Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

Subcortical Volumes as Early Predictors of Fatigue in Multiple Sclerosis.

OBJECTIVE: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM). METHODS: This multicenter cohort study included 601 treatment-naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow-up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis. RESULTS: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001). INTERPRETATION: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192-202.

Association of obesity with disease outcome in multiple sclerosis.

BACKGROUND: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. METHODS: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. RESULTS: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. CONCLUSIONS: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.

Epilepsy as a predictor of disease progression in multiple sclerosis.

BACKGROUND: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. OBJECTIVE: To examine if epilepsy leads to more rapid disease progression. METHODS: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case-control study. RESULTS: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. CONCLUSION: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

Time to diagnosis in multiple sclerosis: Epidemiological data from the German Multiple Sclerosis Registry.

OBJECTIVE: To investigate the time to diagnosis in multiple sclerosis (MS) in Germany. METHODS: Analysis of real-world registry data from the German Multiple Sclerosis Registry (GMSR) and performing a primary analysis in patients where month-specific registration of the dates of onset and diagnosis was available. RESULTS: As of January 2020, data of a total of 28,658 patients with MS were extracted from the GMSR, with 9836 patients included in the primary analysis. The mean time to diagnosis was shorter following the introduction of the first magnetic resonance imaging (MRI)-based McDonald criteria in 2001. This effect was most pronounced in younger adults below the age of 40 years with relapsing onset multiple sclerosis (ROMS), with a decrease from 1.9 years in 2010 to 0.9 years in 2020, while unchanged in patients aged 40-50 years (1.4 years in 2010 and 1.3 years in 2020). In the limited number of paediatric onset MS patients, the time to diagnosis was longer and did not change (2.9 years). CONCLUSION: The current sensitive MRI-based diagnostic criteria have likely contributed to an earlier diagnosis of MS in Germany in younger adults aged 18-39 years with ROMS. Whether this translated to earlier initiation of disease-modifying treatment or had a beneficial effect on patient outcomes remains to be demonstrated.

Dentate-nucleus gadolinium deposition on magnetic resonance imaging: ultrasonographic and clinical correlates in multiple sclerosis patients.

OBJECTIVE: The objective of this study is to find out whether gadolinium accumulation in the dentate nucleus (DN) after repeated gadolinium-based contrast agent (GBCA) administration in multiple sclerosis (MS) patients is related to tissue alteration detectable on transcranial ultrasound. METHODS: In this case-control study, 34 patients (17 with, and 17 age-, sex-, MS severity-, and duration-matched participants without visually rated DN T1-hyperintensity) who had received 2-28 (mean, 11 ± 7) consecutive 1.5-Tesla MRI examinations with application of linear GBCA were included. Real-time MRI-ultrasound fusion imaging was applied, exactly superimposing the DN identified on MRI to calculate its corresponding echo-intensity on digitized ultrasound image analysis. In addition, cerebellar ataxia and cognitive performance were assessed. Correlation analyses were adjusted for age, MS duration, MS severity, and time between MRI scans. RESULTS: DN-to-pons T1-signal intensity-ratios (DPSIR) were larger in patients with visually rated DN T1-hyperintensity compared to those without (1.16 ± 0.10 vs 1.09 ± 0.06; p = 0.01). In the combined group, DPSIR correlated with the cumulative linear-GBCA dose (r = 0.49, p = 0.003), as did the DPSIR change on last versus first MRI (r = 0.59, p = 0.003). Neither DPSIR nor globus pallidus internus-to-thalamus T1-signal intensity-ratios were related to echo-intensity of corresponding ROI's. DPSIR correlated with the dysarthria (r = 0.57, p = 0.001), but no other, subscore of the International Cooperative Ataxia Rating Scale, and no other clinical score. CONCLUSIONS: DN gadolinium accumulation is not associated with trace metal accumulation, calcification, or other tissue alteration detectable on ultrasound. A possible mild effect of DN gadolinium accumulation on cerebellar speech function in MS patients, suggested by present data, needs to be validated in larger study samples.

Prevalence of pediatric multiple sclerosis in Germany: A nationwide population-based analysis.

