Increased cerebrospinal fluid chitinase 3-like 1 and neurofilament light chain in pediatric acquired demyelinating syndromes
Introduction
Acquired demyelinating syndromes (ADS) are inflammatory demyelinating diseases of the central nervous system (CNS). They can be either monophasic or relapsing (Krupp et al., 2013, Boesen et al., 2018). Between 2–11% of persons with multiple sclerosis (MS) present before 18 years of age (Renoux et al., 2007). In young children, acute disseminated encephalomyelitis (ADEM) is the commonest manifestation of ADS; during adolescence, other ADS become increasingly common, e.g. MS, transverse myelitis (TM) and optic neuritis (ON), as well as other clinically isolated syndromes (CIS) (Boesen et al., 2018, Krupp et al., 2013, Neuteboom et al., 2008). However, in the initial stages of the disease, it can be difficult to determine the specific type of ADS and whether the ADS is more likely to be monophasic or relapsing. In this regard, recent studies in adults have shown that cerebrospinal fluid (CSF) levels of chitinase 3-like 1 (CHI3L1) and neurofilament light chain (NFL) may be useful biomarkers in adults, but their diagnostic value in childhood ADS is unclear (Comabella et al., 2010, Modvig et al., 2015, Hinsinger et al., 2015, Cantó et al., 2015, Khademi et al., 2013, Arrambide et al., 2016).
To date, the most sensitive and specific investigation for diagnosis and prognostication of ADS is magnetic resonance imagining (MRI) followed by CSF examination (Sadaka et al., 2012). ADEM is characterized by encephalopathy and multifocal neurological deficits including diffuse bilateral T2 white matter lesions on MRI but only presence of CSF oligoclonal bands (OCB) in 0–10% of all cases (Krupp et al., 2013, Mikaeloff et al., 2007, Tenembaum et al., 2002, Dale and Pillai, 2007, Atzori et al., 2009, Alper et al., 2009, Boesen et al., 2018); in contrast, MS is usually non-encephalopathic, typically presents with periventricular MRI lesions, and presence of OCBs in CSF in 35–81% (Krupp et al., 2013, Sadaka et al., 2012, Alper et al., 2009, Polman et al., 2011, Pohl et al., 2004, Chabas et al., 2010, Heussinger et al., 2015). However, studies have reported that 5% to 29% of pediatric ADEM patients progress to MS with a follow-up ranging 0.5–6.6 years (Neuteboom et al., 2008, Mikaeloff et al., 2007, Tenembaum et al., 2002, Dale and Pillai, 2007, Banwell et al., 2011, Suppiej et al., 2008). Accordingly, more sensitive and specific tests are needed.
In this aspect, two CSF biomarkers are of particular interest: CHI3L1 (also known as YKL40) and NFL. CHI3L1 is produced by macrophages, neutrophils, and astrocytes in the inflamed CNS and plays a role in inflammation and tissue response to injury (Lee et al., 2011, Bonneh-Barkay et al., 2010, Di Rosa et al., 2013). In adults, CHI3L1 has been shown to: a) be elevated in ADS, b) serve as a prognostic biomarker for conversion from monophasic demyelination to multiple sclerosis, and c) predict development of cognitive and physical disability in MS (Comabella et al., 2010, Modvig et al., 2015, Hinsinger et al., 2015, Cantó et al., 2015). NFL forms the basis of the neurofilament fiber abundant in myelinated axons. If elevated, NFL is a sensitive marker of white matter axonal injury (Khademi et al., 2013). In adults, increased levels of NFL in CSF following CIS is a risk factor for MS and provides prognostic information (Modvig et al., 2015, Khademi et al., 2013, Arrambide et al., 2016). In children, increased NFL has been associated with opsoclonus-myoclonus syndrome, CNS Langerhans cell histiocytosis, progressive encephalopathy, and infectious and inflammatory CNS disorders (Pranzatelli et al., 2014, Shahim et al., 2013, Osterlundh et al., 2008). However, it has not been studied in childhood ADS.
Our aim was to determine the diagnostic value of CHI3L1 and NFL in the CSF at onset in distinguishing pediatric ADS from non-ADS and, subsequently, ADEM from MS.
Section snippets
Study population
Children (<18 years) were retrospectively included from June 1, 2010 to July 1, 2016. The children were admitted for diagnostic work-up of possible neuroinflammatory disease including CSF analysis for OCB in the capital region of Copenhagen at either Rigshospitalet/Copenhagen University Hospital or Hvidovre Hospital. All CSF samples were obtained during the initial diagnostic work-up (acute phase). We accessed the CSF samples through a biobank at the Neuroimmunology Laboratory,
Baseline characteristics
Among all children (n = 193), 56% were girls and the median age at onset was 13.8 years (range: 1.3–17.9 years) (Table 1). This was similar for children with ADS (median: 15.0; range 2.5–17.9 years) and for the children of the control group (median: 15.5, range: 10.8–17.7 years). For children with monophasic ADS the median follow-up was 3.3 years (range = 0.9‒7.7 years).
The CSF analyses revealed that 23% had IgG OCB in CSF, 21% had an increased IgG index, and 26% had pleocytosis, which was
Discussion
In children (<18 years) referred to hospital for diagnostic work-up for neurological disease including CSF examination of IgG OCB, we show that CHI3L1 and NFL are significantly higher in those with ADS compared with those without ADS. Furthermore, CHI3L1 ≥ 283 µg/L distinguished ADEM and MS with 75% sensitivity and 93% specificity. To our knowledge, this is the first study investigating CHI3L1 and NFL in the CSF as diagnostic biomarkers for pediatric ADS.
In corroboration with our findings,
Conclusions
This study provides class II evidence that increased CSF concentrations of CHI3L1 and NFL are associated with ADS in children referred to hospital for diagnostic evaluation. Further, CHI3L1 may help in distinguishing between ADEM and MS at onset, although this needs to be further validated. Future studies should investigate the relationship between increased CSF concentrations of CHI3L1 and NFL and establish the optimal combination of biomarkers including cut-off levels to best predict the
Financial disclosure statements
Dr. Boesen has served on scientific advisory board for Teva; has received speaker honoraria for lecturing from Novartis and support for congress participation from Teva, Novartis and Roche.
Dr. Jensen reports no disclosures.
Dr. Magyari has served on the scientific advisory board for Biogen Idec, Novartis, and Merck Serono; has received honoraria for lecturing from Biogen Idec, Merck Serono, Novartis, and Genzyme; has received support for congress participation from Biogen Idec, Novartis,
Acknowledgements
We thank medical technologist Ulla Abildtrup for her invaluable help in performing the ELISAs, and the Danish MS Society and Karen A. Tolstrups Foundation for financial support.
Author Contributions
Dr. Boesen, Dr. Sellebjerg, and Dr. Jensen have contributed to the conception and design of the study, acquisition and analysis of data, and drafting a significant portion of the manuscript or figures. Dr. Magyari, Dr. Uldall, Dr. Born, and Dr. Blinkenberg have contributed to the conception and design of the study as well as commented the final version of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Funding
The study was supported financially by the Danish MS Society (grant numbers: A29625 and A31526), Teva, Novartis, and Genzyme, but none of the sponsors took part in designing or analyzing data derived from the study.
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