Neurofilament Light Chain in Adult and Pediatric Multiple Sclerosis:A Promising Biomarker to Better Characterize Disease Activity and Personalize MS Treatment

Many biological markers have been explored in multiple sclerosis (MS) to better quantify disease burden and better evaluate response to treatments, beyond clinical and MRI data. Among these, neurofilament light chain (Nf-L), although non-specific for this disease and found to be increased in other neurological conditions, has been shown to be the most promising biomarker for assessing axonal damage in MS, with a definite role in predicting the development of MS in patients at the first neurological episode suggestive of MS, and also in a preclinical phase. There is strong evidence that Nf-L levels are increased more in relapsing versus stable MS patients, and that they predict future disease evolution (relapses, progression, MRI measures of activity/progression) in MS patients, providing information on response to therapy, helping to anticipate clinical decisions in patients with an apparently stable evolution, and identifying patient non-responders to disease-modifying treatments. Moreover, Nf-L can contribute to the better understanding of the mechanisms of demyelination and axonal damage in adult and pediatric MS. A fundamental requirement for its clinical use is the accurate standardization of normal values, corrected for confounding factors, in particular age, sex, body mass index, and presence of comorbidities. In this review, a guide is provided to update clinicians on the use of Nf-L in clinical activity.</p

Pregnancy in multiple sclerosis: clinical and self-report scales

Relapse rate is decreased during pregnancy in multiple sclerosis (MS). Risk for postpartum relapse is increased in the first 3 months after delivery. We aimed to study clinical course of MS around pregnancy, using clinical as well as self-report scales, including data on quality of life (QoL), and to identify clinical factors predisposing for postpartum relapse. We performed a prospective, longitudinal study among 35 MS patients and 20 controls. In patients we assessed expanded disability status scale (EDSS), the Guy’s neurological disability scale (GNDS) and the multiple sclerosis impact scale 29 (MSIS-29). In patients and controls we assessed the MOS 36 item short form health survey questionnaire (SF36), consisting of eight domains. The previously described surge in relapses after delivery was also obvious in this study (p = 0.005). At group level EDSS and MSIS-29 did not show overt fluctuations over time. The GNDS, however, improved during the third trimester, compared to the first trimester (p = 0.003). A concomitant improvement in the SF36 domains vitality (p < 0.001) and general health (p = 0.001) was found in patients. At the final visit, at least 9 months after delivery, no worsening of EDSS, GNDS, MSIS-29 or SF36 was observed compared with the (for MS, beneficial) third trimester. Duration of disease, relapses in the year preceding pregnancy or relapses during pregnancy were not associated with postpartum relapse. QoL is improved during pregnancy. Although relapse rate was increased directly after delivery, in the mid long term after delivery no adverse effects of pregnancy on MS were found

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study

Introduction: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. Methods: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. Results: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). Conclusion: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients

OBJECTIVE: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). METHODS: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). RESULTS: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19+B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses. CONCLUSION: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results

E.U. paediatric MOG consortium consensus: Part 5 – Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centrespecific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methy

Pediatric multiple sclerosis: update on diagnostic criteria, imaging, histopathology and treatment choices

Pediatric multiple sclerosis (MS) represents less than 5% of the MS population, but patients with pediatric-onset disease reach permanent disability at a younger age than adult onset patients. Accurate diagnosis at presentation and optimal long-term treatment is vital to mitigate ongoing neuroinflammation and irreversible neurodegeneration. However, it may be difficult to early differentiate pediatric MS from acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) as they often have atypical presentation that differs from that of adult-onset MS. The purpose of this review is to summarize the updated views on diagnostic criteria, imaging, histopathology and treatment choices

Multiple sclerosis in children

In 2 children, both aged 7 years, multiple sclerosis (MS) was diagnosed. In children, the initial clinical features of MS may vary greatly. The first patient presented with an acute disseminated encephalomyelitis (ADEM), and the other with a hemiparesis on the left side. In both patients, the disease was controlled by prolonged pharmacotherapy, starting with methylprednisolone and followed in the first patient by intravenous infusions of immunoglobulins and in the second patient by beta-interferon.</p

Multiple sclerosis in children

In 2 children, both aged 7 years, multiple sclerosis (MS) was diagnosed. In children, the initial clinical features of MS may vary greatly. The first patient presented with an acute disseminated encephalomyelitis (ADEM), and the other with a hemiparesis on the left side. In both patients, the disease was controlled by prolonged pharmacotherapy, starting with methylprednisolone and followed in the first patient by intravenous infusions of immunoglobulins and in the second patient by beta-interferon.</p

White matter microstructural differences in children and genetic risk for multiple sclerosis: A population-based study

Background: MS patients show abnormalities in white matter (WM) on brain imaging, with heterogeneity in the location of WM lesions. The "pothole" method can be applied to diffusion-weighted images to identify spatially distinct clusters of divergent brain WM microstructure. Objective: To investigate the association between genetic risk for MS and spatially independent clusters of decreased or increased fractional anisotropy (FA) in the brain. In addition, we studied sex- and age-related differences. Methods: 3 Tesla diffusion tensor imaging (DTI) data were collected in 8- to 12-year-old children from a population-based study. Global and tract-based potholes (lower FA clusters) and molehills (higher FA clusters) were quantified in 3047 participants with usable DTI data. A polygenic risk score (PRS) for MS was calculated in genotyped individuals (n = 1087) and linear regression analyses assessed the relationship between the PRS and the number of potholes and molehills, correcting for multiple testing using the False Discovery Rate. Results: The number of molehills increased with age, potholes decreased with age, and fewer potholes were observed in girls during typical development. The MS-PRS was positively associated with the number of molehills (beta = 0.9, SE = 0.29, p = 0.002). Molehills were found more often in the corpus callosum (beta = 0.3, SE = 0.09, p = 0.0003). Conclusion: Genetic risk for MS is associated with spatially distinct clusters of increased FA during childhood brain development