This chapter critically reviews the diagnostic criteria of Hashimoto encephalopathy (HE) and the misuse of this diagnosis. HE is usually considered in patients with subacute cognitive deterioration, myoclonus, change in behaviour, or seizures, accompanied by normal or non-specific MRI and CSF findings, normal thyroid function or mild hypothyroidism, increased serum levels of thyroid peroxidase (TPO) antibodies, and clinical response to steroids. The beneficial effect of steroids was emphasized by renaming the disease ‘steroid-responsive encephalopathy associated with autoimmune thyroiditis’ (SREAT). However, the diagnosis of HE has several important limitations. One is that there are no specific biomarkers of the disease. Moreover, the specificity of TPO antibodies is poor as they are also found in 13% of healthy persons. The significance of antibodies against the amino (NH2)-terminal domain of α-enolase, considered a potential biomarker of HE, is also unclear. Another limitation is that the diagnostic confirmation of HE depends on steroid-responsiveness. However, the clinical criteria and paraclinical findings do not identify the patients that will respond to steroids (<30%). Finally, most patients reported with HE are not investigated for neuronal surface antibodies. Overall, the weaknesses of the criteria and their misuse characterizing as HE any neurological syndrome with positive TPO antibodies that responds to steroids, raise doubts about the clinical usefulness of the term HE.

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.

In this chapter we review the CNS syndromes mediated by autoimmune or inflammatory mechanisms in patients with cancer. Paraneoplastic neurological syndromes (PNS) are considered to be immune-mediated disorders against proteins expressed by the tumour and nervous system. The autoimmune hypothesis is supported by the presence in serum and CSF of antibodies against neural proteins that are also expressed in the tumour. Less frequently the tumour does not express neuronal proteins but predisposes to immune dysregulation and autoimmune mechanisms. Novel cancer therapies that enhance anti-tumour immune responses frequently cause inflammatory CNS disorders. Immune checkpoint inhibitors have been associated with a wide range of immune-related adverse effects, including an increased incidence of PNS. Another type of cancer therapy is based on the use of T cells genetically engineered to express chimeric antigen receptors (CARs) that recognize molecules present on the surface of tumour cells. CAR T cell therapy can cause severe, potentially lethal, encephalopathy syndromes mediated by massive release of cytokines instead of autoimmune mechanisms. Post-transplant autoimmune encephalitis are rare disorders that mostly occur after allogeneic haematopoietic stem cell transplantation. They are related to graft versus host disease and, sometimes, they associate with antibodies against neuronal surface antigens.

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.

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.

In this chapter we review the inflammatory mechanisms involved in epileptogenesis, the caveats and limitations of the term autoimmune epilepsy, and two epileptic syndromes of autoimmune origin: epilepsy associated with GAD antibodies and Rasmussen encephalitis. The International League Against Epilepsy (ILAE) recently proposed the definition of acute symptomatic seizures secondary to autoimmune encephalitis for the seizures that occur in the setting of the active phase of immune-mediated encephalitis. In contrast, the term autoimmune epilepsy applies to chronic seizures considered to be secondary to autoimmune brain diseases. If promptly diagnosed and treated, patients with symptomatic seizures due to antibody-mediated encephalitis rarely evolve to develop epilepsy and, therefore, they do not fulfil criteria of autoimmune epilepsy. Scoring systems to predict autoimmune seizures are not very useful because they rely on the presence of additional neurological manifestations or diagnostic tests included in the definition of autoimmune encephalitis. Antibodies against neuronal surface antigens occur in a minority (<5%) of patients with isolated epilepsy; the significance of these antibodies is unclear as the spectrum of symptoms of these patients is not different from that of seronegative cases. In contrast, antibodies against GAD (an intracellular protein) occur in a small subset of patients with temporal lobe epilepsy that is usually refractory to anti-seizure medication.

