Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

Area of Science:

• Neuroimmunology
• Neurology
• Clinical Medicine

Background:

• Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) are associated with acquired neuromyotonia, limbic encephalitis (LE), and Morvan syndrome (MoS).
• The relationship between these conditions and their underlying immunopathogenesis remains unclear, questioning if they represent a single disease spectrum or distinct entities.

Purpose of the Study:

• To investigate whether CASPR2-Abs define a single disease spectrum or distinct clinical entities.
• To differentiate the immunopathogenesis of acquired neuromyotonia, limbic encephalitis, and Morvan syndrome.

Main Methods:

• Retrospective analysis of neurological symptoms in 56 CASPR2-Abs patients using cluster analysis.
• Parallel investigation of immunological features, including human leucocyte antigen (HLA) typing.
• Comparison of clinical phenotypes, serum antibody titers, and cerebrospinal fluid positivity rates.

Main Results:

• Cluster analysis identified two main groups: limbic-predominant (LE) and peripheral nerve hyperexcitability (PNH).
• LE patients (n=29) showed homogeneous immunogenetic characteristics, with a strong association with HLA-DRB1*11:01 and high CASPR2-Ab titers.
• PNH patients (n=27) were further divided; PNH/+ patients (n=16) showed distinct oncological (malignant thymoma) and immunological associations (LGI1-Abs, DCC-Abs, myasthenia gravis), differing from LE and milder PNH/- cases.

Conclusions:

• Clinical and immunogenetic findings support distinct phenotypes for LE and MoS, suggesting different etiopathogeneses.
• Limbic encephalitis represents a homogeneous entity associated with specific HLA and high CASPR2-Ab titers.
• Morvan syndrome, particularly the PNH/+ subtype, is linked to distinct oncological and autoimmune comorbidities, indicating a separate pathogenic mechanism.