Frequencies of neuronal autoantibodies in healthy controls: Estimation of disease specificity

Abstract

Objective: To provide an extensive overview on the prevalence of antibodies against neuronal surfaces (neuronal surface antibody [NSAb]) in healthy participants and disease controls.

Methods: We searched the PubMed database (1974 to October 2016) for studies that analyzed frequencies of 22 different NSAbs in serum or CSF and included controls. Antibody prevalence was calculated for patients with NSAb-mediated disease and controls, including healthy participants, and those with neurologic and nonneurologic diseases. Different assays for antibody detection were compared.

Results: In 309 articles, 743,299 antibody tests for 22 NSAbs were performed, including 30,485 tests for 19 NSAbs in healthy controls (HCs). Of these, 26,423 (86.7%) were tested with current standard methods, usually cell-based assays. Prevalence was very low in HCs (mean 0.23%, absent for 9/19 antibodies), and test numbers ranged from 21 to 3,065 per antibody. One study reported >1,000 healthy participants, and the others contained 21-274 samples. CSF samples were virtually not available from HCs. NSAb prevalence was considerably higher (1.5%) in 69,850 disease controls, i.e., patients not initially suspected to have NSAb-mediated diseases. Antibody determination in controls using nonstandard assays (such as ELISA) resulted in 6% positivity.

Conclusions: NSAbs are rarely found in healthy participants, particularly with standard detection methods, suggesting high disease specificity and supporting their diagnostic usefulness. Conversely, positive titers in atypical patients might point to the still expanding phenotypic spectrum. Future studies should include more CSF samples, data from HCs, and experimental evidence for antibody pathogenicity.

Figure 1. Number of individual antibody tests reviewed in the present analysis

Focusing on the frequency of neuronal surface antibody (NSAb) in healthy controls, almost 26,500 individual antibody tests were performed. Of these, NSAb-positive samples are very rare (0.23%), indicating high disease specificity and supporting their pathogenic role and diagnostic usefulness in clinical routine. The majority of the reviewed 743,299 antibody tests for 22 NSAbs had to be excluded from analysis, as the respective articles did not report on the clinical phenotype of their participants, used assays without defined cutoffs or nonstandard assays, or did not specify whether the test was performed on either serum or CSF.