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We determined activation profiles of the classical and alternative complement pathway in 39 treatment‐naïve patients with early relapse‐onset MS. Plasma concentrations of complement fragments were unchanged in MS compared to 32 patients with non‐inflammatory neurological diseases. Profiles in patients experiencing clinical exacerbations did not differ from patients with stable disease and did not correlate with baseline EDSS, numbers of T2 lesions and time to second relapse. Long‐term EDSS outcomes 4 years after diagnosis did not significantly correlate with baseline complement levels. These data do not support the use of complement activation products as biomarkers for disease activity in early MS.

Objectives: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D 3 supplements were associated with lower circulating NfL levels. Materials & Methods: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D 3 and N = 16 with placebo. Twenty-five hydroxyvitamin D 3 (25(OH)D 3) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. Results: Serum 25(OH)D 3 levels at 48 weeks were increased in the vitamin D 3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P 3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D 3 on this biomarker of neuro-axonal injury.

ObjectivesTo evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS.MethodsComprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments.ResultsIntrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45–6.44], p = 0.003) after adjustment for age (0.96 [0.93–1.00], p = 0.059), OCB (0.92 [0.33–2.61], p = 0.879), intrathecal IgG production (0.98 [0.48–1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11–6.22], p = 0.028).ConclusionIntrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.

We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. By categorical analysis, in patients with IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF < median. Dose-dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging-defined disease activity and sNfL. This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2–10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis., Graphical Abstract Graphical Abstract

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

Progressive multifocal leukoencephalopathy (PML) is one of the most important adverse events in relapsing-remitting MS (RRMS) patients treated with disease-modifying therapies (DMTs). Especially natalizumab is known to increase the risk for PML, depending on the John Cunningham virus (JCV) index in serum and the number of years on therapy with natalizumab.1 Fingolimod and dimethyl fumarate are associated with a considerably lower risk of PML.2

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene ( HLA DRB1)*1501, anti-Epstein–Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( p Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

ObjectiveTo explore the repertoire of glycan-specific immunoglobulin G (IgG) antibodies in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS).MethodsA systems-level approach combined with glycan array technologies was used to determine specificities and binding reactivities of glycan-specific IgGs in treatment-naive patients with RRMS compared with patients with noninflammatory and other inflammatory neurologic diseases.ResultsWe identified a unique signature of glycan-binding IgG in MS with high reactivities to the dietary xenoglycan N-glycolylneuraminic acid (Neu5Gc) and the self-glycan N-acetylneuraminic acid (Neu5Ac). Increased reactivities of serum IgG toward Neu5Gc and Neu5Ac were additionally observed in an independent, treatment-naive cohort of patients with RRMS.ConclusionPatients with MS show increased IgG reactivities to structurally related xenogeneic and human neuraminic acids. The discovery of these glycan-specific epitopes as immune targets and potential biomarkers in MS merits further investigation.

Background Neurofilament light chain level in serum (sNfL) and cerebrospinal fluid (CSF-NfL) is a promising biomarker of disease activity in multiple sclerosis (MS). However, predictive value of neurofilaments for development of cognitive decline over long-term follow-up has not been extensively studied. Objective To investigate the relationship between early neurofilament levels and cognitive performance after 9-years. Methods We included 58 MS patients from the SET study. sNfL levels were measured at screening, at 1 and 2 years. CSF-NfL were measured in 36 patients at screening. Cognitive performance was assessed by the Brief International Cognitive Assessment for Multiple Sclerosis and the Paced Auditory Serial Addition Test-3 s at baseline, at 1, 2 and 9 years. Association between neurofilament levels and cognition was analyzed using Spearman´s correlation, logistic regression and mixed models. Results We did not observe associations among early sNfL levels and cross-sectional or longitudinal cognitive measures, except of a trend for association between higher sNfL levels at screening and lower California Verbal Learning Test-II (CVLT-II) scores at year 1 (rho=-0.31, unadjusted p = 0.028). Higher sNfL level was not associated with increased risk of cognitive decline, except of a trend for greater risk of CVLT-II decrease in patients with higher sNfL levels at 1 year (OR=15.8; 95% CI=1.7–147.0; unadjusted p = 0.015). Similar trends were observed for CSF-NfL. Conclusion We found only weak association between sNfL levels at disease onset and evolution of cognitive performance over long-term follow-up.

The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known.The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis.sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.9 ± 8.0 years) during the first demyelinating event. CSF-NfL was available for 103 (77%) patients.CSF-NfL and sNfL were negatively associated with serum ApoA-II (P = .005, P .001) and positively associated with albumin quotient (P .001, P .0001). In addition, higher CSF-NfL was associated with lower serum ApoA-I (P = .009) levels and higher sNfL was associated with lower high-density lipoprotein cholesterol (P = .010). In stepwise regression, age (P = .045), serum ApoA-II (P = .022), and albumin quotient (P .001) were associated with CSF-NfL; albumin quotient (P = .002) and ApoA-II (P = .001) were associated with sNfL. Path analysis identified parallel pathways from ApoA-II (P = .009) and albumin quotient (P .001) to the sNfL outcome that were mediated by CSF-NfL (P .001). The associations of CSF-NfL with ApoA-I (P = .014) and ApoA-II (P = .015) and sNfL with ApoA-II (P .001) remained significant after adjusting for number of contrast-enhancing lesions and T2 lesion volume.Lower serum ApoA-II and ApoA-I levels are associated with greater neuroaxonal injury as measured by CSF-NfL.

