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Autoimmune encephalitis is an emerging and unique clinical entity that causes severe neuropsychiatric symptoms and results in significant morbidity and mortality. Because it can present with a wide variety of neurologic and psychiatric manifestations, often indistinguishable from other more common neuropsychiatric syndromes, that cause behavioral disturbance, it can often be a very challenging diagnosis for clinicians to make. This article broadly reviews the pathophysiology of the most common forms of autoimmune encephalitis and provides guidelines tailored toward mental health professionals to best identify and manage these rare but important causes of neuropsychiatric illness. Timely diagnosis of these syndromes helps facilitate appropriate, focused management and reduce morbidity, as delay in evaluation and treatment remains one of the most important hurdles facing patients suffering from autoimmune encephalitis.
Pathophysiology and epidemiology of autoimmune encephalitis
Autoimmune encephalitis is a family of syndromes caused by auto-antibodies to various either intra- or extracellular neuronal antigens. We will first provide an overview before examining common syndromes of each group in detail. Table 1 serves to help organize the categories and delineate the most common specific syndromes for each group.1
The first group comprises auto-antibodies to extracellular antigens, including extracellular receptors and ion channels.2,3 The process itself—of antibodies binding to antigens—is what is thought to be pathogenic. This group includes many well-known autoimmune encephalitis syndromes including anti-NMDA receptor encephalitis and anti-LGI1antibody encephalitis. Occasionally, some of the syndromes in this second group can also be associated with cancer, although the associations are not as frequently seen.
The second group comprises auto-antibodies to intracellular antigens and is often paraneoplastic with strong associations to various types of cancer. Disease is thought to result from T-cell activation after auto-antibodies bind to their target intracellular antigen. Finally, clinical symptoms and illness are often refractory to treatment, which is in part thought to be related to its paraneoplastic etiology, as well as T cell-mediated irreversible neuronal injury.
There is a third category of immunologic encephalitis, which is not covered in this article; it comprises brain diseases for which the precise immunological mechanism is uncertain or it is unclear whether auto-antibodies are involved and how they might mediate pathology. This category includes disorders such as CNS lupus, neurosarcoidosis, and acute disseminated encephalomyelitis.
Extracellular antigen auto-antibody syndromes
Anti-NMDA receptor encephalitis. This is one of the first and most well-described syndromes within the extracellular antigen group and now considered the most common form of autoimmune encephalitis. It is also the form in which diagnosis may be most confused for a primary psychotic illness. NMDA receptors are glutamatergic receptors often found in the presynaptic GABA neurons of the thalamus and frontal lobes, and impairment of these receptors leads to dysfunction of glutamate and dopamine throughout the brain.
Dr Deng is Assistant Professor of Neurology, Department of Neurology, Icahn School of Medicine, Mount Sinai Health System, New York, NY; Dr Yeshokumar is Assistant Professor of Neurology, Department of Neurology, Icahn School of Medicine, Mount Sinai Health System, New York, NY. The authors report no conflicts of interest concerning the subject matter of this article.
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