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Table of Contents
EDITORIAL
Year : 2019  |  Volume : 33  |  Issue : 4  |  Page : 175-178

Autoimmune psychosis needs an early immune-modulating therapy


1 Department of Psychiatry, Mackay Memorial Hospital; Department of Child Care, Mackay Medicine, Nursing and Management College, Taipei, Taiwan
2 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
3 Department of Mathematics, Tamkang University, Taipei, Taiwan
4 Department of Psychiatry, China Medical University Hospital; Graduate Institute of Biomedical Sciencesis, Graduate Institute of Biomedical Sciences, China Medical University Medical College; Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung, Taiwan

Date of Submission18-Oct-2019
Date of Decision08-Nov-2019
Date of Acceptance08-Nov-2019
Date of Web Publication23-Dec-2019

Correspondence Address:
Hsien-Yuan Lane
No. 2, Yuh-Der Road, Taichung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_42_19

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How to cite this article:
Tzang RF, Chang CH, Chang YC, Lane HY. Autoimmune psychosis needs an early immune-modulating therapy. Taiwan J Psychiatry 2019;33:175-8

How to cite this URL:
Tzang RF, Chang CH, Chang YC, Lane HY. Autoimmune psychosis needs an early immune-modulating therapy. Taiwan J Psychiatry [serial online] 2019 [cited 2020 Jan 27];33:175-8. Available from: http://www.e-tjp.org/text.asp?2019/33/4/175/273863




  Immune Hypothesis of Schizophrenia Top


Since the 1980s, the “immune hypothesis of schizophrenia” has been suggested to associate immune dysfunction and neuroinflammation with schizophrenia [1], and a remarkable number of studies have shown the rôle of “immune dysregulation in schizophrenia” [2],[3]. The “mild encephalitis hypothesis of schizophrenia” proposed by the German researchers Bechter and Müller is one of the most promising new research concepts, suggesting that subgroups of patients with schizophrenia have a mild, but chronic, form of encephalitis with markedly different etiologies ranging from viral infections to autoimmune dysfunction [4]. Modern psychoneuroimmunology has tried to associate infection-triggered autoimmune dysfunction with risk factors for developing schizophrenia [5].


  What Is Autoimmune Psychosis? Top


Autoimmune psychosis is referred to the condition that a patient has atypical schizophrenia-like symptoms after autoimmune encephalitis, suggesting that the infection triggers autoimmune dysfunction [6],[7]. Such inflammation-triggered autoantibodies or dysregulation of T- and B-cell autoantibodies against a number of receptors, ion channels, and associated proteins causes the patients to present themselves with neurologic and psychotic symptoms [8]. Till the year 2016, 16 kinds of neuronal cell surface antibodies have been introduced to cause autoimmune encephalitis. The anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibodies are the most common, followed by antibodies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (Caspr2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA)-A and -B receptors, dipeptidyl-peptidase-like protein-6, glycine receptor, dopamin-2-receptor, mGluR5, neurexin-32, IgLoN5, DNER (Tr), mGluR1, P/Q type VGCC, and amphiphysin. Twelve of those manifest as autoimmune encephalitis. Anti-NMDAR encephalitis is an autoimmune disease caused by autoantibodies that react specifically against the NR1 subunits of the NMDA receptor. Those NMDAR antibodies in the brain cause glutamate neurotransmission dysfunction, causing the patients to show neurologic and psychiatric symptoms [9],[10].

Sixty percent of patients with such autoimmune dysfunction may exhibit schizophrenia-like symptoms first [11], followed by neurologic symptoms. Therefore, if psychiatrists can recognize these specific symptoms of autoimmune psychosis as early as possible and treat patients with an immune therapy as early as possible, such patients might recover from autoimmune dysfunction [12]. Conversely, if autoimmune psychosis is not recognized, patients might be misdiagnosed with chronic schizophrenia, which is refractory to the existing treatment with antipsychotic drugs [6]. In this editorial on autoimmune psychosis, we intend to help psychiatrists to recognize the possible symptoms and signs of autoimmune psychosis at the earliest possible time.


  Early Recognition of Autoimmune Psychosis Top


Autoimmune disease is quite prevalent, occurring in 7%–9% of the general population [13]. According to a nationwide study from Denmark, the risk of psychosis is increased by 29% after an autoimmune disease diagnosis [14]. Previously, the etiology of psychotic symptoms in patients with schizophrenia was unknown, but now, 9.9% of them are thought to be due to autoimmune encephalitis [15]. In fact, autoimmune disease and schizophrenia are closely correlated, and the correlation may prove to be even higher than the 45% occurrence of autoimmune disease attributed to patients with schizophrenia previously [16].

