Serum Autoantibody Titers and Neurofilament Light Chain Levels in CASPR2/LGI1 Encephalitis: A Longitudinal Study

Abstract

Background and objectives: Autoantibodies against contactin-associated protein-like 2 (CASPR2-IgG) and leucine-rich glioma inactivated 1 protein (LGI1-IgG) identify a subgroup of autoimmune encephalitis (AE). Up to 65% of patients with LGI1/CASPR2 AE show cognitive sequelae that are unpredictable at onset. We aimed to assess the clinical relevance of serum autoantibody titers and neurofilament light chain (NfL) levels as biomarkers in CASPR2/LGI1 AE.

Methods: We selected consecutive CASPR2/LGI1-IgG-positive patients with at least 2 longitudinal serum samples obtained more than 60 days apart. Samples were defined as acute (first diagnostic evaluation after onset or relapse and before immunotherapy) and remission (>2 months from attack). CASPR2/LGI1-IgG was titered with a live cell-based assay. Functional outcome was measured using modified Rankin Scale and Clinical Assessment Scale in AE and cognitive impairment using Montreal Cognitive Assessment (MoCA).

Results: We included 23 patients (LGI1 = 15, CASPR2 = 7, CASPR2/LGI1 = 1) with 130 serum samples (acute = 32; remission = 98). Serum titers in the acute phase were higher than in remission and decreased over time and after immunosuppressive treatment. In 9 of 10 patients, relapses occurred with seropositive samples, and in 4 of 5 patients, these occurred with increased titers. Onset titers did not correlate with functional/cognitive outcome at follow-up.Serum NfL median levels in both patients with LGI1 AE (35.3 pg/mL, range: 5.4-164) and CASPR2 AE (31.4 pg/mL, range: 9.11-120) were higher than in age/sex-matched controls (14.55, range: 5.4-56.8, p = 0.004 and p < 0.001, respectively). Acute-phase samples had higher NfL median levels (47.2, range: 9.11-120) compared with remission (31.2 pg/mL; range, 5.4-114, p = 0.02). NfL levels at onset predicted lower MoCA scores at follow-up in univariate linear regression analysis (B = -3.881, p = 0.0256). NfL levels decreased over time, but at the last follow-up remained higher than those in controls (p = 0.02).

Discussion: Measuring LGI1 and CASPR2-IgG titers in AE could help to confirm the disease stage and define relapses but has no prognostic implications. Serum NfL at onset could be used to identify patients at higher risk of cognitive sequelae that might deserve tailored management.

Figure 1. CASPR2/LGI1-IgG Titers in AE and Across Disease Phases

CASPR2-IgG (blue dots) and LGI1-IgG (yellow dots) titers in the whole patients' cohort (A). CASPR2/LGI1-IgG (purple dots) titers in acute and remission disease phases (B). Red dotted lines indicate positivity cutoff for LGI1-IgG (1:20 dilution) and for CASPR2-IgG (1:100 dilution). ***: p < 0.001. AE = autoimmune encephalitis.

Figure 2. CASPR2/LGI1-IgG Titers Over Time and Treatment

CASPR2-IgG (blue lines) and LGI1-IgG (yellow lines) titers in relationship with the following variables: time points, at onset and longitudinal follow-ups (A); relapses (B); before vs after rituximab (Rtx) treatment (C); or before vs after azathioprine (Aza) treatment (D). Time points are 4 = 4 ± 2 months, 6 = 6 ± 2 months, 9 = 9 ± 2 months, 10 = 10 ± 3 months, late follow-up (Late-Fu; a sample collected at least 20 months after onset), and relapse (Rel). The crux identifies the CASPR2/LGI1-IgG double-positive patient.

Figure 3. Serostatus and Relapses

Serostatus and relapses in patients with CASPR2 AE (blue lines) and LGI1 AE (yellow lines). Red circles indicate relapses. Red rhombi indicate a positive CASPR2/LGI1-IgG sample. Green rhombi indicate a negative CASPR2/LGI1-IgG sample. The crux identifies the CASPR2/LGI1-IgG double-positive patient. AE = autoimmune encephalitis.

Figure 4. Serum NfL Levels in Patients With AE and Controls, Across Disease Phases and at Follow-Up

Serum NfL levels in patients with CASPR2 AE (blue dots/lines), patients with LGI1 AE (yellow dots/lines), in neurodegenerative (patients with amyotrophic lateral sclerosis [ALS] and progressive multiple sclerosis [P-MS]) (red dots) and healthy controls (HCs) (black dots) (A), in CASPR2/LGI1 AE (purple dots) acute and remission disease phases (B), at onset and longitudinal follow-up time points (C), and as measured at late follow-ups vs healthy controls (D). Red dotted lines at 5.4 pg/mL indicate the lowest threshold for NfL quantification. AE = autoimmune encephalitis; NfL = neurofilament light chain.

Figure 5. Serum NfL Levels at Onset in Relation to Disability and Cognitive Outcomes

NfL levels at onset in patients with CASPR2 AE (blue dots) and LGI1 AE (yellow dots) do not correlate with modified Rankin Scale (mRS) (A) and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) (B) at follow-up but inversely correlate with Montreal Cognitive Assessment (MoCA) (C) obtained at follow-up. AE = autoimmune encephalitis; NfL = neurofilament light chain.