Relevant papers were identified through PubMed searches of articles published in English from Jan 1, 1960, up to Oct 1, 2018, using the following search terms (alone or in combination): “autoimmune encephalitis”, “limbic encephalitis”, “anti-NMDA receptor encephalitis”, “autoimmune psychosis”, “antibody-mediated psychosis”, “mild encephalitis”, “neuronal surface antibodies”, and “neuronal autoantibodies”. Additional studies were identified from our own files. The final reference list was
Position PaperAutoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin
Introduction
Human and experimental data indicate the presence of diverse immunological and inflammatory abnormalities in subgroups of individuals who have been diagnosed with a broad range of severe psychiatric disorders, including new-onset psychosis and schizophrenia,1, 2, 3, 4, 5 as defined by existing DSM and ICD criteria. These aberrant inflammatory and immunological responses might contribute not only to psychiatric and behavioural problems, but also to accompanying cognitive impairment, soft neurological signs, and autonomic abnormalities.3, 6 These responses might contribute to disease severity, and could help to explain the substantial proportion of patients whose condition does not respond adequately to conventional antipsychotics or psychotherapies.3, 7 Moreover, the discovery of neuronal surface protein antibodies in autoimmune encephalitis has generated a great deal of interest in the possibility that some psychiatric patients, in particular those with both affective and non-affective psychoses, have a specific autoantibody-mediated disease, or so-called autoimmune psychosis.8, 9, 10
Complementary to previously published criteria and guidelines that provide a clinical approach to the diagnosis of autoimmune encephalitis,11 in this Position Paper we aim to develop an approach to identify psychoses of possible, probable, and definite autoimmune origin. The full aims of this Position Paper are: (1) to summarise the reasons for the hypothesis that some forms of psychosis are autoimmune; (2) to briefly describe autoimmune encephalitis and discuss whether studies of autoimmune encephalitis support the hypothesis of autoimmune psychosis; (3) to propose a future approach for the investigation of possible autoimmune psychoses; (4) to summarise the possible immunotherapies that will help to define autoimmune psychosis; (5) overall, to ensure that psychiatrists think about autoimmune psychosis or autoimmune encephalitis in clinical practice so that neurological referral and appropriate immunotherapies are considered; and (6) to ensure that systematic studies are undertaken on autoimmune psychosis for future validation and to assist the design of clinical trials.
Section snippets
Methods
An initial working draft of this Position Paper was developed by KB and subsequently discussed at two round table sessions held on March 22 and March 25, 2018, at the 14th Psychoimmunology Expert Meeting in Günzburg, Germany. All co-authors contributed to the working draft, the three circulations of the subsequent drafts, and agreed the final submission and revision (appendix).
Evidence linking inflammation, immune dysregulation, and autoimmunity to psychosis neurobiology
There is growing evidence from studies of genetics, inflammatory markers, infections, and neuropathology (table 1) that links low-grade neuroinflammation (ie, cellular-infiltrative or humoral inflammation below the threshold observed in established CNS inflammatory disease) and immune dysfunction to the pathophysiology of psychosis in a subset of individuals who have been diagnosed with acute psychosis or schizophrenia-spectrum disorders.7, 12, 13, 14, 15 These findings include the
Autoimmune encephalitis and associated findings in patients with psychosis
Typically, in addition to psychiatric disturbance, patients with autoimmune encephalitis develop clear neurological features, including seizures, cognitive dysfunction, and movement disorders.28 These patients have pathogenic antibodies that target surface epitopes on synaptic and related proteins, principally the N-methyl-D-aspartate receptor (NMDAR, specifically the NR1 subunit), and the voltage-gated potassium channel (VGKC)-complex proteins, leucine-rich-glioma inactivated 1 (LGI1) and
Consensus multimodal approach to the systematic investigation of patients with suspected autoimmune psychosis
Collectively, the observations summarised in this Position Paper point to a potential overlap between autoimmune encephalitis-associated psychosis and psychotic disorders,76, 77 prompting some authors to adopt the term mild encephalitis78 or autoimmune psychosis10 as a possible incomplete or forme fruste of autoimmune encephalitis with dominant psychotic features.2 Acknowledging that debate exists regarding appropriate terminology,79 here we use the term autoimmune psychosis and propose a
Symptomatic approaches to psychiatric management
Treatment of autoimmune encephalitis and related psychiatric symptoms of confusion, psychosis, or agitation can prove difficult to manage, especially in a general hospital setting where staff might not have the appropriate mental health expertise and where the physical environment presents many additional risks, potentially leading to serious incidents of assaults against staff or patient suicides on acute medical wards.42 It is therefore crucial to establish an appropriate physical environment
Ethical issues and perspectives
The ethical issues regarding the treatment of patients with suspected autoimmune psychosis primarily revolve around the question of whether a trial of immunotherapy is warranted in patients for whom the diagnosis of autoimmune psychosis is uncertain, but considered likely. At present, there are no trials to address this issue and most data available are in the form of case reports and series. Clearly, well conducted trials are needed to inform treatment options, but these are somewhat hampered
Conclusion
In this Position Paper we have summarised an approach for the diagnosis and management of psychosis of probable autoimmune origin, highlighting its inherent diagnostic challenges. The proportion of patients with an acute-onset psychosis and red flag symptoms who have an autoimmune brain disease is unknown. This uncertainty arises because these patients are not routinely investigated. There is preliminary evidence that the epitopes targeted by NMDAR antibodies are different for patients with
Search strategy and selection criteria
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Senior authors