Abstract
This review provides an overview on different antibody test methods that can be applied in cases of suspected paraneoplastic neurological syndromes (PNS) and anti-neuronal autoimmune encephalitis (AIE) in order to explain their diagnostic value, describe potential pitfalls and limitations, and discuss novel approaches aimed at discovering further autoantibodies. Onconeuronal antibodies are well-established biomarkers for PNS and may serve as specific tumor markers. The recommended procedure to detect onconeuronal antibodies is a combination of indirect immunohistochemistry on fixed rodent cerebellum and confirmation of the specificity by line assays. Simplification of this approach by only using line assays with recombinant proteins bears the risk to miss antibody-positive samples. Anti-neuronal surface antibodies are sensitive and specific biomarkers for AIE. Their identification requires the use of test methods that allow the recognition of conformation dependent epitopes. These commonly include cell-based assays and tissue based assays with unfixed rodent brain tissue. Tissue based assays can detect most of the currently known neuronal surface antibodies and thus enable broad screening of biological samples. A complementary testing on live neuronal cell cultures may confirm that the antibody recognizes a surface epitope. In patients with peripheral neuropathy, the screening may be expanded to teased nerve fibers to identify antibodies against the node of Ranvier. This method helps to identify a novel subgroup of peripheral autoimmune neuropathies, resulting in improved immunotherapy of these patients. Tissue based assays are useful to discover additional autoantibody targets that play a role in diverse autoimmune neurological syndromes. Antibody screening assays represent promising avenues of research to improve the diagnostic yield of current assays for antibody-associated autoimmune encephalitis.
Highlights
Since the 1980s, detailed clinical and immunological studies revealed several autoantibodies against intracellular antigens that are associated with specific paraneoplastic or idiopathic neurological syndromes [8,9,10,11,12,13,14,15]
It is important to know that testing for onconeuronal antibodies requires other methods than surface antibodies (CBAs and unfixed/postfixed TBAs)
The highest sensitivity and specificity of a test result can be achieved by cross-validation with different test methods and the combined testing of serum and CSF samples
Summary
Autoimmune diseases in the brain may affect different parts of the nervous system including neurons, glial cells or components of the blood-brain barrier. Autoantibodies against surface antigens may directly mediate the disease (e.g., by antigenic modulation or by recruitment of immune cells or components of the complement system), among the antibodies against neuronal membrane antigens, these effects are often reversible and explain the good response to immunotherapy. Autoantibodies against cell surface antigens on neurons and glial cells can be tumor associated but derive more frequently from an idiopathic origin [1]. Many autoimmune neurological or demyelinating syndromes are currently considered as antibody negative despite some evidence that they are antibody-mediated. Among these are patients with suspected but yet unknown antigenic targets, and further studies are required to discover these.
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