If we only consider one type of autoimmune psychosis – anti-NMDAR-positive patients with schizophrenia – the prevalence of anti-NMDAR encephalitis in patients with schizophrenia is 7.98% [17]. A study of 78 patients with first-episode schizophrenia and 234 patients with chronic schizophrenia in Taiwan found no seropositive reactions for NMDAR; AMPARs 1 and 2; and γ-butyric acid receptor type B1, LGI1, and CASPR2 in either patient groups [18]. By contrast, in a European study, NMDAR antibodies were found in 7.6% of 925 patients admitted to acute psychiatric inpatient care [19]. Some problems regarding diagnosis may explain this difference. As strong and consistent trends have proven that immune dysfunctional disorders require prompt immunotherapy worldwide, psychiatrists nowadays must recognize autoimmune psychosis as soon as possible. Psychiatrists must use the general definitions of autoimmune disorders and a practical, syndrome-based diagnostic approach to identify numerous patients with “masked” schizophrenia who may in fact be patients with autoimmune psychosis.


  Problems in Diagnosis Top


Although the discovery of antibodies against synaptic and neuronal cell membrane proteins such as the anti-NMDAR has been made using live cell-based assays that directly provide evidence of anti-NMDAR encephalitis, many relevant receptors have not been studied in laboratories. Presently, only a few autoantibodies against neurotransmitter receptors (e.g., NMDAR, LGI1, CASPR2, GABAA receptor, and AMPAR) are available in some laboratories. Numerous other receptors remain unreported or undetected. In some countries, autoantibody testing for all the 16 relevant antibodies is not available. In some places, testing is only available or affordable for one common neurotransmitter, the NMDAR antibody. Or some psychiatrists never recognize the early symptoms and signs of autoimmune psychosis, and they often miss the crucial window of time in which they could have earlier made such a diagnosis and started immune therapy. Therefore, it would be reasonable to infer that a serious underdiagnosis problem is currently ongoing [6] in many developing countries. Therefore, only relying on detection in the circulation of autoantibodies against NMDARs may delay diagnosis and starting immunotherapy [11].

A practical, syndrome-based diagnostic approach to autoimmune encephalitis and guidelines should be provided to prevent such delayed diagnosis. Clinicians can logically obtain an initial diagnosis through differential diagnosis; levels of evidence for autoimmune encephalitis (possible, probable, or definite) can then be used to inform the decision of when to start immunotherapy [20]. We must develop a concept that those patients who may have seronegative for one type of autoimmune encephalitis or negative one in the cerebrospinal fluid (CSF) [21], but still have vivid symptoms, should be classified as seronegative but probable autoimmune psychosis (SPAP) [22]. Timely treatment with proper immune modulatory therapies may yield good treatment response because patients still may have one type of seronegative autoimmune encephalitis [23], or their condition may be masked as drug-resistant primary psychotic disorder [12].


  the Symptoms and Signs of Possible Autoimmune Psychosis Top


Limbic encephalitis (LE) was first described by Brievely and Corsellis in 1960 as inflammation of the limbic area, particularly the hippocampus and amygdala, which can also involve the cerebellum and brainstem. Autoimmune LE generally presents itself with amnesia, psychiatric symptoms, an altered level of consciousness, and seizures [24]. We suspect a diagnosis of autoimmune psychosis if all the patients have:

  • Psychiatric symptoms with an abrupt start of disease or rapid worsening of symptoms [25]
  • Early age of onset
  • Neurological signs
  • History of autoimmune disorder
  • First episode of psychosis [26],[27]
  • History of upper respiratory tract infection before psychotic episode [28]
  • Atypical disease course such as disorientation, disturbance of consciousness, or cognitive deficit [25],[29]
  • Refractory responses to antipsychotic drugs [30]
  • History of presence of catatonic, dyskinesia features, or seizures [31],[32]
  • History of the symptom of autonomic disturbance unaccounted by a neurological or other cancer disorder (nonparaneoplastic) [33]
  • Predominance of visual or multimodal hallucinations (visual and tactile)
  • Olfactory hallucinations suggestive of mesial temporal lobe pathology [34]
  • Predominance of specific delusions such as those related to misidentifications (Capgras syndrome)
  • Antecedent or concurrent medical illness or systemic manifestations including significant weight loss
  • Lack of predisposing risk factors for primary psychosis such as a strong family history of schizophrenia·
  • A premorbid schizoid personality, or precipitating stress for mental disorder.


To achieve the main objective of increasing the early recognition and treatment of patients with possible autoimmune psychosis and to exclude other organic causes, we must obtain detailed medical and neurological history for each patient; do thorough general and neurological examinations; recognize atypical psychotic presentations; and identify clinical autonomic dysfunction, memory impairment, epilepsy, or evidence suggestive of immune dysregulation [11].


