Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. 

Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Background:

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.

Results:

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.

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.

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.

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.

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.

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.

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.

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Learning objectives:

(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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.