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Original Investigation |

Characterization of a Subtype of Autoimmune Encephalitis With Anti–Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures

Bastien Joubert, MD1,2,3; Margaux Saint-Martin, MSc2,3; Nelly Noraz, PhD2,3; Géraldine Picard, MSc1; Veronique Rogemond, PhD1,2,3; François Ducray, MD, PhD1,2,3; Virginie Desestret, MD, PhD2; Dimitri Psimaras, MD1,4; Jean-Yves Delattre, MD, PhD1,4; Jean-Christophe Antoine, MD1,5; Jérôme Honnorat, MD, PhD1,2,3
[+] Author Affiliations
1Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.
2Institut NeuroMyoGene, INSERM 1217/CNRS 5310, Université de Lyon, Lyon, France.
3Université Claude-Bernard Lyon 1, Université de Lyon, Lyon, France.
4Département de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
5Service de Neurologie, Hôpital Bellevue, Centre Hospitalier Universitaire de Saint-Étienne, Saint-Étienne, France
JAMA Neurol. 2016;73(9):1115-1124. doi:10.1001/jamaneurol.2016.1585.
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Importance  Autoantibodies against contactin-associated protein-like 2 (CASPR2) are observed in several neurological syndromes, including neuromyotonia (NMT), Morvan syndrome (MoS), and limbic encephalitis.

Objective  To characterize the clinical and biological presentations of patients with anti-CASPR2 antibodies in the cerebrospinal fluid (CSF).

Design, Setting, and Participants  We conducted a retrospective cohort analysis of 18 patients who had anti-CASPR2 antibodies in their CSF between March 2009 and November 2015 at the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques in Lyon, France. Additionally, we analyzed 15 patients who were diagnosed as having NMT or MoS as a comparative group.

Main Outcomes and Measures  Clinical presentations, anti-CASPR2 antibodies specificities, brain magnetic resonance imaging, and CSF analyses, cancer prevalence, and evolution.

Results  In this cohort of 18 patients with anti-CASPR2 antibodies in their CSF, 17 (94.4%) were male and had a median (range) age of 64.5 (53-75) years; in the second group, 9 of 15 patients (60.0%) with NMT or MoS were male and had a median (range) age of 51 years (1 month to 75 years). Only 3 patients (16.7%) in this cohort had a previous or concomitant history of cancer (prostate, hematological, or thyroid), whereas 9 patients (60.0%) in the second group had a malignant thymoma. Symptoms of limbic encephalitis were observed in all patients, including temporal lobe seizures in 16 patients (88.9%) and memory disorders in 17 patients (94.4%) from the cohort. Extralimbic signs were also evident in 12 of 18 patients (66.7%), including cerebellar ataxia in 6 patients (33.3%). Only 2 patients (11.1%) from the cohort were diagnosed as having NMT. Brain magnetic resonance imaging displayed T2-weighted temporolimbic abnormalities in 14 of 15 patients (93.3%) in the second group. Cerebrospinal fluid analysis was abnormal in 9 of 12 patients (75.0%). For 16 of 18 patients (88.9%), follow-up was performed for at least a 6-month period (median [range], 34 [11-114] months). Of these, 15 (93.8%) improved and 6 (37.5%) relapsed. In all patients in this cohort, IgG4 autoantibodies were detected in the CSF. Anti-CASPR2 antibodies in the CSF targeted the laminin G1 and discoidin domains of CASPR2 in all patients. Importantly, anti-CASPR2 antibodies were detected in the serum but not in the CSF of all patients with NMT or MoS.

Conclusions and Relevance  In this cohort study, anti-CASPR2 antibodies in the CSF are associated with a subtype of autoimmune encephalitis with prominent limbic involvement and seizures that is rarely associated with cancer. Conversely, patients with NMT and MoS have anti-CASPR2 antibodies only in the serum but not in the CSF and frequently present with a malignant thymoma. The anti-CASPR2 antibodies found in these patients targeted the discoidin and laminin G1 domains of CASPR2 and always included IgG4 autoantibodies.

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Figure 1.
Fluid-Attenuated Inversion Recovery Imaging of a Patient With Epilepsy, Partial Temporal Seizures, and Anterograde Memory Impairments

In these T2-weighted magnetic resonance images, note the asymmetrical hyperintensities involving both temporomesial regions (arrowheads).

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Figure 2.
Reactivity of Anti–Contactin-Associated Protein-like 2 Antibodies from Patients’ Cerebrospinal Fluid (CSF) With Rat Brain

The CSF of 2 patients was used for immunostaining; fluorescent antihuman IgG mouse antibodies were used as secondary antibodies. Sagittal section of rat brain immunostained with a patient’s CSF (A, dilution 1:10; original magnification × 7). There was diffuse staining of the neuropil that was not observed when rat brain sections were incubated with a control patient’s CSF (B, dilution 1:10; original magnification × 7). Immunoreactivity was particularly strong in the molecular and the granular cell layers of the cerebellum (C; original magnification × 70) and the hippocampus (D; original magnification × 35); in addition, there was diffuse staining of the molecular layer of the dentate gyrus (E; original magnification × 70).

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Figure 3.
CASPR2 Autoantibody Characterization

A, Human embryonic kidney 293 cells were transfected to express the full-length contactin-associated protein-like 2 (CASPR2) protein- or domain-deletion constructs tagged with hemagglutinin (HA), visualized in the first column. The transfected cells were incubated with patients’ cerebrospinal fluid (CSF; dilution 1:10), visualized in the second column. Top left: CASPR2 cells were not recognized in the CSF of any control patients. Bottom left: Constructs only including the discoidin domain (Disc), laminin G1 domain (Lam), or both domains (not shown) were recognized in all 18 samples for patients with CASPR2 cells in the CSF, but the Del1 construct, lacking Disc and Lam, was not recognized in 8 of 18 patients. Top right: Example of 1 of 10 patients in whom the Del1 construct was recognized. Bottom right: Illustration of the different CASPR2 domains deleted in our constructs. B, Human embryonic kidney 293 cells were transfected with the HA-tagged full-length CASPR2 protein and incubated with patients’ CSF (dilution 1:10) to determine the IgG isotypes of CASPR2 autoantibodies. We observed 10 of 17 patients with both IgG4 and IgG1 antibody subtypes (left panel), but only IgG4 antibodies were observed in the remaining 7 patients (right panel).

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