Brain Versus Blood: A Systematic Review on the Concordance Between Peripheral and Central Kynurenine Pathway Measures in Psychiatric Disorders.

Objective: Disturbances in the kynurenine pathway have been implicated in the pathophysiology of psychotic and mood disorders, as well as several other psychiatric illnesses. It remains uncertain however to what extent metabolite levels detectable in plasma or serum reflect brain kynurenine metabolism and other disease-specific pathophysiological changes. The primary objective of this systematic review was to investigate the concordance between peripheral and central (CSF or brain tissue) kynurenine metabolites. As secondary aims we describe their correlation with illness course, treatment response, and neuroanatomical abnormalities in psychiatric diseases. Methods: We performed a systematic literature search until February 2021 in PubMed. We included 27 original research articles describing a correlation between peripheral and central kynurenine metabolite measures in preclinical studies and human samples from patients suffering from neuropsychiatric disorders and other conditions. We also included 32 articles reporting associations between peripheral KP markers and symptom severity, CNS pathology or treatment response in schizophrenia, bipolar disorder or major depressive disorder. Results: For kynurenine and 3-hydroxykynurenine, moderate to strong concordance was found between peripheral and central concentrations not only in psychiatric disorders, but also in other (patho)physiological conditions. Despite discordant findings for other metabolites (mainly tryptophan and kynurenic acid), blood metabolite levels were associated with clinical symptoms and treatment response in psychiatric patients, as well as with observed neuroanatomical abnormalities and glial activity. Conclusion: Only kynurenine and 3-hydroxykynurenine demonstrated a consistent and reliable concordance between peripheral and central measures. Evidence from psychiatric studies on kynurenine pathway concordance is scarce, and more research is needed to determine the validity of peripheral kynurenine metabolite assessment as proxy markers for CNS processes. Peripheral kynurenine and 3-hydroxykynurenine may nonetheless represent valuable predictive and prognostic biomarker candidates for psychiatric disorders.

Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms.

Importance: Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population. Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. Design, Setting, and Participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test. Main Outcomes and Measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies. Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. Conclusions and Relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid.

Aim: Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method. Methodology & results: Ten CSF TRP metabolites were analyzed with ultraperformance LC-MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze-thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters. Conclusion: The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters.

A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists?

OBJECTIVE: Neurofilament light has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid neurofilament light in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for psychiatrists and neurologists. METHODS: This cross-sectional retrospective pilot study assessed cerebrospinal fluid neurofilament light on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, where a neurodegenerative disorder was a differential diagnosis, who received lumbar punctures as part of a comprehensive workup. The most recent gold-standard clinical consensus diagnosis was categorised into psychiatric disorder or neurodegenerative or neurological disorder. Data from healthy controls were available for comparison. Data extraction and diagnostic categorisation was blinded to neurofilament light results. RESULTS: A total of 129 participants were included: 77 neurodegenerative or neurological disorder (mean age 57 years, including Alzheimer's dementia, frontotemporal dementia), 31 psychiatric disorder (mean age 51 years, including schizophrenia, major depressive disorder) and 21 healthy controls (mean age 66 years). Neurofilament light was significantly higher in neurodegenerative or neurological disorder (M = 3560 pg/mL, 95% confidence intervals = [2918, 4601]) compared to psychiatric disorder (M = 949 pg/mL, 95% confidence intervals = [830, 1108]) and controls (M = 1036 pg/mL, 95% confidence intervals = [908, 1165]). Neurofilament light distinguished neurodegenerative or neurological disorder from psychiatric disorder with an area under the curve of 0.94 (95% confidence intervals = [0.89, 0.98]); a cut-off of 1332 pg/mL was associated with 87% sensitivity and 90% specificity. CONCLUSION: Cerebrospinal fluid neurofilament light shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma neurofilament light.

Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry.

