivariable matched logistic regression models. Results Subjects born in spring had a higher risk of MS, but no influence of early gestational levels of the measured risk factors on the risk of MS in the offspring was observed. In prospective samples from MS cases and controls, 25(OH)D levels ≥75 nmol/l, intermediate RBP levels, and elevated CRP levels in young were associated with a decreased risk of MS. Elevated cotinine levels (suggestive of smoking) and high antibody reactivity against EBNA-1 were associated with an increased risk of MS. All factors but RBP were more clearly associated with MS in young subjects. Conclusion All factors analyzed in prospectively collected samples were associated with the risk of MS, and taken together, the data indicate that the key etiopathological events that lead to MS occur before the age of 20–30. Study II provides support for trials exploring the primary preventive potential of oral vitamin D supplementation

Normative video head impulse test data in subjects with and without vascular risk factors

Purpose: There is a paucity of age- and vascular risk factor-stratified video head impulse test (vHIT) vestibulo-ocular reflex (VOR) data in the literature. The aim of this study was to investigate the vHIT VOR properties in healthy subjects of different ages and subjects with vascular risk factors. Methods: This was a prospective observational single-center study at a tertiary referral university hospital in northern Sweden. Healthy participants and subjects with vascular risk factors were investigated with a floor standing external camera vHIT device. Age-stratified mean VOR gain among healthy adults and between group gain and gain asymmetry differences were calculated. Results: We included eighty-eight healthy adults with a mean (range) age of 50 (22-85) years andn = 48 stroke ward patients with vascular risk factors (but without vestibular disease) with a mean (range) age of 74 (42-92) years. The mean VOR gain of horizontal canals decreased at higher ages in healthy subjects (r = - 0.32,p < 0.01,n = 167 canals). The age-stratified mean (SD) VOR gains were < 30 years: 0.98 (0.07), 30-39 years: 0.97 (0.07), 40-49 years: 0.98 (0.06), 50-59 years: 0.99 (0.06), 60-69 years: 0.93 (0.08), >= 70 years: 0.89 (0.15). No consistent differences between healthy subjects and subjects with vascular risk factors were seen except for a trend towards more pronounced gain asymmetries in the latter group. Conclusions: Age, but not vascular risk factors influence VOR gain. Age-adjusted vHIT-measurements may be useful in acute vertigo stroke risk differentiation

Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis

Background: Rituximab is safe and effective for treating relapsing–remitting multiple sclerosis (RRMS) according to phase II and observational studies. There are limited data on disease activity after discontinuation and dose reduction. The objective of this study was to evaluate the effects on inflammatory disease activity after discontinuation or dose reduction of rituximab in patients with RRMS or clinically isolated syndrome (CIS). Methods: In this retrospective observational study, we included all RRMS and CIS patients ever treated with rituximab at the University Hospital of Umeå who had either; (1) discontinued treatment at any time or (2) reduced the dose to a mean of < 1000 mg yearly. The patients served as their own controls by contributing patient years on full dose, reduced dose, and off treatment. Results: A total of 225 patients treated with mean (SD) 6256 (2456) mg rituximab during mean (SD) 6.5 (2.0) years were included. There were no differences regarding the annualized relapse rates during full dose versus reduced dose or off treatment (0.02 versus < 0.01 and 0.02, p = 0.09), neither regarding proportion MRI scans with new or enlarged T2 lesions (0.03 versus 0.01 and 0.03, p = 0.37) or contrast-enhancing lesions (< 0.01 versus 0 and 0.02, p = 0.22). Conclusions: This study indicates that rituximab has long-term effects on inflammatory disease activity and that disease reactivation is rare in MS patients who discontinued treatment for any reason. It also suggests that treatment with low-dose rituximab (< 1000 mg yearly) is sufficient to maintain suppression of inflammatory disease activity in patients with stable disease

