Different pain phenotypes are associated with anti-Caspr2 autoantibodies

Abstract

Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.

Keywords: Autoantibody; Caspr2; IgG subclass; IgG4; Pain.

Fig. 1

Flow chart illustrating the composition of the study cohort. The whole cohort can be divided into painless and painful phenotypes, patients with painful disease were further subdivided into two clusters

Fig. 2

Patient anti-Caspr2 autoantibodies show distinct IgG subclass pattern independent of the pain phenotype. HEK293 cells were transfected with human Caspr2. A Caspr2 was stained with a commercial antibody (1:250; cyan; upper left image). Secondary FITC-coupled IgG subclass antibodies (IgG1-4) were tested with healthy control (HC, 1:250) serum instead of patient (pat) serum as negative controls (upper lane, right images). Representative images following incubation with human patient serum 13 (1:250) detected by secondary antibodies against total human IgG (red; lower left image). Serum of patient 13 (1:50 for subclass determination) was positive for all four IgG subclasses but with different intensities (IgG3 < IgG1 < IgG2 = IgG4; cyan, lower right images). DAPI marks the nuclei. Scale bar refers to 10 µm. B Intensity plot of IgG subclass determination from all patients (40 total) investigated. Intensities were classified from 0–1-2–3 (white—light blue—blue—dark blue; no staining—very weak but visible staining—intense staining—very intense staining). Note, almost all sera contained Caspr2 autoantibodies of subclass IgG4. In (C), the probability of different variables of cluster analysis in cluster 1 and 2 is depicted. Patients of cluster 1 suffer from mostly distal burning and tingling pain that is increased by exercise and cold whereas cluster 2 is characterized by widespread pain, myalgia and cramps. pat patient, HC healthy control