We thank Alcala et al. for their very pertinent comments to our article.1 Although their group used a qualitative method—intrathecal oligoclonal immunoglobulin [Ig]M bands2—and our work applied a quantitative approach—calculation of the fraction of intrathecally produced IgM—for detection of an intrathecal IgM production, their and our work consistently show that the presence of an intrathecal IgM production in patients with a clinically isolated syndrome is clearly associated with an increased risk of conversion to multiple sclerosis (MS). Of note, this conclusion is likewise reached by a recent comprehensive literature review that summarized a total of 12 prospective and retrospective studies addressing this issue.3 However, the key questions of why a certain proportion of patients with MS has an intrathecal production of IgM and whether these patients differ pathogenically from those without an intrathecal IgM production currently remain unanswered. Although further research will be required to clarify these points, it definitely seems highly interesting and warranted to closely evaluate the effectiveness of immunotherapies for MS according to the presence/absence of an intrathecal IgM production, with the aim of developing individualized treatment strategies for patients with early MS.

ObjectiveTo assess whether serum concentrations of the anti-inflammatory cytokine growth differentiation factor 15 (GDF-15) differ in patients with highly active multiple sclerosis (MS) vs patients with stable MS and healthy controls (HCs).MethodsGDF-15 concentrations were measured by ELISA in serum and CSF in a cross-sectional cohort of patients with MS, patients with other inflammatory neurologic diseases (OIND), patients with noninflammatory neurologic diseases (NIND), and healthy controls (HC). Serum GDF-15 concentrations were measured in a longitudinally sampled cohort of clinically and radiologically well-characterized patients with MS and corresponding controls.ResultsCross-sectionally measured median serum GDF-15 concentrations were significantly higher in patients with OIND (n = 42) (600 pg/mL, interquartile range [IQR] = 320–907 pg/mL) compared with HCs (n = 29) (325 pg/mL, IQR = 275–419 pg/mL; p = 0.0007), patients with NIND (n = 46) (304 pg/mL, IQR = 245–493 pg/mL; p = 0.0002), or relapsing MS (n = 42) (356 pg/mL, IQR = 246–460 pg/mL; p = 0.0002). CSF and serum concentrations of GDF-15 were correlated (r = 0.41, 95% CI = 0.25–0.56, p < 0.0001). In a longitudinally sampled cohort of patients with MS (n = 48), deeply phenotyped with quantitative clinical and MRI assessments, mean GDF-15 concentrations were significantly higher in patients with a stable disease course (405 pg/mL, SD = 202) than in patients with intermittent MRI activity (333 pg/mL, SD = 116; p = 0.02).ConclusionsSerum GDF-15 concentrations are increased in patients with MS with a stable disease course. These data suggest that GDF-15 may serve as a biomarker for disease stability in MS.

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection. A characteristic feature of MS is an intrathecal synthesis of immunoglobulin (Ig)G. In 90 patients with clinically isolated syndromes/early relapsing-remitting MS, serum antibodies to Epstein-Barr nuclear antigen-1, but not to EBV viral capsid antigen, rubella, or varicella zoster virus, were higher (p=0.03) in those with than those without a calculated intrathecal IgG synthesis >0% and correlated with the percentage (r=0.27, p=0.009) and concentration (r=0.27, p=0.012) of intrathecally produced IgG. These findings suggest a link between EBV infection and the events leading to intrathecal IgG synthesis in patients with MS.

We thank Ravi Uniyal and colleagues for their comments on our results from the PATH trial1 on subcutaneous immunoglobulin (SCIg) for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). They express concern about the relapse rates in the treatment groups and hypothesise the cause being the pharmacokinetics of SCIg.

Syphilis is caused by the spirochete Treponema pallidum.When nvasion of the central nervous system (CNS) occurs, Neurosyphilis an develop and is able to imitate a wide variety of diseases with any clinical symptoms, including photophobia, headache, nausea nd cranial nerve palsies [1]. For instance Neurosyphilis can be the ause of simultaneous infarction in the territories of the posterior nferior cerebellar arteries [2]. Here we present a patient with an epileptic seizure on the asis of mesiotemporal encephalitis as the first manifestation of he disease and show that auto-antibodies typical of phenotypially similar CNS diseases were absent in this condition. This is of mportance, because in many patients it is usually not ruled out, hat encephalitis might be caused by auto-antibodies and Syphilis s only diagnosed by coincidence. This clinical course highlights the variety of clinical symptoms hatNeurosyphilis can causeand the importanceof considering this

Toscana virus, a neurotropic infectious agent endemic to Mediterranean countries, classified in the sandfly fever virus group (genus Phlebovirus, family Bunyaviridae), is a frequent cause of aseptic meningitis and encephalitis in Italy.1 The disease usually has a favorable outcome, and reports of severe courses are rare.1,2 We present an unusual case of acute hydrocephalus as the initial symptom of Toscana virus meningoencephalitis. ### Case report. A 21-year-old student presented with a 36-hour history of progressive bifronto-temporal headaches, retroorbital pressure, fever, nausea, vomiting, and double vision due to bilateral sixth cranial nerve deficits. Eight days before presentation, he had returned from a 2-week camping trip to Umbria, Italy, where he had suffered multiple tick bites. The patient's past personal and travel history was otherwise unremarkable. Apart from bilateral abductor nerve deficits, neurologic examination was normal, in particular showing no signs …

Editors' Note: Charrel questions the history and diagnosis of the patient presented in Oechtering and Petzold’s article on hydrocephalus following Toscana virus meningoencephalitis. The authors defend their approach and clarify the patient's travel history while educating readers about sandfly behavior in the Umbrian region of Italy. Merkies argues that the negative results of the Tafamidis for transthyretin amyloid study were influenced by methodologic aspects including the rationale and weight of the endpoints. He explains that reanalyzing the data using the Rasch method may yield more accurate results and concludes that modern clinimetric-based outcome measures studies should precede …