Anti-NMDAR encephalitis is the most frequent autoimmune encephalitis. It predominantly occurs in children and young females. Up to 80% of patients present with severe insomnia and psychiatric and behavioural symptoms that resemble those of psychotic episodes caused by primary psychiatric diseases. In addition to the psychiatric manifestations, patients develop neurological symptoms including seizures, abnormal movements, reduced verbal output, and dysautonomic features. Up to 50% of young females have an underlying ovarian teratoma that contains nervous tissue and NMDAR, which probably trigger the immune response. Less frequently, the encephalitis is triggered by an episode of herpes simplex encephalitis probably through the release of antigens by neurons damaged by the virus. The diagnosis of anti-NMDAR encephalitis requires the demonstration of the antibodies in CSF. Up to 14% of patients do not have detectable antibodies in serum. A positive result in serum but negative in CSF must be taken with caution as these patients do not present clinical features of encephalitis and many represent false positive results. Between 80% and 90% of patients respond to treatment which includes immunotherapy and removal of the tumour when it applies.

Some types of autoimmune encephalitis associate with distinct HLA haplotypes that likely predispose to the disease (e.g., anti-LGI1 encephalitis or anti-IgLON5 disease). In other instances the autoimmune mechanisms are triggered by tumours that express the neuronal antigen (e.g., small-cell lung cancer and anti-GABAbR encephalitis), or tumours that cause an immune dysregulation (thymoma and anti-GABAaR or anti-AMPAR encephalitis), or viral encephalitis that lead to neuronal destruction and release of antigens (e.g., herpes simplex encephalitis triggering autoimmune encephalitis with NMDAR or GABAaR antibodies). In most autoimmune encephalitis the pathogenic antibodies are IgG1 and cause symptoms by internalization of the target antigen (anti-NMDAR encephalitis) or antibody-mediated complement activation and cellular injury (aquaporin 4 antibodies in neuromyelitis optica spectrum disorders). Direct functional blocking of the antigen has been demonstrated for glycine receptor antibodies and probably GABAbR antibodies. Some autoimmune encephalitis (e.g., anti-LGI1 or CASPR2 encephalitis, anti-IgLON5 disease) associate with predominant IgG4 antibodies that disrupt normal protein–protein interactions. Confirmation of antibody pathogenicity requires that in passive transfer experiments of patients’ antibodies to animals, the antibodies bind to the target neural antigen, alter the structure or function of the antigen, and result in clinical symptoms.

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.

Antibodies against cell surface antigens (neuronal or glial) usually recognize conformational epitopes. Therefore, these antibodies can only be detected by techniques that preserve the native conformation of the target antigen, for instance, indirect immunofluorescence with tissue adapted to cell surface or synaptic proteins, cultured neurons, cells transfected with the antigen, or radioimmunoassay. Studies using in-vitro models or passive transfer of antibodies to experimental animals strongly suggest that these antibodies are pathogenic. Some antibodies frequently occur in encephalitis associated with cancer (for example, anti-GABAbR antibodies and small-cell lung cancer), but the incidence of cancer is usually lower than that observed in patients with onconeural antibodies. Two antibodies against surface antigens, DNER (Tr) and amphiphysin, are exceptions to the characteristics mentioned above as they recognize linear epitopes and are considered biomarkers of paraneoplastic neurological syndromes associated with Hodgkin lymphoma (DNER) or small-cell lung cancer (amphiphysin). Antibodies against AMPAR, GABAbR, and LGI1 usually associate with limbic encephalitis. Other antibodies characteristically associate with distinct syndromes, for example, anti-NMDAR encephalitis that manifests with a highly characteristic neuropsychiatric syndrome; CASPR2 antibodies that can manifest as Morvan syndrome; aquaporin 4 antibodies that typically associate with neuromyelitis optica spectrum disorders, and glycine receptor antibodies that predominantly associate with progressive encephalomyelitis with rigidity and myoclonus (a disorder in the spectrum of stiff-person syndrome). Antibodies against GABAaR, MOG, and GluK2 subunit of the kainate receptor occur with different types of encephalitis characterized by multiple FLAIR/T2 hyperintense lesion in the brain MRI.

