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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 19

It has been suggested that the presence of CSF OCB, indicative of intrathecal synthesis, may both directly
and indirectly perpetuate the inflammatory damage through the chronic stimulation of microglia via
immunoglobulin and immunocomplexes. Occurring even once acute perivascular inflammation has
stopped, such an activation facilitates further and mutual activation of both microglia and astrocytes. As a
result, antibody-mediated inflammation promotes a microenvironment of chronic inflammatory damage
[33]
and neurodegeneration . From this perspective, the administration of a drug able to affect local humoral
production would be further useful. However, among the currently available drugs, only natalizumab (NTZ)
and cladribine proved to affect intrathecal Ig synthesis, ultimately leading to CSF OCB disappearance in
some cases [34-37] . Nevertheless, the presence of CSF OCB does not seem to be associated with an aggressive
disease course or a faster disease progression in MS [17,38] .

IgG OCB represent a validated and clinically implemented biomarker for both the diagnosis of MS and the
detection of CIS converters. Its validity relies on numerous confirmatory studies conducted in more than
[3]
200 patients, thus providing a strong level of evidence .

IgG index
[39]
The ratio between IgG quotient and albumin quotient, known as the Link Index , is largely used to assess
a quantitative evaluation of intrathecal synthesis, enough to be considered an alternative to the detection of
CSF OCB in previous MS diagnostic criteria [22-24] . However, the latest revision of McDonald criteria clearly
states that the identification of CSF IgG OCB is superior to any quantitative assessments, whose results
[20]
have to be cautiously considered when isolated or conflicting with the aforementioned tool . In addition,
it has been clearly defined in two different consensus statements that IgG index and other quantitative
assessments are just complementary tests, less sensitive than qualitative detection of CSF OCB [18,19] . A value
greater than 0.70 is universally considered suggestive of pathological intrathecal synthesis for IgG index,
[18]
with abnormal values detected respectively in 70%-80% of patients with clinically definite MS . With
a cut-off value of 0.7, a positive predictive value by 60% for the diagnosis of demyelinating CNS disease
[40]
has been found . Considering that a correlation exists between IgG index and positive predictive value
for MS, increasing IgG index values correlate with a greater probability of MS diagnosis . Nonetheless,
[40]
[41]
abnormal values are rarely detected in MS patients with no CSF OCB .
Nephelometry is the most used technique to measure albumin in CSF and serum as well, to provide a
quotient that is a reliable measure of blood-CSF barrier function, especially when age-related [18,19] . This
is crucial, since the increased concentration of a substance in CSF can be the result of either intrathecal
synthesis or increased permeability of the blood-CSF barrier. Moreover, interindividual variability in serum
[18]
IgG concentrations is similarly reduced by using a CSF/serum IgG quotient .
[42]
Applying different mathematical models, several indices have been derived , including Tourtellotte’s,
Reiber’s, Link’s and intrathecal IgG fraction. Actually, although the IgG index is the most commonly
used quantitative measure of intrathecal synthesis in clinical practice, other indices using hyperbolic
mathematical functions, such as Reiber’s index, are considered more accurate, resulting in few false
positives [18,19] . Senel and coworkers found 43% sensitivity and 64% specificity for IgG index regarding
conversion of CIS to clinically definite MS, with a positive predictive value of 53% and a negative one of
[43]
54% .

As a prognostic biomarker, a very high IgG index has been related to a major disability progression with
greater values in secondary progressive MS (SPMS) compared with PPMS and RRMS patients in a study
[44]
conducted by Izquierdo and coworkers .

Finally, a recent retrospective study involving 149 patients with CIS and MS investigated a possible