What causes elevated Immunoglobulin G (IgG) and Immunoglobulin A (IgA) in Cerebrospinal Fluid (CSF)?

From the Guidelines

Elevated Immunoglobulin G (IgG) and Immunoglobulin A (IgA) in Cerebrospinal Fluid (CSF) are primarily caused by inflammatory or immune-mediated processes within the central nervous system, such as autoimmune encephalitis, as supported by the recent study 1. When considering the causes of elevated IgG and IgA in CSF, it's crucial to prioritize the most recent and highest quality evidence. The study published in 2021 in the Journal of Neurology, Neurosurgery and Psychiatry 1 emphasizes the importance of CSF analysis in diagnosing autoimmune encephalitis and other immune-mediated conditions.

Key Findings

• The study highlights that common CSF findings in autoimmune encephalitis include mild to moderate lymphocytic pleocytosis, hyperproteinorrachia, and in some cases, elevated IgG index and/or IgG synthesis rate and positive intrathecal oligoclonal bands 1.
• These findings suggest that inflammatory or immune-mediated processes can lead to elevated IgG and IgA in CSF.
• The presence of oligoclonal bands, which are unmatched in the serum, supports an immune-mediated etiology but requires clinical correlation to differentiate from other conditions 1.

Clinical Implications

• Elevated IgG and IgA in CSF can be caused by various conditions, including autoimmune encephalitis, multiple sclerosis, neurosarcoidosis, and CNS infections.
• The IgG index and synthesis rate can help distinguish between blood-brain barrier dysfunction and intrathecal antibody synthesis.
• Clinical correlation is essential for proper diagnosis and treatment, as elevated immunoglobulins may persist for weeks to months after the initial inflammatory process resolves.

Diagnostic Approach

• CSF analysis should include cell count and differential, protein, glucose, CSF/serum glucose ratio, albumin quotient, IgG index and synthesis rate, oligoclonal bands, and broad viral studies, as recommended by the study 1.
• Testing for specific antibodies, such as NMDAR and GFAP antibodies, may be necessary in both CSF and serum, as sensitivity can vary between the two 1.

From the Research

Causes of Elevated Immunoglobulin G (IgG) and Immunoglobulin A (IgA) in Cerebrospinal Fluid (CSF)

• The presence of elevated IgG and IgA in CSF can be due to local production, diffusion of proteins through the blood-brain barrier, or both 2.
• Studies suggest that lymphocytes from the CSF of patients with multiple sclerosis can produce IgA and IgG in vitro, indicating local production of immunoglobulins 2.
• Elevated protein levels in CSF can also be due to migration of immunoglobulins from serum to CSF because of damage to the blood-brain barrier 2.
• The IgG index, which is the ratio of CSF IgG to serum IgG, can be used to evaluate local IgG synthesis, with an elevated index indicating local production of IgG 3.

Conditions Associated with Elevated IgG and IgA in CSF

• Viral encephalitis, Guillain-Barré syndrome, and meningeal carcinomatosis have been associated with elevated IgA levels in CSF 2.
• Multiple sclerosis, HIV encephalitis, and other chronic inflammatory disorders have been associated with elevated IgG levels in CSF 4.
• Acute viral and bacterial infections of the CNS, including tick-borne meningopolyneuritis Bannwarth, have been associated with elevated IgG, IgA, and IgM levels in CSF 4.
• Malignant tumors have been associated with elevated concentrations of IgG, IgA, IgM, and IgE in CSF 5.

Diagnostic Utility of IgG and IgA in CSF

• The presence of oligoclonal bands of IgG in CSF is a powerful diagnostic tool for multiple sclerosis, with over 95% of patients having CSF oligoclonal bands not detectable in serum 6.
• The IgG index can be used as additional evidence for an augmented B-cell response within the CNS, but it has lower diagnostic sensitivity than CSF oligoclonal bands 6.