Biomarkers of neurodegeneration in neural autoantibody-associated psychiatric syndromes: A retrospective cohort study
Autoantibody-associated psychiatric syndromes are a novel disease entity that is not fully understood. Several lines of evidence suggest that neurodegenerative processes are involved here. We are investigating whether autoantibody-positive psychiatric syndromes differ from those that are autoantibody-negative in cerebrospinal fluid (CSF) neurodegeneration markers.
Antibody-associated psychiatric syndromes do not appear to reveal significantly greater neurodegeneration than their antibody-negative psychiatric syndromes. 71% of antibody-positive patients fulfilled the criteria for a possible and 22% for definitive autoimmune encephalitis. Our autoantibody-positive patient cohort’s relative risk to develop an possible autoimmune encephalitis was 9%. We also noted that phosphorylated tau protein 181 (ptau 181) did not significantly differ between antibody-associated psychiatric syndromes and our Alzheimer cohort. The psycho-organic syndrome usually exhibits the most prominent neurodegeneration markers, both in antibody-positive and antibody-negative psychiatric patients.
Psychiatric manifestations of autoimmune encephalitis
The understanding, diagnosis and treatment of autoimmune encephalitis represents an emerging field in neurology, which presents with a broad range of neurologic and psychiatric manifestations. This group of disorders are currently considered uncommon diagnoses, however given the increasing number of described cases and antibodies they are likely not as rare as first thought [2,8,102]. Psychiatric symptoms are frequently encountered, particularly psychosis and changes in behaviour.
Understanding and management of anti-N-methyl-D-aspartate receptor encephalitis from a child psychiatry perspective: report of five cases
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare autoimmune entity in psychiatry literature that occurs when antibodies attack NMDA-type glutamate receptors in the brain. Principle clinical features include a neurological domain such as seizure, orofacial dyskinesia, dystonia, and choreic-like movements of extremities. Also the psychiatric manifestations of this form of encephalitis may vary from psychotic-like symptoms to mood symptoms like depression or mania. Herein we report on five female child cases diagnosed with anti-NMDAR encephalitis, presented with both neurological and psychiatric clinical picture, and highlight the trajectory of disorder from a psychiatric perspective.
Autoimmune Encephalitis and Autism Spectrum Disorder
There is emerging evidence of a connection between AE and ASD. Multiple reports have described the presentation of ASD and/or autistic features in cases of diagnosed AE. Alongside other important observations of immunological issues being over-represented in ASD and various other types of infection associated with the onset of symptoms, there are important reasons for AE to be treated as a clinical priority in the context of ASD. It can no longer be assumed that regression, for example, is just “a part of autism” without any need for investigations. The cases of ASD appearing alongside AE provide a template for further clinical examination of such regressive onset patterns. There are significant challenges in relation to the assessment and diagnostic pathways toward recognising AE in ASD. Similar challenges are also present with regards to the treatment of AE in this context and in determining whether ASD appearing alongside AE represents a distinct phenotype of ASD or merely a differential diagnosis of ASD.
Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis
Discussion: NfL measured at diagnosis of NMDARe associated with features of disease severity but not with long-term outcome. Young patients with FEP and sNfL≥15pg/mL had 120 times higher chance of having NMDARe than pFEP. This cutoff correctly classified 96% of pFEP and 85% of NMDARe with isolated psychosis. Patients with FEP of unclear etiology and sNfL≥15pg/mL should undergo CSF NMDAR-antibody testing.
Immunopsychiatry: An Update on Autoimmune Encephalitis for Neuropsychiatrists
Immune system dysfunction has been implicated in the pathophysiology of psychiatric symptoms and disorders. The use of diagnostic criteria of possible AIE, especially when specific antibodies of AIE are not available, allows early diagnosis and prompt treatment which are associated with better clinical outcomes. The study of the psychiatric aspects of AIE can broaden our knowledge of the underlying mechanisms of various psychiatric manifestations.
