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.
- limbic encephalitis
- Morvan syndrome
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SM-C and BJ contributed equally.
Contributors Conception and design of the study and drafting the manuscript and figures: SM-C, BJ and JH. Acquisition and analysis of data: all authors.
Funding This study is supported by research grants from ANR (ANR-14-CE15-0001 MECANO) and Fondation pour la recherche medicale DQ20170336751. This work has been developed within the BETPSY project, which is supported by a public grant overseen by the French National Research Agency (ANR), as part of the second ‘Investissements d'Avenir’ program (reference ANR-18-RHUS-0012). SM-C is supported by a research a grant from Fundación Alfonso Martín Escudero (Spain).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Institutional Review Board of Université Claude Bernard Lyon 1 and Hospices Civils of Lyon approved the study (ICARE NCT-04106596).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data reported in this manuscript are available within the article. More information regarding the data is available from the corresponding author on reasonable request. Individual data will not be shared to conform to the privacy statement signed by the patients.
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