In this chapter we critically trace the concept of autoimmune psychosis, and review several well-defined autoimmune diseases that can manifest with psychosis. After the discovery of anti-NMDAR encephalitis, several studies suggested that NMDAR antibodies could occur in patients with psychosis caused by primary psychiatric diseases. This led to a generalized NMDAR antibody testing without much consideration for validation of results, the use of appropriate controls, or whether the antibodies were also present in CSF (most studies only partially examined serum). Two consequences of this uncontrolled testing were: (1) the wide range in prevalence of serum NMDAR antibodies (from 0% to 20% in patients with many different diseases, including healthy controls) among different laboratories often using the same commercial diagnostic test; and (2) the lack of clinical significance of the findings. These inconclusive studies refocused the attention of investigators to search for a specific psychiatric phenotype of anti-NMDAR encephalitis, but no specific phenotype could be identified. However, there are several important clinical clues that suggest when a first episode of psychosis is autoimmune, and we provide a diagnostic algorithm to identify these cases. Aside from anti-NMDAR encephalitis, psychiatric manifestations are prominent in three other disorders: paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), Hashimoto encephalopathy, and neuropsychiatric manifestations of systemic lupus erythematosus (SLE). In the first two disorders the autoimmune basis is unclear and no pathogenic antibodies have been identified. In SLE, none of the antibodies reported to be associated with neuropsychiatric manifestations has shown neuropsychiatric symptom specificity. Moreover, none of the SLE antibodies has shown properties similar to those of neuronal surface antibodies related to autoimmune encephalitis, which associate with specific syndromes, alter neuronal function by direct interaction with the cell surface target, and cause symptoms in animal models, including psychotic-like behaviour.

This chapter focuses on how to recognize anti-NMDAR receptor encephalitis at early stages, when most patients have pure or predominant psychiatric symptoms. We also discuss the differential diagnosis with schizophrenia, acute-onset psychosis, and neuroleptic malignant syndrome, and formulate a general diagnostic and treatment approach to psychiatric symptoms. Anti-NMDAR encephalitis manifests with a wide range of psychiatric symptoms, indistinguishable from that of schizophrenia and other psychiatric diseases, and with a spectrum of psychiatric manifestations that varies according to the stage of the disease. However, >95% of patients develop at early stages of the disease (days or weeks after onset of psychiatric symptoms or concomitant with them) neurological symptoms such as seizures, decreased verbal output, abnormal movements, or dysautonomia. This combination of symptoms usually suggest the diagnosis and prompts NMDAR antibody testing, which should be performed in CSF. The symptomatic treatment of the psychiatric manifestations is largely based on expert opinions, suggesting that conventional antipsychotic drugs should be avoided due to the susceptibility of these patients to developing neuroleptic malignant syndrome. It is unclear whether atypical antipsychotics are associated with lower frequency of these adverse effects, but they are more frequently used. A study suggested that all types of antipsychotic drugs carry a similar enhanced risk of adverse effects, although other studies, and our own experience, suggest that atypical antipsychotics are associated with less adverse effects.

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.

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.