Psychiatric Phenotypes of Pediatric Patients With Seropositive Autoimmune Encephalitis
The psychiatric phenotype of AE in children is highly heterogenous. Involving psychiatry consultation services can be helpful in differentiating features of psychosis and catatonia, which may otherwise be misidentified. Patients presenting with psychiatric symptoms along with impairments in other domains should prompt a workup for AE, including testing for all known antineuronal antibodies.
Anti-NMDAR encephalitis for psychiatrists: the essentials
(a) What is autoimmune encephalitis?
(b) What is anti-NMDAR encephalitis?
(c) When should anti-NMDAR encephalitis be suspected?
(d) How should suspected anti-NMDAR encephalitis be investigated?
(e) How should the practical management and treatment of anti-NMDAR encephalitis be approached?
(f) What is the prognosis for anti-NMDAR encephalitis?
Anti-NMDAR encephalitis typically first presents with a complex constellation of acute-onset psychiatric symptoms, such as agitation, psychosis and catatonia. As in the case described, those with the condition can first present to psychiatry. Therefore, psychiatrists have a crucial role in the early recognition of anti-NMDAR encephalitis, and should be familiar with the features suggestive of it in the patient’s history, mental state and neurological examination. Clinical suspicion should trigger early discussion with neurology colleagues, and prompt testing of serum (and ideally CSF) for NMDAR antibodies. Collaborative working supports early diagnosis and timely immunotherapy, resulting in improved long-term outcomes.
In future, routine screening for autoantibodies in patients presenting with psychiatric symptoms may become common practice, and studies are ongoing assessing the potential role of immunotherapy within psychiatry
Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis
NMDAR-antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurological symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.
Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers
There is emerging evidence of the involvement of various neural autoantibodies and systemic non-CNS autoantibodies in atypical psychotic and mood syndromes. Therefore, it is essential to pay attention to those who present with polymorphic psychiatric symptoms, significant cognitive involvement, and neurological phenomena in daily clinical practice. Further, performing a careful neurological examination as well as a brain MRI scan and an EEG is essential to not miss neural antibody-associated autoimmune conditions. Consequently, in line with the majority of international guidelines, a comprehensive assessment is needed to detect autoimmune encephalitides. Our study highlights the importance of CSF analysis to reliably detect the involvement of immune processes and demonstrates the high specificity of positive CSF test results by the absence of detectable antibodies from our healthy controls.
Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge
Our review aims to delineate the psychiatric spectrum of autoantibody-associated autoimmune encephalitis over time through its discoveries of antibodies. Autoimmune encephalitis is a disorder that can dynamically alter its phenotypical appearance over time. It is often characterized by an initial psychiatric manifestation or reveals predominant or isolated psychiatric features The aim of this review is to depict the historic evolution of the published psychiatric phenomenology of autoimmune encephalitis.
Pro‐inflammatory dopamine‐2 receptor‐specific T cells in paediatric movement and psychiatric disorders
Autoreactive D2R‐specific T cells and a pro‐inflammatory Th1 and Th17 cytokine profile characterise a subset of paediatric patients with movement and psychiatric disorders, further underpinning the theory of immune dysregulation in these disorders. These findings offer new perspectives into the neuroinflammatory mechanisms of movement and psychiatric disorders and can influence patient diagnosis and treatment.
Significance of Autoantibodies in Autoimmune Encephalitis in Relation to Antigen Localization: An Outline of Frequently Reported Autoantibodies with a Non-Systematic Review
The recent discoveries of several autoantibodies produced in patients with autoimmune encephalomyelitis have expanded new clinical entities, such as autoimmune psychosis and autoimmune
epilepsy, and also provide a deep understanding of the background of neurological symptoms in these disorders, together with new insights into the basic neuroscience. For patients with psychotic disorders or intractable epilepsy previously treated in psychiatric wards, there is a
possibility for effective treatment through immunotherapy, such as intravenous methylprednisolone infusion, high-dose immunoglobulin administration, plasmapheresis, or other immunosuppressants.
