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Page 18 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

Considering the extensive number of molecules that are currently under investigation and detected in body
fluids, this review will focus on CSF biomarkers that are currently used in clinical practice, those that have
not been clinically implemented although validated and those requiring further validation after proving
to be useful in small exploratory single-site studies. Since some molecules may potentially fall in more
than one category according to a functional classification, they will be classified according to their main
recognized role.

DIAGNOSTIC BIOMARKERS
IgG oligoclonal bands
CSF IgG oligoclonal bands (IgG OCB) are detected in almost 90% of patients with MS and in nearly 70% of
[16]
patients with CIS . It does not seem that OCB-negative MS shows different characteristics, even though a
[17]
different immunogenetic phenotype of HLA-DRB1 has been identified in some studies . Among several
techniques, isoelectric focusing followed by immunofixation in parallel CSF and serum samples is mainly
used for their detection due to a high sensitivity [18,19] . Of all possible patterns, type 2 is detected when at
least two bands of IgG are present in CSF but not in serum, which is suggestive of intrathecal IgG synthesis
[18]
and thus of an inflammatory disease of the CNS .

As a qualitative assessment, CSF IgG OCB detection is actually considered a more reliable test than
[20]
any quantitative assessments of intrathecal synthesis . With nearly 86% specificity and more than 95%
sensitivity, CSF IgG OCB do not represent a pathognomonic finding of MS, but they may strongly support
the diagnosis of MS when other causes of CNS inflammation have been ruled out .
[19]
In 2017, the latest revised McDonald criteria gave great significance to CSF OCB as a substitute for
[20]
dissemination in time , increasing sensitivity in the diagnosis of relapsing-remitting MS (RRMS) in
[21]
patients with a first clinical event . CSF IgG OCB already had a role as a diagnostic biomarker before,
[22]
first in Poser’s criteria (1983) to define “laboratory supported” definite and probable MS diagnosis . Years
later, both the McDonald et al. and Polman et al. criteria considered the presence of CSF IgG OCB as
[24]
[23]
sufficient to provide the evidence of dissemination in space (DIS), together with the detection of at least
two MRI lesions consistent with MS. Although not being included in 2010 revised criteria , CSF analysis
[25]
with IgG OCB detection still represents a common step of the diagnostic program, particularly because
it may allow us to exclude other diagnoses adding a different type of information compared with MRI,
[26]
which may be unable to allow the distinction between MS and mimics at early stages . Moreover, it has
been argued that the presence of CSF OCB may increase the specificity of those criteria when considered
[27]
together with DIS .
Concerning the diagnosis of primary progressive MS (PPMS), the presence of CSF OCB is one of the
required criteria and its role has been confirmed over time in the consecutive revisions after Poser’s
[20]
criteria [23-25] . In addition to a diagnostic role, CSF IgG OCB also has a prognostic role for conversion to MS,
since their identification in patients with CIS increases the risk to convert into clinically definite MS with a
[28]
negative predictive value of 88% . In a prospective study conducted by Tintoré and coworkers in 572 patients
with CIS, the detection of CSF IgG OCB almost doubled the risk of a second relapse, regardless of baseline
[29]
MRI, without affecting disability outcomes during a follow-up of 50 months .

Despite recognizing the presence of CSF IgG OCB as one of the factors predicting an increased risk to
[30]
[20]
develop MS in patients with RIS , specific criteria have not been established in the 2017 latest revision .
Results from a recent study showed that the presence of CSF OCB in children with RIS increased the
[31]
risk to develop pediatric MS and improved specificity of MRI criteria in these patients . In another
study conducted in 75 patients with RIS, CSF OCB also proved to be an independent risk factor for the
[32]
conversion to CIS and MS and were associated with shorter times of conversion .