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.

In this chapter we describe different types of movement disorders that associate with autoimmune encephalitis, and the antibodies more frequently involved. In children the most common disorders are Sydenham chorea and anti-NMDAR encephalitis. Abnormal movements occur in ~80% of patients with anti-NMDAR encephalitis and include multiple different types such as chorea, oromandibular dystonia, stereotypies, opistotonus, catatonia, or myorhythmia. Children who develop anti-NMDAR encephalitis as a complication of previous herpes simplex viral encephalitis present prominent generalized chorea or choreoathetosis. In adults the most frequent autoimmune neurological disease that associates with movement disorders is anti-IgLON5 disease. More than 80% of patients this disease develop at least one type of movement disorder; gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea are the most common combination of movement disorders. Hyperekplexia is a major manifestation of progressive encephalomyelitis with rigidity and myoclonus (PERM), which is usually associated with glycine receptor antibodies; some patients with similar symptoms have DPPX antibodies. Autoimmune chorea in adults may also be a paraneoplastic manifestation of small-cell lung cancer and CRMP5 antibodies. The most common paroxysmal abnormal movement of autoimmune origin is faciobrachial dystonic seizures associated with LGI1 antibodies. Patients with anti-CASPR2 encephalitis may have paroxysmal episodes of cerebellar ataxia that precede the encephalitis. Anti-CASPR2 encephalitis can also cause orthostatic myoclonus.

Anti-IgLON5 disease is a neurological disorder that associates with antibodies against IgLON5, a neuronal cell-adhesion protein of unknown function. Most patients develop a combination of prominent sleep alterations (non-rapid eye movement (NREM) and REM parasomnias with obstructive sleep apnoeas), bulbar dysfunction (dysarthria, dysphagia, vocal cord palsy, or episodes of respiratory failure), and gait instability. Initial autopsy studies showed deposits of phosphorylated tau protein predominantly in neurons of the tegmentum of the brainstem, suggesting a primary neurodegenerative disease. However, findings in subsequent studies have provided increasing support to an immune-mediated pathogenesis. First, there is a strong association with the human leukocyte antigen (HLA) haplotype DRB1*10:01–DQB1*05:01 which is present in ~60% of patients (compared to 2% in the normal population); second, recent autopsy studies showed absence of abnormal deposits of tau; and third, in live neurons in culture, IgLON5 antibodies cause an irreversible loss of surface IgLON5 clusters and changes in the cytoskeleton such as dystrophic neurites and axonal swellings. Taken together, these studies suggest that an antibody-mediated disruption of IgLON5 function leads to neurofilament and cytoskeletal alterations that can potentially result in tau accumulation.

This chapter focuses on several types of sleep disorders in patients with autoimmune encephalitis, including narcolepsy, REM sleep behaviour disorder (RBD), NREM sleep parasomnias, and central and obstructive sleep apnoeas. Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness and severe and irresistible episodes of daytime sleep. Narcolepsy is caused by a T cell-mediated destruction of hypocretin-synthetizing neurons located in the hypothalamus. Patients with anti-NMDAR encephalitis develop severe insomnia at disease onset, and many of them have hypersomnia after the acute stage of the disease or during clinical recovery. Patients with anti-LGI1 encephalitis frequently develop REM sleep behaviour disorder. Patients with Morvan syndrome and CASPR2 antibodies present a sleep disorder called agrypnia excitata that consists of severe insomnia, motor and sympathetic hyperactivity, quasi-purposeful movements, and enacted dreams in the setting of loss of slow-wave sleep and circadian rhythmicity. Sleep alterations occur in >80% of patients with anti-IgLON5 disease; the most characteristic are sleep apnoeas and non-REM and REM parasomnias. Symptoms of excessive daytime sleepiness, sometimes with findings suggestive of narcolepsy, were reported in about 30% of patients with paraneoplastic anti-Ma2 encephalitis, and less frequently in patients with neuromyelitis optica spectrum disorders associated with aquaporin 4 antibodies.