Effectiveness of care in acute dizziness presentations

Purpose: This study aims to evaluate whether a management algorithm has improved the effectiveness of care for dizzy patients at Umea University Hospital. Methods: This was an interventional study using medical records to collect data for acute dizziness presentations before (period 1, 2012-2014) and after (period 2, 2016-2017) the implementation of a management algorithm. Outcomes were changes in a set of pre-defined effectiveness markers and health economic effects. Results: Total n = 2126 and n = 1487 acute dizziness presentations were identified in period 1 and 2, respectively. Baseline characteristics were similar. The proportion of patients undergoing Dix-Hallpike testing increased, 20.8% [95% confidence interval (CI) 18.8-23.0%] vs. 37.7% (95% CI 35.2-40.2%), as did BPPV diagnoses, 7.6% (95% CI 6.6-8.8%) vs. 15.3% (95% CI 13.6-17.3%). Hospitalization became less common, 61.5% (95% CI 59.4-63.6%) vs. 47.6% (95% CI 45.1-50.2%). The proportion undergoing any neuroradiological investigation decreased, 44.8% (95% CI 42.7-47.0%) vs. 36.3% (95% CI 33.8-38.7%) with a shift from CT to MRI, with unchanged sensitivity for diagnosing cerebrovascular causes. The average cost for the care of one dizzy patient decreased from $2561 during period 1 to$1808 during period 2. Conclusions: This study shows that the implementation of a management algorithm for dizzy patients was associated with improved effectiveness of care

Comparison Between the Video Head Impulse Test and Caloric Irrigation During Acute Vertigo

Caloric irrigation (CI) is the gold standard to investigate peripheral vestibular dysfunction. The video head impulse test (vHIT) is faster and more accessible and may be useful during acute vertigo stroke risk differentiation. Comparative studies between the two methods are needed. The objective of this study was to compare vestibular function data derived from caloric irrigation with that from vHIT. This study included 80 patients with acute onset vertigo who underwent caloric irrigation and vHIT. CI derived sum of slow phase velocities (SPVs) and unilateral weakness (UW) were compared with vHIT vestibulo-ocular reflex (VOR) gain and gain asymmetry (GA) using correlation analyses. Optimal cut offs for vHIT VOR gain and GA were calculated using Youden indexes. There was a strong positive correlation between the asymmetry measures UW and GA whereas the correlation between the sum of SPVs and VOR gain was weaker. The optimal cut offs to diagnose unilateral vestibular weakness were 0.80 for VOR gain and 28% for GA; with specificities for predicting normal caloric irrigation results of 55% and 93%, respectively. In one third of cases the results from caloric irrigation and vHIT dissociated. The results from vHIT correlated with those from CI, still neither test seem to have the accuracy to replace the other. GA appears as an attractive measure in acute vertigo as the high specificity can be used to identify those with a substantial probability of normal vestibular function in need of more comprehensive work-up for central causes. To diagnose vestibular dysfunction, CI remains gold standard

Characteristics of in-hospital stroke patients in Sweden : a nationwide register-based study

INTRODUCTION: Few studies have reported the characteristics of patients with in-hospital stroke (IHS) including the reason for hospitalization and invasive procedures before the stroke. We aimed to extend current knowledge. PATIENTS AND METHODS: All adult patients with IHS in Sweden during 2010-2019 registered in the Swedish Stroke Register (Riksstroke) were included. The cohort was cross-linked to the National Patient Register and data extracted on background diagnoses, main discharge diagnoses, and procedure codes for the hospitalization when IHS occurred and any hospital-based healthcare contacts within 30 days before IHS. RESULTS: 231,402 stroke cases were identified of which 12,551 (5.4%) were in-hospital and had corresponding entries in the National Patient Register. Of the IHS patients, 11,420 (91.0%) had ischemic stroke and 1131 (9.0%) hemorrhagic stroke; 5860 (46.7%) of the IHS patients had at least one invasive procedure prior to ictus. 1696 (13.5%) had a cardiovascular procedure and 560 (4.5%) a neurosurgical procedure. 1319 (10.5%) patients only had minimally invasive procedures such as blood product transfusion, hemodialysis, or central line insertion. Common discharge diagnosis in patients with no invasive procedures were cardiovascular disorders, injuries, and respiratory disorders. DISCUSSION AND CONCLUSION: One in every 17 strokes in Sweden occur in a hospital. In this unselected large cohort the previously reported major causes for in-hospital stroke, cardiovascular and neurosurgical procedures, preceded IHS in only 18.0% of cases suggesting that other etiologies are more common than previously reported. Future studies should aim at determining absolute risks of stroke after surgical procedures and ways of risk reduction