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.