Limbic encephalitis is characterized by the subacute onset, usually <3 months, of memory and cognitive deficits, behavioural changes, and seizures. The most typical deficit is impairment of short-term memory. Brain MRI shows FLAIR and T2 signal abnormalities involving bilaterally, less frequently unilaterally, the hippocampus and amygdala. Limbic encephalitis was initially considered a paraneoplastic syndrome, but after the discovery of several immunological subtypes we now know that >60% of cases are non-paraneoplastic and usually associated to LGI1 antibodies. Paraneoplastic limbic encephalitis mainly associates with small-cell lung cancer and Hu or GABAbR antibodies, testicular seminoma and Ma2 antibodies, Hodgkin disease and mGluR5 antibodies, and thymoma and AMPAR antibodies. Limbic encephalitis may be triggered by treatment of cancer with immune checkpoint inhibitors. The response to immunotherapy and outcome vary according to the type of antibody and presence or absence of an underlying tumour. In patients with antibodies against intracellular antigens (onconeural, AK5), immunotherapy is usually ineffective. In contrast, most patients with LGI1 antibodies show substantial improvement after treatment with steroids and immunotherapy. Patients with cancer and GABAbR or AMPAR antibodies respond better to treatment than those with the same type of cancer and onconeural antibodies, and worse than those of patients with LGI antibodies.

The description of VGKC antibodies detected by radioimmunoassay (RIA) led to mischaracterizing as autoimmune an extensive number of syndromes in many patients who in fact did not have autoimmune disorders. We now know that VGKC antibodies demonstrated by RIA have no clinical value, unless the presence of LGI1 and CASPR2 antibodies are demonstrated by cell-based assays. Limbic encephalitis is by far the most frequent disorder associated with LGI1 antibodies. It usually occurs in the elderly (median age ~65 years) and ~65% are male. Anti-LGI1 encephalitis is frequently preceded by faciobrachial dystonic seizures that are very characteristic of this disorder and should prompt early-onset immunotherapy to prevent the development of memory and cognitive deficits. Most patients do not have cancer or other types of tumours, with the exception of thymoma in a few cases. Patients with CASPR2 antibodies may present with symptoms of encephalitis or peripheral nervous system hyperexcitability (neuromyotonia), and sometimes they develop Morvan syndrome. This disorder is characterized by a severe sleep dysfunction named agrypnia excitata, along with hallucinations, cognitive decline, dysautonomia, and neuromyotonia. Up to 50% of patients with Morvan syndrome have an underlying thymoma. As with other encephalitis associated with antibodies against neuronal surface antigens, patients with encephalitis associated with LGI1 and CASPR2 antibodies usually respond to immunotherapy.