Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

[Multiple sclerosis: interventions to halt disease : Which patients can be considered for autologous stem cell transplantation]. / Multiple Sklerose: Stillstand durch Interventionen : Welche Patienten für eine autologe Stammzelltransplantation infrage kommen.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) for treatment of multiple sclerosis (MS) is gaining increasing prominence in the therapeutic landscape. This review article focuses on describing the evidence and European guidelines for aHSCT so that neurologists in Germany can consider this treatment option for appropriate MS patients. In this context, it must be taken into consideration that in every case a cost transfer must be individually applied for. AIM: To provide information for neurologists considering aHSCT for patients with MS. MATERIAL AND METHODS: In this narrative review articles from PubMed were pooled and analyzed. RESULTS AND DISCUSSION: High quality data from randomized, controlled clinical trials are required to compare the efficacy of aHSCT to the currently available highly effective disease-modifying therapies (DMT) so that reliable conclusions can be drawn regarding the relationship between the risks and benefits of aHSCT in MS; however, the studies discussed in this review provide important points of reference for patient selection and the transplantation protocol. Further advice is available from the European Society for Blood and Marrow Transplantation (EBMT) for experienced centers considering aHSCT. The available data and the European guidelines suggest that patients aged less than 45 years, an expanded disability status scale (EDSS) ≤ 5.5, highly active MS, a disease duration of less than 10 years, an ineffective course of DMT or rapidly progressive MS may be eligible for aHSCT and should be referred to an experienced center for further assessment.

Experiences in treatment of multiple sclerosis with natalizumab from a real-life cohort over 15 years.

Natalizumab (NTZ) has been used for treatment of highly active relapsing-remitting multiple sclerosis (MS). When stopping NTZ the risk of severe rebound phenomenon has to be considered. We aimed to investigate the use of NTZ in clinical routine and focused on identification of potential risk factors for disease reactivation after treatment discontinuation. At the Medical University of Innsbruck, Austria, we identified all MS patients who were treated with NTZ and performed a retrospective analysis on therapeutic decision making, disease course before, during and after treatment with NTZ and on risk factors for disease reactivation after NTZ discontinuation. 235 NTZ treated MS patients were included, of whom 105 had discontinued treatment. At NTZ start disease duration was 5.09 (IQR 2.09-10.57) years, average number of total relapses was 4 (IQR 3-6) and median EDSS 2.0 (range 0-6.5), whereby these values significantly decreased over time. Reduction of annualized relapse rate (ARR) on treatment was 93% and EDSS remained stable in 64%. In multivariate regression models only conversion to secondary progressive MS (SPMS) on treatment was significantly associated with lower risk of disease reactivation after NTZ, while ARR before treatment was associated with earlier disease reactivation. We could confirm the high therapeutic efficacy of NTZ which trends to be used earlier in the disease course nowadays. Discontinuation of NTZ seems safe only in patients who convert to SPMS during treatment, while higher ARR before NTZ increases the risk of disease reactivation after treatment discontinuation.

Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis.

OBJECTIVE: It has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS. METHODS: We used two Swedish population-based case-control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale. RESULTS: All environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype. INTERPRETATION: Our finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.

Entropy of human leukocyte antigen and killer-cell immunoglobulin-like receptor systems in immune-mediated disorders: A pilot study on multiple sclerosis.

BACKGROUND: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems. METHODS: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS). RESULTS: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS. CONCLUSIONS: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.

Cord-Age-Gender Connections Shape the Pathophysiology of Multiple Sclerosis Progressive Forms.

There is increasing evidence that sex hormones, aging, and the occurrence of spinal cord (SC) tissue alterations exert combined effects on the development and outcome of multiple sclerosis (MS) progressive forms [...].

Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. METHODS: We measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. FINDINGS: B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. INTERPRETATION: We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.

Infectious agents and different course of multiple sclerosis: a systematic review.

Multiple sclerosis (MS) causes demyelination of white matter of central nervous system and neuro-degeneration due to inflammation. Different types of MS, as well as disease progression, come with different pathology and pathophysiology. The objective of this study was to evaluate the possible association between different micro-organisms and the relapse or progression of MS. Studies indexed in Medline/PMC, Scopus and Web of Science published without time and language limitation until March 2017 were identified through the search terms "infection" or "infectious" and "multiple sclerosis". A total of 20878 abstracts were identified through the initial search terms. Selection of articles and assessment of their quality was done based on Cochrane library guidelines. Full texts were reviewed for 33 articles out of which 14 articles met the criteria for inclusion. Different micro-organisms are known to play roles in the pathogenesis of MS and its relapse; including Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7), Epstein-Barr virus (EBV), Chlamydia pneumoniae and Torque teno virus (TTV). But in this review only HHV-6, C. pneumoniae and TTV have been considered to play a role in disease progression in some studies and not all of them. This review concluded that some micro-organisms such as HHV-6, C. pneumoniae and TTV have been considered as cofactors to make MS a progressive type. It should be considered that these findings do not necessarily rule out the role of other pathogens in MS progression but may represent population differences or different sensitivity of the technique used.

