Clinical, Electrophysiologic, and Pathologic Features of Anti-Contactin-Associated Protein 1 Autoimmune Nodopathy.

BACKGROUND AND OBJECTIVES: The significance of anti-contactin-associated protein 1 (Caspr1) antibodies in autoimmune nodopathies (ANs) has not been fully established. The aim of this study was to elucidate the clinical profiles of Caspr1 AN. METHODS: Consecutive serum samples were included from patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) nationwide who were referred to our laboratory for antibody testing with questionnaires as part of routine clinical practice and who fulfilled definite European Federation of Neurological Societies and Peripheral Nerve Society electrodiagnostic criteria. Anti-Caspr1 immunoglobulin (Ig) G was screened using in-house ELISA and confirmed using immunohistochemistry and Western blotting. Clinical data, electrophysiologic findings, and treatment responses were retrospectively collected. The pathologic features of sural nerves were also examined. Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores, antibody titers, and serum neurofilament light chain (NfL) levels were analyzed at baseline and follow-up. RESULTS: Of 559 screened serum samples from patients with CIDP (median age at onset 54 years, 35% female), 19 cases with anti-Caspr1 IgG were identified; the main subclass was IgG4 (17 cases). Patients with IgG4 Caspr1 AN cases exhibited an older age at disease onset (median 67 years); male predominance (82%); high proportions of limb weakness (100%), gait disturbance (100%), tremor (65%), and sensory ataxia (82%); and very high CSF protein levels (249 mg/dL). Nerve conduction studies showed prolonged F-wave and distal motor latencies and reduced sensorimotor conduction velocities in all nerves tested. Light microscopy findings of sural nerve biopsy specimens from 4 patients with Caspr1 AN indicated a loss of myelinated fiber density and myelin ovoids without macrophage-mediated demyelination or onion bulbs. Electron microscopic evaluation demonstrated axo-glial detachment. Patients with IgG4 Caspr1 AN showed a poor response to IVIg (31%) and needed combined immunotherapies. Even after correcting for age, serum NfL levels were higher in patients with IgG4 Caspr1 AN than in healthy controls (p = 0.0609) and correlated with INCAT scores (p = 0.0143). In the 7 patients with 2 consecutive serum samples, antibody titers decreased with clinical improvement. DISCUSSION: IgG4 Caspr1 AN presents with a similar clinical phenotype to other nodopathies (e.g., neurofascin 155 and contactin 1), but with an older age at onset. Changes in antibody titers may be a potential biomarker for monitoring disease activity.