Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia.

OBJECTIVE: To determine the pathogenic mechanisms of autoantibodies to the cell adhesion molecule Caspr2 in acquired neuromyotonia and autoimmune encephalitis. METHODS: Caspr2-positive samples were confirmed using a cell-based assay, and their IgG subtypes were determined by enzyme-linked immunosorbent assay and cell-based assay. A solid phase binding assay quantified the binding of Caspr2 to contactin-2 in the presence of Caspr2 autoantibodies. Living cultures of primary rat hippocampal neurons were incubated with Caspr2-positive or control sera, and the distribution of Caspr2-positive immunofluorescent puncta and total surface Caspr2 was quantified. HEK cells transfected to express Caspr2 were incubated with Caspr2-positive or control samples, and cell-surface biotinylation and Western blot were used to assess total, internalized, and surface levels of Caspr2. RESULTS: We confirmed 6 samples with strong Caspr2 reactivity. IgG4 Caspr2 antibodies were present in all 6 cases. Caspr2 interacted with another cell adhesion molecule, contactin-2, with nanomolar affinity in the solid phase assay, and Caspr2 autoantibodies inhibited this interaction. Caspr2 autoantibodies did not affect the surface expression of Caspr2 in rat primary hippocampal neurons or transfected HEK cells. INTERPRETATION: Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 but do not cause internalization of Caspr2. Functional blocking of cell adhesion molecule interactions represents a potential mechanism with therapeutic implications for IgG4 autoantibodies to cell adhesion molecules in neurological diseases. Ann Neurol 2018;83:40-51.

Acquired neuromyotonia in childhood: case report and review.

Recently characterized as an immune-mediated channelopaty, Isaacs' syndrome (also known as acquired neuromyotonia) was first described in 1961 in two men with persistent, generalized muscle stiffness, in addition to spontaneous, rapid discharges of motor-unit potentials on electromyography. In the peripheral nervous system, antibodies targeted to voltage-gated potassium channels induce hyperexcitability of motor axons, resulting in signs of muscle stiffness or of pseudomyotonia. A spontaneous burst of single motor-unit activity, and myokymic and neuromyotonic discharges, are the most characteristic features found in electromyography studies. This report describes Isaacs' syndrome in a child, in whom the diagnosis was made by clinical features of acquired, spontaneous muscle overactivity and typical electromyographic findings.