BACKGROUND AND PURPOSE: Prevalence data are needed to reveal trends regarding the pediatric multiple sclerosis (MS) situation worldwide. The aim was to identify changes in MS diagnosis prevalence in pediatric patients over a 10-year period in Germany. METHODS: This analysis is based on nationwide outpatient claims data of children aged <18 years covered by the German statutory health insurance (n = 11,381,939 in 2018). People with MS (PwMS) had ≥1 documented MS diagnosis (International Classification of Diseases, 10th Revision, German modification code G35.x). The annual pediatric MS diagnosis prevalence was analyzed regarding age, sex, and place of residence during 2009-2018. RESULTS: The prevalence of pediatric MS developed from 5.3 (2009) to 5.4 (2018)/100,000 insured population aged <18 years. The MS prevalence in patients aged 15-17 years showed a moderate increase over 10 years (19.6-22.7/100,000), whereas patients ≤14 years old showed a slight decrease (1.9-1.7/100,000). The sex ratio (female:male) in 2018 was relatively balanced in PwMS aged ≤14 years (1.32) but female-dominated in those aged 15-17 years (2.47). The formerly different prevalence of pediatric MS between East and West Germany has converged since 2012. CONCLUSIONS: So far, this is the largest study of pediatric MS prevalence in terms of source population size (87% of German children <18 years of age, n = 11,381,939 in 2018) and study period (2009-2018) worldwide. The analyses revealed an increase in MS prevalence and a female-dominated sex ratio in "older" adolescents compared to younger patients.

Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases.

Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1ß and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics.

[The corona pandemic and multiple sclerosis: vaccinations and their implications for patients-Part 2: vaccine technologies]. / Die Corona-Pandemie und Multiple Sklerose: Impfungen und deren Implikationen für Patienten ­ Teil 2: Impfstofftechnologien.

Along with the challenges posed by the globally circulating COVID-19 pandemic, there have been some epochal advances in the field of vaccine technologies. In addition to the traditionally used dead, live and protein-based vaccines, vector-based and gene-based vaccines gained enormous attention in the course of this health crisis. The aim of this article is to provide an overview of multiple sclerosis (MS) and vaccination, recent advances in the SARS-CoV­2 vaccine landscape as well as a detailed discussion of the various vaccine technologies. Finally, clear recommendations in the context of disease-modifying treatment and vaccination in MS are highlighted.

[The corona pandemic and multiple sclerosis: vaccinations and their implications for patients-Part 1: recommendations]. / Die Corona-Pandemie und Multiple Sklerose: Impfungen und deren Implikationen für Patienten ­ Teil 1: Empfehlungen.

The ongoing COVID-19 pandemic is a global health crisis. New challenges are constantly emerging especially for the healthcare system, not least with the emergence of various viral mutations. Given the variety of immunomodulatory and immunosuppressive therapies for multiple sclerosis (MS) and the immense developments in vaccine production, there is a high need of information for people with MS. The aim of this article is therefore to provide an overview of MS and COVID-19 as well as to clarify the implications for patients with MS, especially regarding vaccination and to formulate appropriate recommendations.

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)]. / Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper).

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).

Prevention and management of adverse effects of disease modifying treatments in multiple sclerosis.

PURPOSE OF REVIEW: To summarize the currently known side effects of the approved therapies of multiple sclerosis and to suggest monitoring procedures. RECENT FINDINGS: The progress in the treatment of multiple sclerosis with new very effective therapies is accompanied by a number of side effects. Some of these have already been described in the approval studies, but some only after approval in a real world situation. The reason for this is the short duration of the clinical studies, the very heterogeneous patient profile in the real world setting with a number of comorbidities, pretherapies, and wider age range. The side effects may occur during application of therapies or afterwards during the course of the treatment. The side effects may range from mild infections, mild laboratory abnormalities, secondary autoimmune diseases to life-threatening side effects such as progressive multifocal leukoencephalopathy. SUMMARY: It has to be pointed out that these side effects are not to be considered as final and neurologists should be vigilant against new unknown side effects. The doctor should be aware of these undesirable effects, should weigh the benefits of the therapies against the risks, but at the same time she/he should keep in mind that multiple sclerosis can be a very disabling disease if not treated properly.