[Multiple sclerosis in childhood and adolescence : Complex, chronic and differentiated]. / Multiple Sklerose im Kindes- und Jugendalter : Komplex, chronisch, differenziert.

Pediatric multiple sclerosis (MS) is one of the most important acquired neurological disorders in childhood and adolescence. A timely recognition, diagnosis and treatment are of utmost importance. This article highlights the current state of knowledge on the etiology, pathogenesis, diagnosis, clinical presentation and treatment in childhood. Although the rate of progression of disability in the early years is slower in younger patients compared to adults, a disease-modifying therapy should be started once MS is diagnosed.

Immune responses against Helicobacter pylori-specific antigens differentiate relapsing remitting from secondary progressive multiple sclerosis.

To assess whether Helicobacter pylori (Hp) antibody (ab) reactivity against individual Hp antigens is pathogenetically relevant to multiple sclerosis (MS), we systematically investigated prevalence and clinical significance of abs against 14 immunodominant and subdominant Hp antigens by ELISA and immunoblotting in 139 consecutive MS patients with relapsing-remitting (RRMS, n = 102) or secondary progressive (SPMS, n = 37). Sera from 39 patients with Parkinson's disease (PD), 21 with Alzheimer's disease (ALZ) and 68 healthy controls (HCs), were also tested. Anti-flagellin (18.3%) and anti-p41 (25.0%) abs in MS were less frequent than in HCs (39.4%, 48.5%, respectively). Abs against 5 of the 14 antigens were less frequent in RRMS than HCs, including p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA. Anti-VacA abs were more frequent in SPMS than in HCs (42.1 vs 12.1%, p = 0.019). Anti-p54, anti-p29-UreA and anti-p26 correlated with extended disability status scale (EDSS) (p = 0.017, p = 0.005, p = 0.002, respectively). Anti-p26 and anti-p17 correlated with the number of relapses (p = 0.037 and p = 0.047, respectively). This is the first comprehensive analysis of ab reactivities against most Hp antigens in MS patients. Ab responses differ between MS and HCs and between RRMS and SPMS, being more prevalent in SPMS than RRMS, thus suggesting an association between anti-Hp and the former type of MS.

Pathological mechanism of secondary-progressive multiples sclerosis and its animal model.

Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2, which we have previously reported to be upregulated in peripheral blood T cells from patients of multiple sclerosis (MS). EAE induced in mice lacking NR4A2 in T cells showed a great reduction in Th17-mediated acute symptoms, whereas a late-onset disease independent of NR4A2 was still inducible. We identified cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes) as a pathogenic component for the development of the late-onset disease. Furthermore, T cell-specific deletion of the Eomes gene or Eomes-specific RNA interference in vivo remarkably ameliorated the late-onset EAE. Intriguingly, similar Eomes-expressing CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid only from patients with secondary-progressive MS accompanied by neurodegenerative symptoms, but not in relapsing-remitting MS. Mechanistic analysis revealed that granzyme B was secreted by Eomes-expressing CD4+ T cells and the activation of protease-activated receptor-1 by granzyme B is involved in the neuroinflammation observed in the late-onset EAE.

Beginning of the end of two-stage theory purporting that inflammation then degeneration explains pathogenesis of progressive multiple sclerosis.

PURPOSE OF REVIEW: The review discusses future directions in research on multiple sclerosis and neuromyelitis optica, as long-held beliefs about these diseases are undermined with data from recent clinical trials. RECENT FINDINGS: Results of clinical trials for registration (phase 3) were reported in the last year. Anti-inflammatory approaches, such as daclizumab high-yield process targeting IL-2 receptor, and ocrelizumab targeting CD20 B cells, confirmed a beneficial role of immune suppression in relapsing-remitting disease. And now for the first time achieving the primary end point in primary progressive multiple sclerosis was attained with ocrelizumab. SUMMARY: The results in the past year challenge the long-held belief that relapsing-remitting disease is inflammatory, whereas progressive forms of the disease are 'less inflammatory' and more 'degenerative.'

Progressive multiple sclerosis: pathology and pathogenesis.

Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing-remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.

Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis.

