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Summary:

  • In patients with intrathecal immunoglobulin synthesis, κ FLC concentrations in cerebrospinal fluid are typically high, whilst λ FLC concentrations are only moderately elevated.
  • It is preferable to calculate a κ FLC index by correcting for FLC diffusion into the CSF.
  • An elevated κ FLC index can support a diagnosis of multiple sclerosis.
  • An elevated κ FLC index has been found more diagnostically sensitive than oligoclonal band detection.

Inflammation of the central nervous system (CNS) may be caused by infections (e.g. viral encephalitis, cerebral malaria) or autoimmune disorders such as Guillain-Barré syndrome or, notably, multiple sclerosis (MS). When inflammation of the CNS occurs, there is usually synthesis of intrathecal immunoglobulins [838]. Since the blood-brain barrier largely prevents their escape into the blood, the immunoglobulins gradually accumulate in the cerebrospinal fluid (CSF). They are then detectable as oligoclonal bands on electrophoretic gels or can be quantitated using protein assays.

When determining the clinical relevance of oligoclonal bands, CSF samples should always be assessed alongside paired serum samples to determine whether the immunoglobulin was synthesised locally within the CSF or has diffused from the blood [839]. The presence of oligoclonal bands in the CSF that are not present in the serum is consistent with intrathecal synthesis. However, if the patient’s serum contains monoclonal immunoglobulins produced in the bone marrow, some will cross the blood-brain barrier, making interpretation of intrathecal production difficult [839]. Similarly, if there is inflammation of the meninges, serum proteins will enter the CSF more readily. The gold standard for detection of oligoclonal bands is isoelectric focusing (IEF), followed by immunoblotting [839]. However, this protocol is non-quantitative, time-consuming, and interpretation may be difficult; consequently, it is not always routinely available.

Alternatively, quantitative IgG analysis may be used as a measure of intrathecal immunoglobulin synthesis. To ensure that measurements represent local (intrathecal) synthesis and not IgG which has diffused from the blood, values are corrected using albumin measurements. This serves as a marker of the blood-CSF barrier function because albumin is never synthesised within the CNS. For example, the IgG index is calculated using the IgG and Albumin quotients (Q) as follows: QIgG/QAlb = [IgGCSF/IgGserum]/[AlbuminCSF/Albuminserum]. Alternative, non-linear formulae improve the diagnostic accuracy of IgG measurements and are recommended [839]. However, in general, quantitative IgG analysis will only identify around 75% of oligoclonal-band positive patients [839]. Consequently, there is a need for alternative, sensitive tests to identify intrathecal immunoglobulin synthesis.

Immunoglobulin free light chains (FLCs) are typically secreted along with intact immunoglobulins from plasma cells (Section 3.4). If they are produced intrathecally, they should accumulate locally and significant diffusion from the blood is unlikely as serum concentrations are low due to rapid renal clearance (Section 3.5). For these reasons, the measurement of FLCs in CSF is a potentially sensitive marker of intrathecal immunoglobulin synthesis and it has been investigated a number of times using various assay techniques (Section 36.2).

36.1.1. Multiple sclerosis and intrathecal immunoglobulin synthesis

The majority of the studies exploring the measurement of FLCs as an alternative marker of intrathecal immunoglobulin synthesis have focused on MS.

MS is an autoimmune inflammatory disease of the CNS, characterised by myelin loss, axonal pathology, and progressive neurologic dysfunction [840]. The majority of patients will first present with what is termed a clinically isolated syndrome (CIS). However, over a period of 20 years, about 60% of patients will suffer a second demyelinating event and progress to a diagnosis of clinically definite MS [841]. The diagnosis of MS is made primarily on the basis of medical history and physical examination, with Magnetic Resonance Imaging (MRI) used to identify neurological lesions [842]. Positive CSF findings (ie. 2 or more oligoclonal bands, or an elevated IgG index) can be important in supporting the inflammatory demyelinating nature of the condition, evaluating alternative diagnoses, and predicting clinically definite MS [842].