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Page 20 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

association between CSF parameters and MRI activity. IgG index was highly correlated with the detection
[45]
of new cerebral lesions on MRI scan and proved to be an independent predictor of future MRI activity .

Currently, IgG index is clinically implemented as additional evidence of CNS local humoral response, with
[46]
the advantage of being based on easily achievable information from a simple CSF analysis . Thus, it is
useful in supporting the diagnosis of MS and could represent a complementary screening test in patients
[41]
suspected of MS, without replacing the diagnostic value of CSF OCB .
Kappa free light chains and kappa index
CSF kappa free light chains (KFLC) result from intrathecal humoral activity of plasma cells. Being
normal constituents of human Ig structure together with lambda light chains, they tend to accumulate
[47]
[48]
together with Ig in inflammatory disease of CNS and can be detected by ELISA, Western blotting
or nephelometry [49-51] . Several studies reported an increased concentration of free light chains in CSF of
patients with MS [49,51] . As for IgG index, the use of a ratio between KFLC CSF/serum quotient and albumin
quotient has been considered by the majority as the best method to represent intrathecal FLC synthesis [47,51] ,
with some exceptions [49,52] . Conversely, lambda FLC Index did not prove to have comparable values of
sensitivity and specificity, and it is currently not considered a potential diagnostic biomarker for MS [49,53] .

KFLC index has been explored as a diagnostic biomarker, despite the lack of an unequivocal cut-off value
currently causes some difficulties in comparing results from several studies [Table 2]. As an indicator of
[54]
intrathecal synthesis, KFLC index correlates well with IgG index , using a cut-off value of 5, although
showing greater sensitivity (more than 96% vs. nearly 50%) for CSF IgG OCB identification and MS
diagnosis and according to higher negative predictive values, with comparable specificity.

[53]
[55]
Although different thresholds have been used in several studies, ranging from 4.25 to 12.3 , KFLC
index extensively proved to have a higher sensitivity and a lower specificity with a similar diagnostic
accuracy compared with IgG OCB in discriminating MS and controls [53,55-59] . In a recent study by Gaetani
and coworkers, KFLC index distinguished precisely as did IgG OCB between MS and non-inflammatory
[56]
diseases using a cut-off value of 7.83 . It has been suggested that a higher cut-off value (10.6) could
be useful to differentiate MS from other inflammatory diseases by increasing specificity and to predict
[56]
conversion in CIS with greater accuracy as compared with OCB . Similarly, high levels of CSF KFLC
have also been demonstrated in CIS patients, showing a correlation with the risk of conversion to clinically
definite MS within 2 years [43,60] . Moreover, unlike KFLC index threshold, a cut-off value for intrathecal
KFLC synthesis has proved to be more reproducible [58,61,62] .

Noteworthy, KFLC index proved to be increased in MS patients with no evidence of IgG OCB, amounting
to almost 5% of cases [50,55,62] , showing a greater sensitivity but a less specificity by using a threshold of 5.9.
In a recent study by Ferraro and coworkers, a KFLC index ≥ 5.8 was detected in 25% of OCB-negative MS
[63]
patients and in 98% of OCB-positive ones .
It has been hypothesized that KFLC index may replace IgG index as a first-line test, but some disagreement
remains about the need to determine both KFLC index and IgG OCB in patients with suspected MS or
[63]
[56]
to use them sequentially . Probably, the higher sensitivity of KFLC index compared with IgG OCB would
allow clinicians to screen patients in a shorter time, with lower costs and the advantage of a quantitative
assessment [49,58] , restricting the use of IgG OCB to patients with positive KFLC index. Such a diagnostic
route would allow clinicians to reduce false positive results when faced with an inflammatory disease of the
CNS. Showing a comparable or higher specificity [50,54] , IgG index could still have a role as a screening test
complementary to KFLC index for the detection of intrathecal Ig synthesis. However, KFLC index currently
shows an intermediate level of evidence as a diagnostic biomarker, requiring other confirmatory studies in
larger cohorts .
[3]