Synaptic receptor dysfunction due to antibody binding causes various neurological symptoms of encephalopathy-associated pathologies.
Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment
Results: Disturbances of consciousness and orientation, catatonia, speech dysfunction, focal neurological signs, epileptic seizures/EEG abnormalities or autonomic dysfunction are warning signs in psychiatric patients which should always induce cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Currently established immunotherapy strategies are summarised, taking into account international expert advice.
Conclusions: Guided by clinical warning signs, our qualitative review enables rapid and reliable diagnosis of definite autoimmune encephalitis. This is of high relevance for the affected individuals, since early and sufficiently intense immunotherapy often leads to a good prognosis despite severe illness.
Psychiatric Manifestation of Anti-LGI1 Encephalitis
Case Report- Conclusion: This case study describes a patient with anti-LGI1 encephalitis in the chronified stage and a predominant long-lasting psychiatric course with atypical symptoms of psychosis and typical neurocognitive deficits. The patient’s poor response to anti-inflammatory drugs was probably due to the delayed start of treatment. This delay in diagnosis and treatment may also have led to the FDG-PET findings, which were compatible with frontotemporal dementia (“state of damage”). In similar future cases, newly occurring epileptic seizures associated with psychiatric symptoms should trigger investigations for possible autoimmune encephalitis, even in patients with addiction or other pre-existing psychiatric conditions. This should in turn result in rapid organic clarification and-in positive cases-to anti-inflammatory treatment. Early treatment of anti-LGI1 encephalitis during the “inflammatory activity state” is crucial for overall prognosis and may avoid the development of dementia in some cases.
Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations
The awareness of the fact that psychotic syndromes may have autoimmune, Ab-associated causes opens up a new field in psychiatry for a small but probable relevant subgroup of patients. For clinicians, this raises the question as to how far the diagnostic workup and immunomodulating therapy attempts should be advanced in individual cases. This article investigates this question by illustrating constellations in which extended organic diagnostic procedures, especially Ab analyses, should be carried out.
Reviews Red Flags, the syndrome of possible autoimmune encephalitis, Diagnostic approach: Taking Extended history, Medical and neurological physical examination, Neuropsychological testing, Laboratory measurements, EEG, Imaging, tumor screening.
Screening for anti-NMDAR Encephalitis in Psychiatry
Anti-NMDAR encephalitis most commonly presents to psychiatric services, so early identification of this disorder is essential. We aim to validate the two screening criteria (Scott et al. and Herken and Pruss) which have been proposed to identify first episode psychosis patients who should have anti-NMDAR antibody testing.
Psychosis associated to CASPR2 autoantibodies and ovarian teratoma: A case report
First report of CASPR2 associated psychosis related to an ovarian teratoma. Prompt reduction of psychotic symptoms after excision of teratoma. The diagnosis of autoimmune psychosis can be made in the presence of autoantibodies in the serum while CSF is unremarkable.
Patients with depressive and psychotic symptoms non-responding to antidepressant and antipsychotic treatment should be screened for neuronal autoantibodies including CASPR2.
Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin
2 years in the making, top experts in the field make a valueable contribution in this work. They 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. Investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses are outlined, and discuss the ethical issues posed by this challenging diagnostic category.
Autoimmunity in psychotic disorders. Where we stand, challenges and opportunities
Take home message
- To date, pathogenic autoantibodies targeting neuronal surface antigens are very rare in psychotic disorders without any form of neurological manifestation.
- Awareness from psychiatrist of the existence of symptoms which overlap between autoimmune encephalitis and psychotic disorders is essential to prompt early diagnosis and intervention for cases with an atypical disease course.
