A nationwide survey of the influence of month of birth on the risk of developing multiple sclerosis in Sweden and Iceland

Previous studies have shown that the risk of multiple sclerosis (MS) is associated with season of birth with a higher proportion of MS patients being born in spring. However, this relationship has recently been questioned and may be due to confounding factors. Our aim was to assess the influence from season or month of birth on the risk of developing MS in Sweden and Iceland. Information about month of birth, gender, and phenotype of MS for patients born 1940–1996 was retrieved from the Swedish MS registry (SMSR), and their place of birth was retrieved from the Swedish Total Population Registry (TPR). The corresponding information was retrieved from medical journals of Icelandic MS patients born 1981–1996. The control groups consisted of every person born in Sweden 1940–1996, their gender and county of birth (TPR), and in Iceland all persons born between 1981 and 1996 and their gender (Statistics Iceland). We calculated the expected number of MS patients born during each season and in every month and compared it with the observed number. Adjustments were made for gender, birth year, and county of birth. We included 12,020 Swedish and 108 Icelandic MS patients in the analyses. There was no significant difference between expected and observed MS births related to season or month of birth in Sweden or Iceland. This was even the results before adjustments were made for birth year and birth place. No significant differences were found in subgroup analyses including data of latitude of birth, gender, clinical phenotype, and MS onset of 30 years or less. Our results do not support the previously reported association between season or month of birth and MS risk. Analysis of birth place and birth year as possible confounding factors showed no major influence of them on the seasonal MS risk in Sweden and Iceland

The role of blood and CSF biomarkers in the evaluation of new treatments against multiple sclerosis

Introduction: Multiple sclerosis (MS) is an immune-mediated chronic neurodegenerative disease of the central nervous system (CNS). Therapeutic interventions with immunomodulatory agents reduce disease activity and disability development, which are monitored clinically and by magnetic resonance imaging (MRI). However, these measures largely lack information on the impact from these therapies on inflammation, demyelination and axonal injury, the essential pathophysiological features of MS. Several biomarkers for inflammation and neurodegeneration have been detected in cerebrospinal fluid (CSF). In MS, some of these biomarkers seem to reflect disease activity, disability progression, and therapeutic response. Areas covered: In this review, we describe the most promising CSF biomarkers of inflammation and degeneration for monitoring therapeutic interventions in MS. We also describe the evolution of highly sensitive immunoassays that enable determination of neuron-specific biomarkers in blood. Expert commentary: Together with clinical and MRI measures, CSF biomarkers may improve the assessment of therapeutic efficacy and make personalized treatment possible. One disadvantage has been the need of repetitive lumbar punctures to obtain CSF. However, the technical development of highly sensitive immunoassays allows determination of extremely low quantities of neuron-specific proteins in blood. This will potentially open a new era for monitoring disease activity and treatment response in MS

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

BACKGROUND: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. OBJECTIVE: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients (n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001–2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. RESULTS: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499–2744] ng/L) than those without relapse (264 [125–537] ng/L, p < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8–3210] ng/L) than those without (426 [IQR 221–851] ng/L, p < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) ⩾ 3 (p < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44–2.65) and conversion to secondary progressive MS (SPMS, p = 0.001, HR = 2.5, 95% CI = 1.4–4.2). CONCLUSIONS: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset

Neurofilament light protein levels in cerebrospinal fluid predict long-term disability of Guillain-Barre syndrome: A pilot study

Objectives: Although the recovery from Guillain‐Barré syndrome (GBS) is good in most patients, some develop permanent severe disability or even die. Early predictors would increase the likelihood to identify patients at risk for poor outcome at the acute stage, allowing them intensified therapeutic intervention. Materials and Method: Eighteen patients with a history of GBS 9‐17 years ago were reassessed with scoring of neurological disability and quality of life assessment (QoL). Their previous diagnostic work‐up included clinical examination with scoring of disability, neurophysiological investigation, a battery of serology tests for infections, and cerebrospinal fluid (CSF) examination. Aliquots of CSF were frozen, stored for 20‐28 years, and analyzed by ELISA for determination of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP). Results: Patients with poor outcome (n = 3) had significantly higher NFL and GFAP levels at GBS nadir than those with good outcome (n = 15, P < .01 and P < .05, respectively). High NFL correlated with more prominent disability and worse QoL at long‐term follow‐up (r = .694, P < .001, and SF 36 dimension physical component summary (PCS) (r =−.65, P < .05), respectively, whereas GFAP did not correlate with clinical outcome or QoL. Conclusion: High NFL in CSF at the acute stage of GBS seems to predict long‐term outcome and might, together with neurophysiological and clinical measures, be useful in treatment decisions and clinical care of GBS

