Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome

Abstract

Objective: We investigated a series of patients with LGI1 antibody (Ab)-related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution.

Methods: We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab-related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18-200).

Results: Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%-49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4-215.6, p = 0.006) and clinical relapses (odds ratio 10.2, 95% CI 1.0-100.1, p = 0.047) that occurred in 13 patients (27%). In all patients, the LGI1 Abs were IgG4 and usually detectable in both serum and CSF (only CSF, 8%). Abs remained positive in serum of 4 of 16 patients with long-term follow-up; 3 of these 4 patients fully recovered and none showed class switch to IgG1.

Conclusions: Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery.

Figure 1. Analysis of IgG subclasses of LGI1 antibodies

Cell-based assay with HEK293 cells showing the 3 different combinations of IgG subclasses among 57 sera examined at disease onset. Each row represents an anti-LGI1–positive serum revealed by a specific secondary antibody against total human IgG (A, E, I), IgG1 (B, F, J), IgG2 (C, G, K), and IgG 4 (D, H, L). The frequency of each IgG subclass combination is shown on the right side of each row. The green signal indicates reactivity against transfected LGI1. Nuclei counterstained with DAPI (4′,6-diamidino-2-phenylindole). Scale bar = 20 μm. IgG = immunoglobulin G.