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.

Seizures are common in all types of autoimmune encephalitis, but their frequency and severity are particularly relevant in anti-NMDAR, anti-GABAbR, anti-GABAaR, and anti-LGI encephalitis. Seizures occur in>70% of patients in the acute phase of anti-NMDAR encephalitis without specific or distinctive features that may suggest this disorder. In anti-GABAbR and particularly anti-LGI1 encephalitis, seizures may precede in weeks the development of cognitive and psychiatric symptoms. Faciobrachial dystonic seizures (FBDS) are very typical of anti-LGI1 encephalitis and their recognition is important to make an early diagnosis. New-onset refractory status epilepticus (NORSE) is a clinical presentation of epilepsy that occurs in patients without previous history of seizures. When NORSE is preceded by a febrile episode, the term FIRES (febrile infection-related epilepsy syndrome) is frequently used, particularly in the paediatric literature. FIRES is considered a subtype of NORSE that may occur at any age. Only a small number of patients with anti-NMDAR or anti-GABAbR encephalitis presents as NORSE. The term FLAMES (FLAIR-hyperintense Lesions in anti-MOG associated encephalitis with seizures) has been used to describe the encephalitis of some patients with MOG antibodies. The clinical presentation includes seizures associated with isolated or predominantly unilateral cortical hyperintense lesions in FLAIR MRI images.

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.

This chapter focuses on the MOG-antibody-associated disease as a distinct neurological disorder that includes several demyelinating syndromes, and it follows a monophasic or more frequently a relapsing–remitting course. In children, MOG antibody-associated disease usually presents as acute disseminated encephalomyelitis (ADEM), ADEM variants, or encephalitis that may present with seizures and isolated or predominant cortical hyperintense lesions in FLAIR MRI studies (FLAMES). In teenagers and adults the common clinical presentation is optic neuritis, myelitis, or brainstem syndromes. Some of the patients fulfil criteria of neuromyelitis optica spectrum disorders (NMOSD). Persistence of MOG antibodies is common in patients with relapses. The optimal treatment to prevent relapses has not been established. ADEM is the most frequent autoimmune encephalitis in children. The syndrome was characterized before the description of MOG antibodies and associates with distinct clinical and neuroimaging features. Brain MRI shows multiple hyperintense T2 lesions similar to those seen in anti-GABAaR encephalitis. As occur with NMOSD, ADEM is probably caused by different pathogenic mechanisms as MOG antibodies are only found in ~60% of patients. Besides MOG antibody-associated disease there are two other antibody-associated neurological syndromes that target oligodendrocytes as part of an immune attack: anti-NMDAR encephalitis and paraneoplastic encephalomyelitis with CRMP5 antibodies.