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Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12 Page 29

As a disease activity and prognostic biomarker, the amount of CSF NF-L levels showed a significant
association with NEDA-3 status, MRI activity and brain atrophy and significantly correlated with serum
[11]
NF-L ones . In several studies, serum NF-L also correlated with MRI activity, predicted the development
of brain volume loss in a period of 2 years and decreased under DMDs [236,237] . A recent study obtained
similar results, with serum NF-L detected in early phases contributing to the prediction of lesion load and
brain volume loss over a period of 10 years [238] .

CSF NF-L concentrations proved to decrease after 12-24 months of immunosuppressive therapy in active
progressive MS patients [239] and after switching from first-line therapies to fingolimod in RRMS ones [240] .
Moreover, compared with NF-H, CSF NF-L has been found to be superior as a therapeutic biomarker
after 12 months of NTZ-treatment in RRMS patients [241,242] . Nevertheless, the potential role of CSF NF-L
as a treatment response biomarker is severely limited by the invasiveness of performing serial lumbar
punctures. Conversely, serial serum NF-L assessments would represent a more easily detectable marker
and a reliable indicator of CSF NF-L levels [219,221] . Results from a recent study conducted on 15 MS patients
treated with alemtuzumab and monitored with serial serum NF-L measurements were significant [243] .
Indeed, serum NF-L levels correlated well with clinical and radiological activity at baseline and during
follow-up, decreasing within 6 months from drug administration until reaching stable values under 8 pg/ml
in those patients who achieved NEDA-3. Moreover, patients who showed clinical and radiological disease
activity during follow-up also exhibited increased levels of serum NF-L up to 5 months before relapses.

So far, several studies have confirmed the reliability of NF-L as a disease activity and treatment response
biomarker for MS, even though it does not represent a MS-specific biomarker. However, a precise cut-off is
still missing, precluding the chance to stratify the risk of clinical and radiological disease activity according
to NF-L levels. The opportunity to consider only intra-individual values is still debated, without focusing
on their deviation from values reported in healthy people [237] .

Further replication in larger, multicenter cohorts is needed. A randomized controlled trial, prospectively
recruiting 900 patients from 45 sites in the USA, will provide further information about the potential role
of serum NF-L as a prognostic and treatment response biomarker for MS [244] .

IgM oligoclonal bands
Unlike small and monomeric IgG, IgM are large molecules consisting of pentameter units and ten
antigen-binding sites and are strong activators of complement [245] . In a similar way to CSF IgG OCB, their
identification is considered a sign of intrathecal synthesis, suggesting an inflammatory disease of the
CNS [246] . However, CSF IgM oligoclonal bands (IgM OCB) are mainly considered a prognostic and disease
[1]
activity biomarker than a diagnostic one, though not routinely used in clinical practice .
In a study involving 29 MS patients who were followed-up for 5 to 16 years, the presence of CSF IgM OCB
was strongly associated with conversion to SPMS and the achievement of greater EDSS scores [247] . In a
similar way, IgM OCB-positivity strongly predicted a severe disease course influencing the probability of
developing greater disability in a cohort of 64 MS patients [248] .

In patients with CIS, the identification of CSF lipid-specific IgM OCB was associated with greater MRI
lesion load and brain atrophy at the first clinical event [249] and with an aggressive disease course [250] .
Periventricular lesion load during the first years of disease proved to be related as well to the entity of IgM
intrathecal synthesis in CIS patients, so that an active role of IgM in the development of demyelinating
lesions has been supposed [251] .

Moreover, both the risk of a second clinical event and its earliness were strongly increased when both CSF
lipid-specific IgM OCB and IgG OCB were detected, as in 22% of 192 patients with CIS [252] . In another