Clinical trial
Cerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis

https://doi.org/10.1016/j.msard.2019.07.025Get rights and content

Highlights

  • CSF NfL at onset predicted subsequent disease activity in early MS.

  • Early MS patients with future disease activity had higher CSF NfL concentration.

  • A baseline CSF NfL ≥ 500 pg/mL identified patients with future disease activity.

Abstract

Background

The prediction of disease activity in patients with a first demyelinating event suggestive of multiple sclerosis (MS) is of high clinical relevance. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has shown to have prognostic value in MS patients. In this work, we measured CSF NfL in patients at the first demyelinating event in order to find a cut-off value able to discriminate patients who will have disease activity from those who will remain stable during the follow-up.

Methods

We included CSF samples collected within 30 days after the onset of the first demyelinating event from 32 patients followed-up for 3.8 ± 2.5 years. CSF NfL was measured with a newly developed in-house enzyme linked immunosorbent assay (ELISA).

Results

At the first demyelinating event, patients with subsequent disease activity had significantly higher baseline CSF NfL values compared to clinically and radiologically stable patients (median 812.5 pg/mL, range 205–2359 pg/mL vs 329.5 pg/mL, range 156–3492 pg/mL, p = 0.002). A CSF NfL cut-off value of 500 pg/mL significantly discriminated these two groups of patients with a 90% sensitivity and an 83.3% specificity.

Conclusion

Our results confirm that CSF NfL is a prognostic marker in the very early phases of MS. The validation of a cut-off value of 500 pg/mL could provide clinicians with a dichotomous variable that can simplify the prognostic assessment of patients at the first demyelinating event.

Introduction

In 85% of cases, multiple sclerosis (MS) presents at onset with an isolated central nervous system (CNS) demyelinating event, the clinically isolated syndrome (CIS) (Miller et al., 2012). CIS patients have an intrinsic high risk to subsequently develop MS, since about 2/3 of them will experience a second relapse or additional changes on follow-up magnetic resonance images (MRI) (Fisniku et al., 2008). For this reason, CIS is now included among the clinical phenotypes of MS (Lublin et al., 2014). Moreover, the two most recent revisions of diagnostic criteria have made it possible to define both dissemination in space and in time of demyelinating lesions soon after the first manifestation of the disease, thus facilitating an earlier diagnosis of MS (Polman et al., 2011, Thompson et al., 2018).

In the management of patients at the first demyelinating event, there is a compelling need for reliable tools that could help to identify those patients who will subsequently show disease activity. Indeed, these patients could benefit from an early and, consequently, more effective treatment (Comi et al., 2017).

Several studies, performed on large multicenter CIS populations, have shown that a combination of demographical, clinical, laboratory and MRI features is able to stratify the risk of subsequent conversion into MS (Kuhle et al., 2015, Spelman et al., 2016, Tintore et al., 2015). Among baseline characteristics of CIS patients, the presence of cerebrospinal fluid (CSF) oligoclonal bands (OCBs) is one of the factors associated with a higher risk of MS development (Tintore et al., 2015). Importantly, in the most recent update of diagnostic criteria for MS, CSF-specific OCBs have been re-entered as a diagnostic tool (Thompson et al., 2018), which gives the opportunity to analyze additional CSF biomarkers reflecting other early pathophysiological mechanisms underlying MS, such as axonal damage.

Neurofilament light chain (NfL) is a structural protein of axonal cytoplasm and it is highly expressed in large-calibre myelinated axons within the CNS (Zetterberg, 2016). NfL levels increase in the CSF as a consequence of axonal damage and their changes reflect ongoing disease activity in MS (Teunissen et al., 2009a). So far, studies on CSF NfL have been performed using the same commercially available enzyme-linked immunosorbent assay (ELISA) (Norgren et al., 2002). In the present study, we measured CSF NfL in a cohort of patients at the first demyelinating event by means of a newly developed ELISA (Gaetani et al., 2018). We retrospectively investigated the prognostic value of CSF NfL in defining the risk of subsequent disease activity, and we looked for a possible cut-off value able to discriminate patients who presented clinical and/or radiological signs of disease activity from those who were stable during the follow-up.

Section snippets

CSF sample collection and storage

We analyzed 32 CSF samples stored in the Biobank of the Section of Neurology, Department of Medicine, University of Perugia (Perugia, Italy). CSF was collected over a 10-year period (from 2006 to 2016), via lumbar puncture, in the same Institution, with the same standard operating procedures, and stored according to a protocol following international guidelines (Teunissen et al., 2009b). Specifically, in all patients lumbar punctures were performed in the morning between 8:00 and 11:00 and CSF

Statistical analysis

Continuous variables are reported as mean ± standard deviations (median; range). For continuous variables, normal distribution was tested with the Shapiro–Wilk test. Group differences were assessed with an unpaired t-test for normally distributed variables or Mann–Whitney test for variables with a skewed distribution. Categorical variables are reported as numbers and percentages. Fisher exact test was performed to test for group differences. The accuracy of the diagnostic value of NfL was

Characteristics of the patients

The selected CSF samples were from 32 consecutive patients (mean age 38.3 ± 11.5 years, F/M = 1.7) followed-up for a mean time of 3.8 ± 2.5 years. The details of demographic, clinical and neuroradiological characteristics of the patients are reported in Table 1. During the follow-up, 20 patients (62.5%) presented disease activity, with a mean time to the appearance of clinical/MRI signs of disease activity of 1.4 ± 1.1 years. The remaining 12 patients (37.5%) were stable during the follow-up

Discussion

The main finding of our study is that CSF NfL, as measured with a new ELISA soon after the first demyelinating event, is able to predict future inflammatory disease activity. Indeed, patients with subsequent relapses or new/enhancing MRI lesions at the follow-up had, at baseline, significantly higher concentrations of CSF NfL than clinically and MRI stable patients. CSF NfL was able to discriminate with a high accuracy between these two groups of patients.

Previously, CSF NfL has been repeatedly

Declaration of Competing Interest

LGa participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Almirall, Biogen, Biogen-Idec, Genzyme, Mylan, Novartis, Roche, Teva. AM received travel grants from Teva and Sanofi Genzyme to attend national conferences. PC received/receive research support from Bayer Schering, Biogen-Dompé, Boehringer Ingelheim, Eisai, Lundbeck, Merck-Serono, Novartis, Sanofi-Aventis, Sigma-Tau, and UCB Pharma. KB has served as a consultant or at advisory

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