Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features

J Neurol Neurosurg Psychiatry. 2020 Oct;91(10):1076-1084. doi: 10.1136/jnnp-2020-323226. Epub 2020 Jul 10.

Abstract

Objective: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.

Methods: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.

Results: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10-10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).

Interpretation: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Keywords: CASPR2; HLA; Morvan syndrome; limbic encephalitis; neuromyotonia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Ataxia / physiopathology
  • Autoantibodies / immunology*
  • Cluster Analysis
  • DCC Receptor / immunology
  • Epilepsy, Temporal Lobe / physiopathology
  • Executive Function / physiology
  • Female
  • HLA Antigens / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / immunology
  • Isaacs Syndrome / genetics
  • Isaacs Syndrome / immunology
  • Isaacs Syndrome / physiopathology*
  • Limbic Encephalitis / genetics
  • Limbic Encephalitis / immunology
  • Limbic Encephalitis / physiopathology*
  • Male
  • Membrane Proteins / immunology*
  • Memory Disorders / physiopathology
  • Middle Aged
  • Myokymia / genetics
  • Myokymia / immunology
  • Myokymia / physiopathology*
  • Nerve Tissue Proteins / immunology*
  • Phenotype

Substances

  • Autoantibodies
  • CNTNAP2 protein, human
  • DCC Receptor
  • DCC protein, human
  • HLA Antigens
  • Intracellular Signaling Peptides and Proteins
  • LGI1 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins