Elsevier

The Lancet Psychiatry

Volume 7, Issue 1, January 2020, Pages 93-108
The Lancet Psychiatry

Position Paper
Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin

https://doi.org/10.1016/S2215-0366(19)30290-1Get rights and content

Summary

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

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

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

References (182)

  • J Varley et al.

    Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy

    Neuropharmacology

    (2018)
  • JC Masdeu et al.

    NMDA receptor internalization by autoantibodies: a reversible mechanism underlying psychosis?

    Trends Neurosci

    (2016)
  • DM Pearlman et al.

    Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder

    Schizophr Res

    (2014)
  • N Gresa-Arribas et al.

    Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

    Lancet Neurol

    (2014)
  • A Al-Diwani et al.

    The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data

    Lancet Psychiatry

    (2019)
  • BR Lennox et al.

    Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

    Lancet Psychiatry

    (2017)
  • J Dalmau et al.

    Paraneoplastic syndromes of the CNS

    Lancet Neurol

    (2008)
  • J Heine et al.

    Imaging of autoimmune encephalitis—relevance for clinical practice and hippocampal function

    Neuroscience

    (2015)
  • U Heresco-Levy et al.

    Clinical and electrophysiological effects of D-serine in a schizophrenia patient positive for anti-N-methyl-D-aspartate receptor antibodies

    Biol Psychiatry

    (2015)
  • EG Severance et al.

    Autoimmune phenotypes in schizophrenia reveal novel treatment targets

    Pharmacol Ther

    (2018)
  • K Bechter

    Updating the mild encephalitis hypothesis of schizophrenia

    Prog Neuropsychopharmacol Biol Psychiatry

    (2013)
  • S Ramanathan et al.

    Long duration between presentation of probable anti-N-methyl-D-aspartate receptor encephalitis and either clinical relapse or positive serum autoantibodies

    J Clin Neurosci

    (2013)
  • AM Lascano et al.

    Diagnostic tools for immune causes of encephalitis

    Clin Microbiol Infect

    (2019)
  • S Magaki et al.

    Brain biopsy in neurologic decline of unknown etiology

    Hum Pathol

    (2015)
  • YC Tanguturi et al.

    Anti-N-Methyl-D-Aspartate receptor encephalitis and electroconvulsive therapy: literature review and future directions

    Child Adolesc Psychiatr Clin N Am

    (2019)
  • MS Zandi et al.

    Immunotherapy for patients with acute psychosis and serum N-Methyl D-Aspartate receptor (NMDAR) antibodies: a description of a treated case series

    Schizophr Res

    (2014)
  • S Orlovska-Waast et al.

    Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis

    Mol Psychiatry

    (2018)
  • S Najjar et al.

    A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis

    J Neuroinflammation

    (2018)
  • FA Radtke et al.

    Modulating neuroinflammation to treat neuropsychiatric disorders

    Biomed Res Int

    (2017)
  • MO Trepanier et al.

    Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review

    Mol Psychiatry

    (2016)
  • CF van Kesteren et al.

    Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies

    Transl Psychiatry

    (2017)
  • S Najjar et al.

    Neuroinflammation and psychiatric illness

    J Neuroinflammation

    (2013)
  • TA Pollak et al.

    Neuronal surface autoantibodies, encephalitis, and psychosis: from neurology to psychiatry

    Adv Clin Neurosci Rehabil

    (2017)
  • A Al-Diwani et al.

    Synaptic and neuronal autoantibody-associated psychiatric syndromes: controversies and hypotheses

    Front Psychiatry

    (2017)
  • P Ellul et al.

    The clinical challenge of autoimmune psychosis: learning from anti-NMDA receptor autoantibodies

    Front Psychiatry

    (2017)
  • N Müller et al.

    The role of inflammation in schizophrenia

    Front Neurosci

    (2015)
  • Biological insights from 108 schizophrenia-associated genetic loci

    Nature

    (2014)
  • A Sekar et al.

    Schizophrenia risk from complex variation of complement component 4

    Nature

    (2016)
  • Genome-wide association study identifies five new schizophrenia loci

    Nat Genet

    (2011)
  • ME Benros et al.

    A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis

    Am J Psychiatry

    (2014)
  • ME Benros et al.

    Autoimmune diseases and infections as risk factors for schizophrenia

    Ann N Y Acad Sci

    (2012)
  • ME Benros et al.

    Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study

    JAMA Psychiatry

    (2013)
  • S Najjar et al.

    Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: a theoretical integration of clinical and experimental evidence

    Front Psychiatry

    (2017)
  • J Dalmau et al.

    Antibody-mediated encephalitis

    N Engl J Med

    (2018)
  • TA Pollak et al.

    Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications

    Psychopharmacology (Berl)

    (2016)
  • EG Hughes et al.

    Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis

    J Neurosci

    (2010)
  • EH Moscato et al.

    Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis

    Ann Neurol

    (2014)
  • A Nibber et al.

    Pathogenic potential of antibodies to the GABAB receptor

    Epilepsia Open

    (2017)
  • MS Kayser et al.

    Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-D-aspartate receptor encephalitis

    JAMA Neurol

    (2013)
  • B Yoshimura et al.

    Anti-NMDA receptor antibody positivity and presentations without seizure, involuntary movement, hypoventilation, or tumor: a systematic review of the literature

    J Neuropsychiatry Clin Neurosci

    (2017)
  • Cited by (235)

    • Paraneoplastic encephalitis

      2024, Handbook of Clinical Neurology
    View all citing articles on Scopus

    Senior authors

    View full text