Kappa free light chain index as a diagnostic biomarker in multiple sclerosis: a real-world investigation

Kappa free light chain (KFLC)-index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal-bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC-index in MS. KFLC-index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n=327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC-index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, pIF and better than for IgG-index. We show that KFLC-index was influenced neither by DMT, nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF

Chronic brain stimulation using Micro-ECoG devices

Recording and stimulating brain activity has had great success both as a research tool and as a clinical technique. Neural prosthetics can replace limbs, restore hearing, and treat disorders like Parkinson’s and epilepsy, but are relatively crude. Current neural prosthetic systems use penetrating electrodes to achieve high precision, but the invasive nature of these devices provoke a strong immune response that limits chronic use. (Polikov et al) In our study we evaluate micro-electrocortiographic (micro-ECoG) devices which sit under the skull and on the surface of the brain for stimulation over chronic timescales. We anticipate these devices with their less invasive placement will evoke less extreme immune responses compared to penetrating electrodes and allow for stable stimulation over long periods of time (months to years). These devices were developed by the NITRO Lab of University of Wisconsin. (Thongpang et al) In short, Sprague Dawley rats were implanted with micro-ECoG devices over either somatosensory or auditor cortex. They were stimulated electrically through these devices on a daily basis to evaluate their chronic performance in vivo. Sensitivity to stimulation was determined via an operant behavioral task and the implants’ electrical properties were measured daily to monitor functionality and approximate of the immune response. After at least two months of implantation, animals were perfused and a histological analysis was performed to evaluate the chronic immune response. From preliminary results we expect to see that the micro-ECoG devices are capable of long term stimulation and evoke a smaller immune response from the brain than penetrating neural implants. In addition, we have found that removing the dura in rats for device implantation causes significant brain swelling, which indicates a strong immune response preventing effective stimulation. This research shows that micro-ECoG devices can chronically stimulate brain tissue and show great promise as a less invasive method of neural interfacing compared to traditional penetrating electrodes

Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis

Cerebrospinal fluid (CSF) biomarkers can reflect different aspects of the pathophysiology of relapsing-remitting multiple sclerosis (RRMS). Understanding the impact of different disease modifying therapies on the CSF biomarker profile may increase their implementation in clinical practice and their appropriateness for monitoring treatment efficacy. This study investigated the influence of first-line (interferon beta) and second-line (natalizumab) therapies on seven CSF biomarkers in RRMS and their correlation with clinical and radiological outcomes. We included 59 RRMS patients and 39 healthy controls. The concentrations of C-X-C motif chemokine 13 (CXCL13), C-C motif chemokine ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein, neurofilament light protein (NFL), and neurogranin were determined by ELISA, and chitotriosidase (CHIT1) was analyzed by spectrofluorometry. RRMS patients had higher levels of NFL, CXCL13, CHI3L1, and CHIT1 than controls (p < 0.001). Subgroup analysis revealed higher NFL, CXCL13 and CHIT1 levels in patients treated with first-line therapy compared to second-line therapy (p = 0.008, p = 0.001 and p = 0.026, respectively). NFL and CHIT1 levels correlated with relapse status, and NFL and CXCL13 levels correlated with the formation of new magnetic resonance imaging lesions. Furthermore, we found an association between inflammatory and degenerative biomarkers. The results indicate that CSF levels of NFL, CXCL13, CHI3L1, and CHIT1 correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy

Cerebrospinal fluid growth-associated protein 43 in multiple sclerosis

Neurodegeneration in multiple sclerosis (MS) correlates with disease progression and reparative processes may be triggered. Growth-associated protein 43 (GAP-43) exhibits induced expression during axonal growth and reduced expression during MS progression. We aimed to evaluate if GAP-43 can serve as a biomarker of regeneration in relapsing-remitting MS (RRMS) and whether disease-modifying therapies (DMTs) influence GAP-43 concentration in cerebrospinal fluid (CSF). GAP-43 was measured using an enzyme-linked immunosorbent assay in 105 MS patients (73 RRMS, 12 primary progressive MS, 20 secondary progressive MS) and 23 healthy controls (HCs). In 35 of the patients, lumbar puncture, clinical assessment, and magnetic resonance imaging was performed before initiation of therapeutic intervention, and at follow-up. CSF GAP-43 concentration was significantly lower in progressive MS compared with HCs (p = 0.004) and RRMS (p =  < 0.001) and correlated negatively with disability (p = 0.026). However, DMTs did not alter CSF GAP-43. Interestingly, in RRMS CSF GAP-43 levels were higher in patients with signs of active inflammatory disease than in patients in remission (p = 0.042). According to CSF GAP-43 concentrations, regeneration seems reduced in progressive MS, increased during disease activity in RRMS but is unaffected by treatment of highly active DMTs