An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models
The Psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data
Neuropsychiatric symptoms in autoimmune encephalopathies: a clinician’s guide
Psychotic and Non Psychotic Mood Disorders In Autoimmune Encephalitis: Diagnostic Issues and Research Implications
Autoantibodies to central nervous system neuronal surface antigens: psychiatric symptoms and psychopharmacological implications
Autoimmune encephalitis in psychiatric institutions: current perspectives
Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment
Antibody Mediated Psychosis
Neuropsychological And Psychopathological Profile Of Anti-Nmdar Encephalitis: A Possible Pathophysiological Model For Pediatric Neuropsychiatric Disorders
Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
Anti-NMDA receptor encephalitis presenting as postpartum psychosis—a clinical description and review
Anti-NMDA Receptor Encephalitis: Diagnostic Issues for Psychiatrists
Autoimmune Encephalitis: Not Rare and Increasing
Anti-NMDA receptor encephalitis: An emerging differential diagnosis in the psychiatric community
Psychiatric manifestations of anti-NMDA receptor encephalitis: neurobiological underpinnings and differential diagnostic implications
Ethical Implications of the Mild Encephalitis Hypothesis of Schizophrenia
Immunopsychiatry: an update on autoimmune encephalitis for neuropsychiatrists
This text will review the main aspects of AIE to psychiatrists and/or neuropsychiatrists.
The estimated annual incidence of autoimmune encephalitis (AIE) is between 8 and 15 cases per 1.000.000 people per year.
Psychiatric syndromes have been described in other AIE. For instance, they have been reported in 67% of patients with anti-GABA-B encephalitis and 63% of patients with anti-LGI1 encephalitis. Discerning between AIE and primary psychiatric disorders can be a challenging task.
There are warning signs, or ‘red flags,’ which point to the diagnosis of AIE.
Developing Consensus in the Assessment and Treatment Pathways for Autoimmune Encephalitis in Child and Adolescent Psychiatry
There is a clear need for child and adolescent psychiatrists to become familiar with ways in which the clinical presentation of patients with autoimmune encephalitis may differ from a primary psychiatric disorder. Clinicians must then be able to articulate these differences to our multi-disciplinary colleagues in order to advocate for the diagnostic workup needed while still maintaining hypothesis flexibility. Randomized controlled studies dedicated to pediatric AE are lacking and without a clearly defined standard of care inequities will inevitably exist. Patients that are able to gain access to subspecialty and academic centers often receive care that is different from what may be available in more rural areas.
Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis
In this study, potentially pathogenic serum IgG autoantibodies against neuronal surface proteins were found in serum, but not CSF, from 4% of first-episode psychosis patients who lacked overt neurological features. These seropositive patients showed no distinctive clinical features and no laboratory or imaging evidence of a skewed peripheral or CSF immune response. This observation stands in striking contrast to patients with autoantibody-mediated encephalitis, who typically have highly characteristic clinical features often with inflammatory paraclinical findings. Hence, phenotypes and parameters fundamental to encephalitis and neuroinflammation were not enriched in seropositive first-episode psychosis patients, suggesting that these autoantibodies do not indicate the presence of mild encephalitis, and may represent clinically irrelevant results.
Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Detailed Review of the Different Psychiatric Presentations and Red Flags to Look for in Suspected Cases
This review aimed to discuss the different ways anti-NMDAR encephalitis could present and manifest on the psychological, mainly, and the neurological spectrum of signs and symptoms. The signs and symptoms expressed by anti-NMDAR encephalitis patients can be categorized into psychosis (represented by delusions and hallucinations), catatonia, seizures, speech and movement abnormalities, and autonomic instability, in addition to cognitive dysfunction.
The temporal association between those signs and symptoms varied among cases; first presentations tend to overlap with psychiatric diagnoses, especially on the schizophrenic spectrum. Catatonia is one of the disease hallmarks as well. Movement disorders are commonly seen among the anti-NMDAR encephalitis pediatric population. The autoimmune link between anti-NMDAR encephalitis and schizophrenia has been described before; antibody-positive patients go on to develop neurological manifestations later on. Anti-NMDAR encephalitis can also present with affective manifestations. Narcolepsy and hypersomnia as manifestations of anti-NMDAR encephalitis have been described, as well as the association between alcohol or drug abuse and NMDAR encephalitis. There are some clinical red flags that could be of use to make the diagnosis.
