Clinical trialCerebrospinal fluid neurofilament light chain predicts disease activity after the first demyelinating event suggestive of multiple sclerosis
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
References (23)
- et al.
Evolving concepts in the treatment of relapsing multiple sclerosis
Lancet
(2017) - et al.
Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis
J. Neuroimmunol.
(2013) - et al.
Diagnosis of multiple sclerosis: 2017 revisions of the Mcdonald criteria
Lancet. Neurol.
(2018) Neurofilament Light: a dynamic cross-disease fluid biomarker for neurodegeneration
Neuron.
(2016)- et al.
Neurofilament light chain level is a weak risk factor for the development of MS
Neurology
(2016) - et al.
Protein biomarkers for multiple sclerosis: Semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis
Mult. Scler. J.
(2012) - et al.
Guidelines from the italian neurological and neuroradiological societies for the use of magnetic resonance imaging in daily life clinical practice of multiple sclerosis patients
Neurol. Sci.
(2013) - et al.
Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis
Brain
(2008) - et al.
A new enzyme-linked immunosorbent assay for neurofilament light in cerebrospinal fluid: analytical validation and clinical evaluation
Alzheimer's Res. Ther.
(2018) - et al.
Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing remitting multiple sclerosis
Eur. J. Neurol.
(2017)
CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome
Mult. Scler. J.
Cited by (18)
Cerebrospinal fluid neurofilament light chains predicts early disease-activity in Multiple Sclerosis
2023, Multiple Sclerosis and Related DisordersNeuropsychiatric manifestations in childhood-onset systemic lupus erythematosus
2022, The Lancet Child and Adolescent HealthCitation Excerpt :Differential diagnoses with other demyelinating diseases have to be considered on the basis of clinical and immunological features, because neuroimaging features might overlap with multiple sclerosis or neuromyelitis optica spectrum disorder.82 In multiple sclerosis, cerebrospinal NfL is associated with subsequent demyelinating lesions; however, no association in SLE has been reported so far.83 With a pooled prevalence of 4·2% (95% 2·3–7·6) in patients with childhood-onset SLE,12 myelopathy might occur in the absence of systemic manifestations and is frequently associated with other neuropsychiatric manifestations.84
Profiling serum neurofilament light chain and glial fibrillary acidic protein in primary progressive multiple sclerosis
2021, Journal of NeuroimmunologyCitation Excerpt :The minimal variation observed within participants over time in Fig. 3 and the lack of association between disease duration at enrollment and biomarker level in Fig. 4 suggest that sNfL and sGFAP concentrations are not a function of disease severity in PPMS and do not appear to change substantially over time in a disease that is marked by persistent decline and degeneration. In relapsing populations, there is evidence of NfL predicting future relapses or disease worsening after a first demyelinating event (Varhaug et al., 2018; Gaetani et al., 2019a); however, the predictive utility of this biomarker for progression in PPMS is unclear. In our analyses, we found that enrollment sNfL does not predict worsening in walking distance, walking speed, and balance (Table 3).
Serum neurofilament light-chain levels and long-term treatment outcomes in relapsing-remitting multiple sclerosis patients: A post hoc analysis of the randomized CombiRx trial
2023, Multiple Sclerosis Journal - Experimental, Translational and Clinical