About 20 years ago the group of diseases currently known as ‘autoimmune encephalitis’ or ‘antibody-mediated encephalitis’ was unknown and the entire field of ‘autoimmune neurology’ non-existent. Since then, 18 autoimmune encephalitis and the corresponding syndromes have been described, including 16 in which the antigens are expressed on the cell surface of neurons and two on the surface of glial cells. The characterization of these autoimmune encephalitis was facilitated by the cumulative knowledge provided by research on autoimmune disorders of the neuromuscular junction (myasthenia gravis and Lambert–Eaton myasthenic syndrome) and the paraneoplastic neurological syndromes. Up to 12.6 per 100,000 persons are affected by encephalitis annually. Of these, it has been estimated that 20–30% are caused by autoimmune mechanisms. In children the most frequent types of autoimmune encephalitis are acute disseminated encephalomyelitis (ADEM), anti-MOG, and anti-NMDAR encephalitis. In young adults, particularly women, anti-NMDAR encephalitis, and in late adulthood, anti-LGI1 encephalitis, are the most prevalent autoimmune encephalitis. The most frequently used classifications combine information related to three features: mechanisms of disease (cytotoxic T cell or antibody-mediated mechanisms), type of antigen (intracellular vs cell surface), and presence or absence of a tumour. The detection of a neoplasm frequently serves to categorize the autoimmune encephalitis as paraneoplastic.

In this chapter we have selected relevant questions that over the years many colleagues have asked us at conferences or in consultations. Some answers are straightforward, but others are difficult because they reflect grey areas in our knowledge of autoimmune encephalitis that require further research. The chapter includes 90 questions covering 14 general topics: definitions and general concepts, diagnostic issues, pathogenesis and mechanisms of disease, limbic encephalitis, anti-NMDA receptor encephalitis, autoimmune cerebellar/brainstem encephalitis, autoimmunity against the inhibitory synapses, neurological syndromes and glial antibodies, autoimmune and inflammatory encephalopathies as a complication of cancer treatment, autoimmunity and psychiatric manifestations, seizures and autoimmunity, autoimmunity and sleep, abnormal movements in neurological autoimmune disorders, and CNS syndromes at the frontier of autoimmune encephalitis. The answers are short, and we strongly recommend readers go to the suggested sections in the book and read the related references, where more comprehensive answers can be found.

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 diagnosis of autoimmune encephalitis should be considered in patients with rapid progression (<3 months) of short-term memory loss, decreased or altered level of consciousness, lethargy, personality change, or psychiatric manifestations in association with at least one of the following criteria: new-onset seizures or focal CNS symptoms, CSF pleocytosis, or MRI features suggestive of brain inflammation. Many alternative causes of encephalitis can be excluded after a careful clinical history and evaluation of the CSF, brain MRI, and routine blood tests. Some types of encephalitis can be suspected before receiving the results of neural antibodies, according to the clinical presentation (for instance, faciobrachial dystonic seizures in anti-LGI encephalitis, or psychotic manifestation in anti-NMDAR encephalitis) or brain MRI features (temporal lobe involvement in limbic encephalitis). Antibody testing may show false positive and negative results, particularly when only serum is examined, results are not confirmed with additional laboratory studies, or the test is used indiscriminately without selection of patients.

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.