Taken together, we provide evidence in vitro and in vivo that patientderived CASPR2 mAbs are directly pathogenic, can bind to the discoidin domain of CASPR2 with affinities in the pico- to nanomolar range, interfere with CASPR2/contactin 2 binding, and lead to robust changes in rodent models of CASPR2 encephalitis including hyperexcitability and widespread reduced functional connectivity. Here, CNTNAP2 is linked to viral encephalitis.