Clinical Insights Into CASPR1 and CASPR1/Contactin-1 Complex Autoimmune Nodopathies

Background and Objectives Clinical phenotypes of neuropathies associated with contactin-associated protein-1 (CASPR1) or isolated CASPR1/contactin-1 (CNTN1)-complex-IgG are not well characterized, and we aimed to describe the same. Methods Patient sera positive for CASPR1 or CASPR1/CNTN1-complex-IgG by cell-based assay (CBA) at Mayo Clinic Neuroimmunology Laboratory (January 1, 2010–May 31, 2024) was identified retrospectively and prospectively. Clinical and paraclinical data were collected. CASPR1/CNTN1-complex-IgG–positive sera were tested using tissue indirect immunofluorescence assay, murine teased nerve fibers, and ELISAs for CASPR1 and CNTN1 to elucidate antigenic targets. Patients were compared with CNTN1-IgG and NF155-IgG4 autoimmune nodopathy cohorts. Results Among 17 CASPR1 or isolated CASPR1/CNTN1-complex-IgG–seropositive patients identified, 14 had clinical data (CASPR1-IgG = 8 [50% males, median age 50 years], CASPR1/CNTN1-complex-IgG = 6 [67% males, median age 42 years]). Neuropathic pain was more common in CASPR1-IgG (88% vs 33%), while sensory ataxia was more frequent in CASPR1/CNTN1-complex-IgG cases (100% vs 75%). All showed primarily demyelinating electrophysiology (1 CASPR1/CNTN1-complex-IgG case presented as chronic inflammatory sensory polyradiculopathy). Intravenous immunoglobulin (IVIg) refractoriness occurred in 63% of CASPR1-IgG and 40% of CASPR1/CNTN1-complex-IgG. Rituximab was effective in 6 of 7 (86%) treated patients. One patient with CASPR1/CNTN1-complex-IgG who was refractory to multiple immunotherapies underwent allogenic hematopoietic stem cell transplant after which she was off immunotherapies and is in sustained remission for the past 10 years. CASPR1-IgG patients progressed faster to nadir than NF155-IgG4 ( p = 0.003). CASPR1/CNTN1-complex-IgG patients had more frequent asymmetric onset ( p = 0.009) and greater long-term disability than NF155-IgG4 ( p = 0.035). Five of the 7 CASPR1-IgG patients had IgG4 antibodies, compared with 2 of the 5 CASPR1/CNTN1-complex-IgG patients. Four isolated CASPR1/CNTN1-complex-IgG sera tested positive by tissue immunofluorescence assay; 3 also bound paranodes on teased nerve fibers. CASPR1-IgG cases had higher titers compared with CASPR1/CNTN1-complex-IgG cases by CBA. Three of the 5 CASPR1/CNTN1-complex-IgG cases had CASPR1-IgG reactivity by ELISA, while the other 2 were negative by both CASPR1 and CNTN1 ELISA. Discussion CASPR1-IgG and CASPR1/CNTN1-complex-IgG neuropathies, though rare, usually have a rapidly progressive course. Both are frequently IVIg-refractory and respond to rituximab. Compared with NF155-IgG4 nodopathies, CASPR1-IgG exhibits faster progression, while some CASPR1/CNTN1-complex-IgG nodopathies can cause greater long-term disability.