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Bozzetti et al. Neuroimmunol Neuroinflammation 2021;8:1-13 I http://dx.doi.org/10.20517/2347-8659.2020.26 Page 3

NfL IN SUBJECTS WITH CLINICALLY ISOLATED SYNDROME AND RADIOLOGICALLY
ISOLATED SYNDROME
Clinically isolated syndrome (CIS) is defined as the first episode of clinical symptoms that potentially
precedes MS. About 85% of patients with CIS experience a second clinical episode, thus evolving into
[23]
MS within the subsequent 10 years . Radiologically isolated syndrome (RIS) is defined by MRI findings
suggestive of MS in the absence of clinical symptoms. Progression to MS usually occurs in approximately
[24]
66% of patients with RIS . The uncertain evolution and variable long-term prognosis of patients with CIS/
RIS make attractive the discovery and validation of specific biomarkers able to identify cases that will have
future clinical attacks.

In this scenario, the potential utility of CSF NfL as a predictive marker of disease evolution has
been recently explored. In particular, Håkansson et al. analyzed CSF levels of NfL, NfH, and other
[25]
neurodegenerative and inflammatory markers in 19 patients with CIS, 22 cases with relapsing remitting
multiple sclerosis (RRMS), and 22 sex- and age-matched healthy controls in a prospective longitudinal
study. Disease activity (i.e., radiological lesion load, presence of relapses, and disability worsening) was
recorded at 2 years follow-up and compared with the levels of specific biomarkers measured at baseline.
Interestingly, NfL values were the only prognostic marker potentially able to predict disease activity in
subjects with CIS and MS. A different study compared CSF NfL levels with brain volume measured in 41
patients with CIS and 30 controls and demonstrated that NfL values were higher in subjects with CIS and
[26]
were inversely associated with grey matter volume . CSF NfL and progranulin levels were also evaluated
[27]
in subjects with RIS and compared with those determined in subjects with CIS, MS, and healthy controls .
Interestingly, NfL levels were significantly lower in subjects with CIS and RIS in comparison with patients
with RRMS and primary progressive multiple sclerosis (PPMS), suggesting that the detection of this
biomarker could parallel clinical evolution in these disorders. In addition, CSF NfL values recently emerged
as an independent risk factor for clinical conversion in subjects with RIS with higher levels associated with
shorter time to progression .
[28]
After the discovery of highly sensitive techniques able to measure the lower values of NfL in plasma/serum,
[29]
the potential utility of serum NfL in predicting CIS conversion to MS has been explored. Disanto et al.
demonstrated that serum NfL levels are higher in subjects with CIS in comparison with healthy controls
and are associated with T2 hyperintense MRI lesions, gadolinium-enhancing lesions, and disability score
at CIS diagnosis, but do not allow subjects with CIS who will convert to definite MS after a short interval
(n = 100) to be distinguished from subjects with CIS who will not evolve (n = 100). The potential effect
of riluzole treatment in subjects with CIS and early MS (n = 22 CIS/MS cases randomized to riluzole and
n = 21 to placebo) in comparison with clinical parameters and serum NfL/NfH values was also analyzed.
Despite the absence of treatment effect, the authors demonstrated that NfL levels correlated with Expanded
[30]
Disability Status Scale (EDSS) changes and neuropsychological outcome . Furthermore, higher NfL levels
at baseline were associated with a more rapid decrease in brain volume and predicted higher number of
enhancing lesions, confirming the role of NfL as a potential marker of neuronal and axonal damage in CIS
and early MS. Finally, in a case-control study performed among US military that analyzed serum samples
of 60 subjects asymptomatic at time of sampling who then developed MS (6 years later as a median), the
authors observed increased serum NfL levels in cases that would develop MS in comparison to healthy
controls, demonstrating a potentially useful value of serum NfL in predicting future development of/
evolution to MS .
[31]

Taken together, available data support the role of CSF NfL levels as a predictive and prognostic marker of
CIS/RIS. On the other hand, serum NfL levels are increased in patients with a recent relapse and a high
number of T2/enhancing lesions on MRI. Despite the more evident association between NfL levels and