Hence, for physicians trying to familiarize themselves with this diagnosis, this is a good place to start. The review included a general scheme that covers almost all aspects of the psychiatric presentation, similarities, and differences in contrast to other differential diagnoses, in addition to clinical pearls that aid diagnosis. However, this paper did not discuss the different ways this disorder presents in pediatrics; hence, this remains an area future reviews might be more inclusive of.
Autoimmune encephalitis or autoimmune psychosis?
The characterization of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has impacted the field of psychiatry for two main reasons: first, up
to 85% of these patients present with psychiatric symptoms indistinguishable from first episodes of psychosis (FEP), and
second, the NMDAR dysfunction caused by the patients’ antibodies fits well with the hypothesis of NMDAR hypofunction
in schizophrenia (Dalmau et al., 2008).
Based on these features and mimicking the term autoimmune encephalitis, the term autoimmune psychosis was
coined to designate patients with schizophrenia or FEP suspected to be autoimmune in origin on the basis of the detection of serum NMDAR antibodies (NMDAR-abs) or other neuronal autoantibodies. This resulted in a remarkable number of publications aimed at identifying these patients in
order to treat them with immunotherapy In our opinion many of these studies have important methodological limitations and none has demonstrated a distinct autoimmune psychiatric syndrome beyond that of anti-NMDAR encephalitis.
Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis
At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. Seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 versus 4.0 months; p=0.031). 11 seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: following treatment, there was no between-groups difference in improvement in Positive and Negative Symptom Scale (PANSS) scores, nor in the frequency of adverse medication effects.
Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis
Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens. Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not.
This study, NMDAR antibodies did not predict transition to psychosis, as defined by operationalized criteria, or nonremission from the CHR state. NMDAR antibody seropositivity was however associated with a deterioration in disability-associated functioning, short of transition, and indeed greater antibody titre was associated with greater deterioration in function, overall suggesting that NMDAR antibody serostatus should be further evaluated as a predictive marker of functional outcome.
Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases
We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes.
Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment.
Conclusions: Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.
Neuropsychological and psychiatric outcomes in encephalitis: A multi-centre case-control study
Objectives Our aim was to compare neuropsychological and psychiatric outcomes across three encephalitis aetiological groups: Herpes simplex virus (HSV), other infections or autoimmune causes (Other), and encephalitis of unknown cause (Unknown).
Conclusions Neuropsychological and psychiatric outcomes after encephalitis vary according to aetiology. Memory and naming are severely affected in HSV, and less so in other forms. Neuropsychological functioning improves over time, particularly in those with more severe short-term impairments, but subjective cognitive complaints, depression, and anxiety persist and should be addressed in rehabilitation programs.
Novel Antineuronal Autoantibodies With Somatodendritic Staining Pattern in a Patient With Autoimmune Psychosis
This case report shows an association of a psychotic syndrome with predominant catatonic symptoms and antineuronal autoantibodies against an unknown epitope detected by a tissue-based assay. The basic diagnostics were mostly unremarkable with the exception of a conspicuous EEG. The application of tissue-based assays for the detection of so far unknown autoantibodies might also be helpful in other psychiatric patients with suspected autoimmune pathophysiology.
Association of Primary Humoral Immunodeficiencies With Psychiatric Disorders and Suicidal Behavior and the Role of Autoimmune Diseases
In this population-based cohort study of 8378 patients in Sweden, having a record of primary humoral immunodeficiencies was associated with greater odds of psychiatric disorders and suicidal behavior, even after controlling for autoimmune diseases and familial confounding. The associations were significantly stronger in women and among those exposed to primary humoral immunodeficiencies and autoimmune diseases.
A prospective three-year follow up on the clinical significance of anti-neuronal antibodies in acute psychiatric disorders
The clinical significance of anti-neuronal antibodies for psychiatric disorders is controversial. We investigated if a positive anti-neuronal antibody status at admission to acute psychiatric inpatient care was associated with a more severe neuropsychiatric phenotype and more frequent abnormalities during clinical work-up three years later.