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.

In this chapter, two autoimmune disorders against astrocytes are reviewed: neuromyelitis optica (NMO), recently renamed NMO spectrum disorders (NMOSD) which frequently associates with antibodies against AQP4; and a meningoencephalitis without specific clinical or brain MRI features, which occurs in association with antibodies against glial fibrillary acidic protein (GFAP) that are mainly detected in CSF. NMOSD should be considered a syndrome rather than a disease because it associates with different antibodies and pathogenic mechanisms. In epidemiological studies, 73% of patients with NMOSD have aquaporin 4 (AQP4) antibodies whereas 12% harbour myelin oligodendrocyte glycoprotein (MOG) antibodies and 15% are seronegative. The diagnosis of NMOSD is based on clinical and laboratory criteria that require the presence of one or two core clinical syndromes, depending on the positivity of AQP4 antibodies. Relapses in NMOSD are common and several treatments with monoclonal antibodies have shown efficacy, including the following targets: the C5 complement protein (eculizumab), the interleukin 6 receptor (satralizumab), and the CD19 B cell receptor (inebilizumab). The pathogenic role of AQP4 antibodies is supported by the neuropathological findings in patients with NMOSD, and by in-vitro studies and passive transfer of antibodies to experimental animals.

Antibodies against neural intracellular antigens have been classified in three groups: (1) markers of paraneoplastic neurological syndromes (onconeural antibodies) and therefore the presence of an underlying cancer; (2) markers of non-paraneoplastic neurological syndromes; and (3) markers of autoimmune retinopathies. All antibodies against neural intracellular proteins recognize linear epitopes, are detected by immunoblot, and are considered non-pathogenic. An exception is the amphiphysin antibodies that can potentially reach the antigen that is briefly exposed to the extracellular space during the process of synaptic vesicle recycling. The most common onconeural antibodies are Hu (markers of paraneoplastic neurological syndromes associated with small-cell lung cancer), Yo (paraneoplastic cerebellar degeneration and breast and ovarian cancer), and Ma2 (limbic and brainstem encephalitis with testicular seminomas). The two most common antibodies present in non-paraneoplastic CNS syndromes are glutamic acid decarboxylase (GAD) and glial fibrillary acidic protein (GFAP) antibodies. GAD antibodies are biomarkers of stiff-person syndrome and also occur in some patients with cerebellar ataxia or drug-resistant temporal lobe epilepsy. GFAP antibodies associate with meningoencephalitis and a broad spectrum of symptoms without a clear specific syndrome. Unlike the other antibodies against intracellular antigens that are usually detectable in serum and CSF, GFAP antibodies are predominantly detected in CSF.

Brainstem encephalitis represents around 20% of all cases of encephalitis and has unique clinical and epidemiological features. The best-characterized brainstem encephalitis include opsoclonus-myoclonus syndrome (OMS), Bickerstaff encephalitis, paraneoplastic brainstem encephalitis, and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). The main causes of OMS are paraneoplastic, post-infectious, and idiopathic; it is likely that they share an immune-mediated pathophysiology, although neuronal antibodies only occur in a subgroup of patients with OMS and breast cancer who develop Ri antibodies. Other paraneoplastic brainstem encephalitis can associate with Ma2 and Hu antibodies. Patients with Bickerstaff encephalitis frequently develop overlapping features with Miller–Fisher syndrome (characterized by bilateral ophthalmoplegia, ataxia, and areflexia). The identification of GQ1b antibodies in both disorders suggests that they are part of the same spectrum of disease that has been designated anti-GQ1b syndrome. The diagnosis of CLIPPERS is mainly based on the presence of suggestive brain MRI abnormalities. However, similar MRI lesions can occur in systemic autoimmune diseases that may affect the brainstem, particularly Behçet disease or sarcoidosis, and in primary lymphoma of the central nervous system. CLIPPERS does not have a specific biological marker.