Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

Abstract

Objective: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.

Methods: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.

Results: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.

Conclusions: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Keywords: Autoimmune encephalitis; Immunotherapy; Laboratory test evaluation; Neural autoantibodies; Outcome.

Fig. 1

Age, sex, and prevalence. Distribution of age (in 5-year-intervals) and sex (red = female, blue = male) in the four major groups and the negatives. In the diagrams to the right, the bars indicate antibody prevalences, i.e., the proportions of positives related to all investigated patients (divided into subgroups defined by age and sex)

Fig. 2

Disease durations, CSF/serum/CSF–serum pairs, IgG subclasses, and clinical ratings. a Latency (in months) between disease manifestation and antibody diagnostics in the antibody-positive cases with known disease onset. The lines indicate medians with quartiles. Antibody groups are given in ascending order of their median latencies. A₁: linear x-axis, A₂: logarithmic x-axis (note that “1” was added to all values to be able to include values of zero). b Ratio of cases with serum-only or CSF-only antibody positivity in the four major antibody groups plus onconeural and GABABR antibodies. The small groups with serum-only and CSF-only findings in the GAD65 group are cases with either very low CSF titers (N = 3) and negative serum or serum titers of just 1:500 and negative CSF samples (N = 2). In the onconeural group, there was one Ma2 case that was not fully appreciated in serum (blot positivity only) but clearly diagnosed in CSF (blot and tissue-based assay positive). c IgG subclasses in the four major antibody groups. d Clinical retrospective ratings (“Autoimmune disease of the CNS or PNS?”) in descending order of the positive ratings

Fig. 3

Immunotherapy and outcome in the four major antibody groups (NMDAR-high, LGI1, CASPR2, and GAD65). a Mean number of immunotherapies per patient with standard deviations. b Proportions and extent of changes according to the modified Rankin scale (mRS). Blue boxes indicate improvements, grey boxes stability, and reddish boxes deterioration. Labeling of the x-axis: after the N values, the median follow-up is given (mo = months). c–f Clinical performance (mRS) at antibody diagnostics (“pre”) and at most recent follow-up (“post”). Lower values indicate better performance. Left-most bars: all patients with rating at antibody diagnostics; second bars: patients with “post” ratings available at the time-point “pre” (there are no relevant differences between the total groups and those with an outcome); third bars: outcome; right-most bars: proportions of number of immunotherapies used. Please note that information on “no. of therapies” was only available for 34 LGI1 patients