BACKGROUND: Early life events have been suggested to influence multiple sclerosis (MS) susceptibility, and to potentially modulate its clinical course. We assessed vitamin D-related exposures from childhood to disease onset and their associations with MS progression. METHODS: Among veterans in the Multiple Sclerosis Surveillance Registry, 219 reported having the progressive form and met the inclusion criteria. Participants reported their past sun exposure, vitamin D-related intake and age at disability milestones using the Patient-Determined Disease Steps (PDDS). The Cox proportional hazards model was used to examine the association between vitamin D-related exposures and time (years) to disability. RESULTS: Low average sun exposure in the fall/winter before disease onset was associated with an increased risk of progressing to a PDDS score of 8 (hazard ratio, HR: 2.13, 95% confidence interval, CI: 1.20-3.78), whereas use of cod liver oil during childhood and adolescence was associated with a reduced risk (HR: 0.44, 95% CI: 0.20-0.96). CONCLUSIONS: These results suggest that exposure to vitamin D before MS onset might slow disease-related neurodegeneration and thus delay progression to disability among patients with the progressive subtype.

Progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) had been suggested to play a major pathogenetic role in multiple sclerosis (MS), but recent data on early stages of MS have not confirmed this theory. Nonetheless, CCSVI could represent a late phenomenon of MS or be associated with progression of disability. Thus, we studied CCSVI prevalence in primary progressive (PP) and secondary progressive (SP) MS, to clarify whether CCSVI characterizes the progressive forms of this disease. METHODS: A total of 35 patients with SPMS, 25 patients with PPMS, and 60 age- and gender-matched normal controls (NC) were enrolled into a cross-sectional study. Extracranial and transcranial high-resolution venous echo color Doppler sonography (ECDS-TCDS) was performed in all patients and NC. Those patients having any abnormal ultrasound finding were asked to undergo selective venography (VGF). RESULTS: Patients with PPMS (11 women, 14 men; mean age 47 ± 11 years) had a disease duration of 11 ± 7 years and Expanded Disability Status Scale (EDSS) score of 6.0 ± 0.5. Patients with SPMS (22 women, 13 men; mean age 45 ± 14.5 years) had a disease duration of 18 ± 14 years and EDSS score of 6.0 ± 0.8. TCDS was normal in all patients. ECDS showed one or more abnormal findings in 9/60 (15.0%) patients (7/35 [20.0%] SPMS, 2/25 [8.0%] PPMS) and in 14/60 (23.3%) NC (p not significant for all comparisons). CCSVI criteria were fulfilled in 0 NC and 4 (6.7%) patients with MS: 3 SPMS and 1 PPMS. VGF, performed in 6/9 patients, was abnormal only in one case who had bilateral internal jugular vein stenosis. CONCLUSION: Our findings indicate that CCSVI is not a late secondary phenomenon of MS and is not associated with disability.

Varicella zoster virus in progressive forms of multiple sclerosis.

OBJECTIVE: The apparent association between varicella zoster virus (VZV) and multiple sclerosis (MS) has been described. In patients with relapse/remission (R/R) MS we have found high loads of VZV DNA in lymphocytes and in cerebrospinal fluid (CSF), as well as abundant viral particles in CSF visualized by electron microscopy at the time of relapse. Both, the molecular and the ultrastructural evidence of VZV became negative in the same patients at the time of remission. METHODS: In the present study we analyzed the presence of VZV in patients with progressive forms of MS; DNA from VZV was searched by real-time PCR in blood lymphocytes and in CSF of 20 patients with progressive MS. Ultrastructural study searching for viral particles in CSF was made with transmission electron microscopy. RESULTS: VZV DNA was found in the CSF from 65% of cases with progressive MS- and VZV-like viral particles were found in 30% of these patients. Nonetheless, the amount of DNA and the number of viral particles were lower than those that have been found in MS patients with R/R at the time of relapse, but higher than those found during remission. CONCLUSION: Similar to findings in patients with R/R MS, VZV might be associated to progressive MS, but in minor quantity. In these cases, the virus may produce a chronic, relentless infection or trigger a process of immune-mediated demyelination.

Latitudinal variation in incidence and type of first central nervous system demyelinating events.

Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55% (95% confidence interval (CI) 7.37-11.78, p < 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69% (95% CI 9.68-19.94, p < 0.001); female 8.13% (95% CI 5.69-10.62, p < 0.001)); and also by the presenting FDE type: optic neuritis 11.39% (95% CI 7.15-15.80, p < 0.001); brainstem/cerebellar syndrome 9.47% (95% CI 5.18-13.93, p < 0.001); and spinal cord syndrome 5.36% (95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.