[Headache in multiple sclerosis]. / Kopfschmerzen bei Multipler Sklerose.

The relationship between headache and multiple sclerosis (MS) has been a matter of controversy for over 60 years. Headaches are still rated as a "red flag", indicating alternative diagnoses to MS, although in the last few years numerous studies have shown a frequent association between headache and MS. In recent studies on MS patients, a link was found between lower age/shorter disease duration of MS and frequent headaches. A study of 50 patients manifesting MS for the first time showed the highest headache prevalence in MS of 78% reported so far.Headaches can also be a possible side effect of most disease-modifying MS drugs. In many cases, however, the headache appears to be a symptom of MS in terms of secondary headache. This is also supported by pathophysiological implications, for example, by detecting B cell follicles in the meninges of MS patients.Migraine is the most common type of headache in MS. In some cases, this is a comorbidity of two diseases with many similarities, but headaches caused by inflammatory MS lesions also appear to be phenomenologically very similar to classic migraines; thus, distinguishing between them is often only successful with the help of thorough differential diagnostics (cerebrospinal fluid, MRI etc.).The task of future studies must be to specify the phenomenology of headache in MS even more precisely, in order to, to gain knowledge in, among others, patients with radiologically isolated syndrome, who often suffer from headache, because in these patients a considerable differential diagnostic and therapeutic uncertainty exists.

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis.

BACKGROUND: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. OBJECTIVE: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. METHODS: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. RESULTS: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. CONCLUSIONS: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS.

Headache in the course of multiple sclerosis: a prospective study.

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system (CNS). Early diagnosis and treatment is important to prevent progression of disability in the course of the chronic disease. Therefore, correct and fast identification of early symptoms is vital. Headache is generally not recognized as an early symptom of MS, although numerous studies could show a high prevalence of headache in MS patients. The most common misdiagnosis is migraine. The aim of this study is to investigate the prevalence as well as the phenomenology of headache in MS especially with regard to the progression of the disease. In a prospective, multicenter study, we unbiasedly recruited 150 patients with manifest MS based on the criteria of McDonald. 50 patients at the timepoint of initial diagnosis and 100 of them with a long-term course of the disease were included. Based on a semi-structured interview, we evaluated the occurrence of headache over the last 4 weeks as well as case history, clinical-neurological investigation and questionnaires about depression, fatigue, and quality of life. Prevalence of headache in all patients was 67%. Patients at the timepoint of symptom manifestation of MS showed the highest prevalence of headache that was ever been recorded of 78%. In general, patients with headache were younger, had a shorter duration of the disease, and were less physically affected. We noticed frequent occurrence of migraine and migraine-like headache. In the course of the disease, patients without disease-modifying drug (DMD) complained more frequently headaches than patients with any kind of therapy. Headache is an important early symptom of MS. This could be shown especially among 78% of patients with clinically isolated syndrome (CIS). Therefore, young people with frequent headache should undergo MRI of the head and in the case of abnormal findings a consecutive detailed differential diagnosis. This could reduce the latency until final diagnosis of MS, which is in general much too long. That way these patients could get the earliest possible treatment, which is important to stop the progression of the disease.

Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome.

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.

[Indications for varicella zoster and herpes zoster vaccination in multiple sclerosis: current situation]. / Varicella-zoster- und Herpes-zoster-Impfindikation bei Multipler Sklerose: aktuelle Situation.

In patients with multiple sclerosis (MS) primary varicella zoster virus (VZV) infections (chickenpox) or reactivation (shingles, herpes zoster) pose a particular challenge for neurologists and physicians in everyday clinical practice. On the one hand the various immunotherapeutic agents for treatment of MS have differently expressed risks for VZV-associated infections and on the other hand the currently available vaccination strategies (dead vs. live vaccines, single vs. combination vaccines) require an individualized approach. Moreover, in addition to the optimal timing of vaccination during the course of MS, the appropriate vaccine and, where indicated, the use of antiviral drugs should be determined.

NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients.

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNß) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNß treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNß and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNß in MS patients.