  Autoimmune Psychosis Needs Immune Therapy Top


Atypical psychotic presentations are well-known to be originated from autoimmune dysfunction [34]. But at present, no indication exists for using immune therapy in patients with schizophrenia. In fact, anti-NMDAR encephalitis may be mislabeled as schizophrenia clinically [17],[26]. Thus, we must consider the nature of proper immune therapy.


  First-Line Immune Therapy Top


First-line immune therapy includes pulse therapy with methylprednisolone 1,000 mg for 5 days and plasma exchange (plasmapheresis) every other day for 5 cycles and/or intravenous immunoglobulin (IVIG).

Favorable treatment effects have been reported after immune therapy, but about half or more patients are given second-line immunotherapy (rituximab and cyclophosphamide) [35].


  Second-Line Immune Therapy Top


While this autoimmune encephalitis is caused by tumor, the first-line immune therapy must include pulse therapy and plasma exchange or IVIG after tumor removal. But for autoimmune encephalitis caused by nonparaneoplastic autoimmunity, first-line immunotherapy have failed in up to half of all children treated for anti-NMDAR encephalitis; this is especially severe for some pediatric patients who are unlikely to have associated tumors [36]. Studies of these patients with poor treatment response have reported that about 65% of patients show substantial improvements with the second-line immunotherapy, which tends to be well-tolerated [36],[37]. The second-line therapy, most commonly rituximab or cyclophosphamide (or both), is often required in patients without tumors and in those with a late diagnosis [38]. The second-line immunotherapies using rituximab have been shown to have a rôle in patient recovery and improving long-term outcomes. Rituximab can be directed against the CD20 antigen on the surface of B-lymphocytes, which can decrease maturation of B-cells into antibody-secreting cells, giving a favorable immunotherapy option in anti-NMDAR encephalitis [39].


  Immune-Modulating Therapy Top


Glutamate (glutamic acid) can regulate the neurotransmission of the central nervous system. Neuroimaging, family, genetic, and animal studies have shown that glutamate can improve mood disturbance and executive function. Excessive glutamate can be released when GABA is reduced by enhanced postsynaptic glutamatergic transmission. Any agent which can adjust the function of glutamate or NMDAR can be a new add-on immune-modulating therapy or effective for patients with schizophrenia currently treated with antipsychotic drugs [40]. Such NMDA modulation agent might help patients with autoimmune psychosis.

Benzoate is an inhibitor of D-amino acid oxidase that can decrease the metabolism of D-amino acid, especially D-serine; increase the level of synaptic D-amino acid; and have therapeutic effects on major depressive disorder by enhancing NMDA function [41]. Therefore, investigators have studied its effectiveness in treating major depressive disorder [41] and schizophrenia [42],[43]. Sodium benzoate can modulate glutamate and can enhance the function of NMDA receptors. Cycloserine (a type of amino acid) has been reported to be effective for patients with anti-NMDAR encephalitis after first-line immune therapy [44]. Benzoate may have some therapeutic effect for such immune dysfunctional disorders mislabeled as schizophrenia in future.


  Conclusion Top


Some types of dysfunctional immunity that influence dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission in the brain may lead to disruption of affect and cognition. Nowadays, psychiatrists must apply new methods to diagnose autoimmune-related conditions as early as possible. Psychiatrists must recognize autoimmune psychosis and must not mislabel it as schizophrenia; patients with autoimmune psychosis must obtain immune therapy as rapidly as possible for relieving their psychotic symptoms [45]. In the near future, detecting biological markers of autoimmune autoantibodies (e.g., cytokines, decreased lymphocytes, imbalance of serum immunoglobulin levels, and T-cell-mediated immune profile), in addition to taking maternal infection history or children's infection history, should be allowed for the diagnosis of autoimmune psychosis in Taiwan. Further studies exploring immune function profiles for patients with schizophrenia are warranted in future.




  Financial Support and Sponsorship Top


This work was partly supported by grants from the Ministry of Science and Technology, Taiwan (MOST 108-2314-B-039-002), National Health Research Institutes (NHRI-EX108-1073NI), and China Medical University, Taiwan (CMU107-BC-4).


  Conflicts of Interest Top


The authors declare that we do not have any conflicts of interest in writing this editorial.



 
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  In this article
   Immune Hypothesi...
   What Is Autoimmu...
   Early Recognitio...
   Problems in Diag...
   the Symptoms and...
   Autoimmune Psych...
   First-Line Immun...
   Second-Line Immu...
   Immune-Modulatin...
  Conclusion
   Financial Suppor...
   Conflicts of Int...
   References

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