Peter Sundström

An altered immune response to Epstein-Barr virus in multiple sclerosis: A prospective study

Objective: To investigate the association between human herpesviruses and multiple sclerosis (MS), as well as between measles virus and MS. Methods: The authors identified prospectively collected serum samples from 73 MS cases and retrospective sera from 161 MS cases in two population-based serum bank registers. Analyses of IgG antibody responses in cases and matched referents were performed for Epstein-Barr virus (EBV [EBNA-1 and VCA]), human herpesvirus 6 (HHV-6), herpes simplex virus (HSV), varicella zoster virus (VZV), and measles. Results: All cases showed signs of past EBV infection. High activity to EBNA-1 and HHV-6 significantly (borderline significance for HHV-6) increased the risk for MS in prospective sera. A discrepancy between activities to EBNA-1 and VCA was striking in MS samples collected less than 5 years before relapsing-remitting MS onset, where high activity to EBNA-1 significantly increased, and high VCA activity significantly decreased the risk for MS. There was no support for major causal roles for HSV, VZV, or measles. Conclusion: Individuals who will develop MS exhibit an altered immune response against the EBV virus characterized by a high IgG activity to EBNA-1 in the absence of high activity to VCA, this being most pronounced in the 5-year period preceding MS onset.

Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab

The impact of present disease‐modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain‐specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study.

The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing‐remitting multiple sclerosis cases and 20 healthy controls with phase‐contrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrast‐enhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis. ANN NEUROL 2010;68:255–259

Neurofilament and glial fibrillary acidic protein in multiple sclerosis

Objective: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease. Methods: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of “ongoing relapse” or “clinically stable disease,” and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course. Results: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001). Conclusions: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

Vitamin D as a protective factor in multiple sclerosis

ABSTRACT Objective: To examine the association between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation. Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression. Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were associated with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16–0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95% CI 0.53–5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976–2005 (p trend = 0.005). Conclusion: This study supports the presence of an association between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no association between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH)D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiologic studies.

Neurofilament light as a prognostic marker in multiple sclerosis

Relapsing-remitting multiple sclerosis has a variable prognosis and lacks a reliable laboratory prognostic marker. Our aim in this study was to investigate the association between neurofilament light levels in cerebrospinal fluid in early multiple sclerosis and disease severity at long-term follow-up. Neurofilament light levels in cerebrospinal fluid collected at diagnostic lumbar puncture were measured in 99 multiple sclerosis cases. Clinical data were obtained from 95 out of those at follow-up visits made 14 years (range 8—20 years) after disease onset. Significant correlations between neurofilament light levels and the multiple sclerosis severity score were found for all cases (r = 0.30, p = 0.005), for relapsing-remitting multiple sclerosis cases (r = 0.47, p < 0.001) and for cases with a recent relapse (r = 0.60, p < 0.001). In the multivariate logistic regression analysis, neurofilament light levels >386 ng/L (median value of cases with detectable levels) increased the risk for severe multiple sclerosis fivefold (odds ratio 5.2, 95% confidence interval 1.8—15). Kaplan—Meier analysis showed that conversion to secondary-progressive multiple sclerosis was more likely in cases with neurofilament light levels >386 ng/L than in those with neurofilament light levels <60 ng/L (p = 0.01) or 60—386 ng/L (p = 0.03). We conclude that elevated levels of neurofilament light in cerebrospinal fluid collected at diagnostic lumbar puncture were associated with unfavourable prognosis. These data suggest that the neurofilament light level could be used as a prognostic marker in early relapsing-remitting multiple sclerosis.

Epstein-Barr virus and multiple sclerosis: interaction with HLA.

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45–2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38–2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385–420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75–4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45–0.76 95%CI) and AP 0.39 (0.18–0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.

Incidence (1988–97) and prevalence (1997) of multiple sclerosis in Västerbotten County in northern Sweden

Objective: To investigate the incidence and prevalence of multiple sclerosis in Västerbotten County in northern Sweden. Methods: Multiple sources were used in the case identification process. Follow up interviews with clinical examinations were undertaken and, when indicated, additional paraclinical investigations were done. In this way case ascertainment was assured and supplemental clinical data were collected. The incidence rate was based on symptom onset. Onset adjusted prevalence was applied. Results: The crude incidence rate of multiple sclerosis in 1988–97 in Västerbotten County was 5.2/105 (95% confidence interval, 4.4 to 6.2): 6.7/105 (6.0 to 8.3) in women and 3.7/105 (2.7 to 4.9) in men. The onset adjusted prevalence for 31 December 1997 was 154/105 (139 to 170): 202/105 (179 to 228) in women and 105/105 (89 to 125) in men. When compared with a previous estimate of prevalence, a yearly 2.6% increase in prevalence between 1990 and 1997 was found, mainly attributable to a higher incidence than mortality. Conclusions: The present incidence rate and prevalence confirms earlier findings that Västerbotten is a high risk area for multiple sclerosis. The adjusted incidence was twice as high as the incidence from 1974–88 in the only previous Swedish population based study from Göteborg, but comparable with other recent Fennoscandian multiple sclerosis incidence rates.

Season of birth and multiple sclerosis in Sweden

Objective – To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. Materials and Methods – Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900– 2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. Results – More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February–July as compared with August– January. Conclusions – This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research. J. Salzer, A. Svenningsson, P. SundstrçmOBJECTIVE To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. MATERIALS AND METHODS Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. RESULTS More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. CONCLUSIONS This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Smoking worsens the prognosis in multiple sclerosis

Objective To estimate the effect of smoking on the risk for progression in multiple sclerosis (MS). Methods Self-reported data were used on smoking habits in 122 incident cases with disability assessments made after a median of 6 years disease duration. Results Ever smokers were more likely to have progressive disease compared with never smokers (P < 0.01). This was most pronounced in ever smokers with early smoking debut (≤15 years of age) for whom progressive disease was significantly more likely and occurred at an earlier age, compared with those with later smoking debut (P < 0.01 for both) or never smokers (P < 0.01 for both). Earlysmoking start also predisposed to a progressive disease from onset when compared with never smokers (P = 0.012). A multivariate Cox regression analysis of sex, age at disease onset (above vs. under median) and smoking (ever vs. never) status showed that cases with late disease onset had three times higher risk and ever smokers had twice as high a risk for progression. Conclusion Past smoking is associated with a worsened prognosis in MS. The negative effect from smoking is most obvious in ever smokers with early smoking debut, which also affects MS phenotype significantly.