Improving the antibody-based evaluation of autoimmune encephalitis

Abstract

Objective:We tested whether antibody screening samples of patients with suspected autoimmune encephalitis with additional research assays would improve the detection of autoimmune encephalitis compared with standard clinical testing alone.Methods:We examined 731 samples (333 CSF, 182 sera, and 108 pairs) from a cohort of 623 patients who were tested for CNS autoantibodies by the University of Pennsylvania clinical laboratory over a 24-month period with cell-based assays (CBAs) on commercially obtained slides of fixed cells for antibodies to NMDA receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid-B receptor (GABABR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (Caspr2), and glutamic acid decarboxylase (GAD65). In parallel, our research laboratory screened all samples for reactivity to brain sections and for anti-NMDAR using in-house CBAs. Samples with brain reactivity or positive clinical studies were examined with CBAs for a larger panel of antibodies.Results:The clinical laboratory reported positive findings for NMDAR (80 samples), GAD65 (8), LGI1 (5), Caspr2 (2), and GABABR (4). Sixty-five serum samples and 32 CSF samples were indeterminate for one or more antibodies. In our research laboratory, all but 4 positive results were confirmed, 88 of 97 indeterminate results were resolved, and 15 additional samples were found positive (10 NMDAR, 1 AMPAR, 3 LGI1, and 1 Caspr2). Clinical information supported these diagnoses. Overall, informative autoantibodies were detected in 15.5% of cases.Conclusions:Standard clinical laboratory kits were specific, but some tests were insensitive and prone to indeterminate results. Screening with immunohistochemistry for reactivity to brain sections, followed by additional CBAs for cases with brain reactivity, improves the diagnostic accuracy of testing for autoimmune encephalitis.

Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study

“…Extrapolated from a series of 163 cases, 11 Ab-negative-LE patients (8%) had clinical phenotypes mainly characterized by cognitive features and, differently from ours, a low frequency of seizures [19]. Different Ab-detecting techniques, as one-third of our Ab-negative-AE patients were tested with possibly suboptimal commercial tests only [6] could explain the discrepancies.…”

“…These Abs bound to live neurons, suggesting pathogenic potential, and reactivities to novel, yet-tobe-characterized antigenic targets [8]. Our data confirm that in-house tests for AE are fundamental to improve diagnostic accuracy [6]. CSF inflammatory features, as defined by the AE-DC [8] were markers of relapses, but the predictive value needs confirmation in further series.…”

Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment

“…Notably, the superiority of CSF for antineuronal antibody testing was primarily shown for NMDA receptor antibodies, in which 10-20% of patients have detectable antibody levels in CSF only. However, some other common antibodies, such as against LGI1 and Caspr2, are always present in serum and may be absent in CSF (van Sonderen et al 2016;McCracken et al 2017). Thus, positive serum detection by commercial assays is sufficient for these antibodies.…”

AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity

“…Studies were performed as previously described. 56 Adult female Wistar rats were anesthetized and decapitated. Brains were removed and washed in 1Â PBS and then bisected sagitally and fixed in 4% paraformaldehyde in PBS at 4 C for 1 hr.…”