OBJECTIVE: The authors examined and compared the clinical presentation of CSF positive and negative N-methyl-d-aspartate receptor (NMDAR) antibody. METHODS: The investigators performed a retrospective chart review of NMDAR-antibody-positive cases (serum or CSF) involving patients presenting to psychiatric services from 2010 to 2018 in Queensland, Australia. Presentation, progress, investigations, and efficacy of treatment are detailed. RESULTS: There were 24 serum or CSF NMDAR-antibody-positive cases and three equivocal serum results. High rates of prodromal cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity were observed in the 16 CSF NMDAR-antibody-positive case patients and two CSF NMDAR-antibody-negative case patients, all evident before neurological deterioration with seizures, movement disorder, and autonomic disturbance occurring in the weeks following admission. The majority of these patients (N=17) were treated successfully with immunomodulatory therapy. The nine remaining patients, who were CSF NMDAR antibody negative or equivocal, did not demonstrate any of these features and improved with psychiatric care alone. CONCLUSIONS: These findings suggest that traditional psychiatric care may be appropriate for patients with isolated psychiatric symptoms who have positive serum NMDAR testing when CSF is negative and there are no key clinical features such as cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity. However, if these key features are present, a trial of immunomodulatory treatment should be considered with repeated examination of CSF for neuronal antibodies.

Mental disorders, attrition at follow-up, and questionnaire non-completion in epidemiologic research. Illustrations from the CoLaus|PsyCoLaus study.

OBJECTIVE: This study aimed to investigate the associations between mental disorders recorded at baseline and participation in the subsequent follow-up interview (vs. attrition) or baseline questionnaire completion (vs. non-response) within the psychiatric arm of a population-based study. METHODS: Participants of a physical health survey were initially invited to also participate in a semi-structured interview covering mental disorders and were reassessed approximately 5.5 years later. They were also asked to complete self-rating questionnaires at baseline. Associations between the presence of lifetime mental disorders assessed at baseline and attrition at follow-up as well as non-completion of self-rating questionnaires at baseline were established. RESULTS: After controlling for sociodemographic variables, a significant negative association was found between anxiety disorders at baseline and attrition at follow-up (Adjusted odds ratio (AOR) = 0.84; 95% confidence interval (CI) = 0.71-1.00) and a positive association between major depressive disorders (MDD) and non-response to the self-rating questionnaires at baseline (AOR = 1.24; 95% CI = 1.05-1.45). CONCLUSIONS: The associations of anxiety disorders during lifetime with a higher participation rate in interviews at follow-up and of MDD during lifetime with the non-completion of self-rating questionnaires are potential sources of bias and should be taken into account in future longitudinal research.

Cerebrospinal Fluid Correlates of Neuropsychiatric Symptoms in Patients with Alzheimer's Disease/Mild Cognitive Impairment: A Systematic Review.

BACKGROUND: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. METHODS: For this systematic review, four databases, PubMed (1946-2018), Cochrane (2005-2018), EMBASE (1947-2018), and PsycINFO (1806-2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. RESULTS: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. CONCLUSION: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized "objective" approach for the evaluation of NPS.

Has the time arrived for cerebrospinal fluid biomarkers in psychiatric disorders?

Psychiatric disorders are currently classified, in the majority of cases, by clinical syndromes. However, advances over the last decade in imaging and biochemical biomarkers in several Central Nervous System (CNS) disorders anticipate the incorporation of some of these markers in the diagnostic work-up of psychiatric conditions. In particular, CSF biomarkers offer the possibility of detecting a wide range of pathophysiological processes in the CNS. Newer CSF markers can measure axonal and synaptic damage, glial activation, and oxidative stress in CNS disorders with high precision. The possibility that these markers can be applied in the differential diagnosis of common psychiatric disorders such as Schizophrenia, Major Depressive or Bipolar Disorders not only to rule out neurodegenerative diseases but also to identify specific biomarker signatures has yet to be explored. In particular, synaptic proteins in CSF could be useful as markers of synaptic and neurotransmitter transmission impairment since these are key molecular features of psychiatric conditions. In this paper we outline the current and potential applications of CSF biomarkers in psychiatric disorders.

A prospective three-year follow-up study 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. Patients admitted to acute psychiatric inpatient care who tested positive for N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (CASPR2) and/or glutamic acid decarboxylase 65 (GAD65) antibodies (n = 24) were age - and sex matched with antibody-negative patients (1:2) from the same cohort (n = 48). All patients were invited to follow-up including psychometric testing (e.g. Symptom Checklist-90-Revised), serum and cerebrospinal fluid (CSF) sampling, EEG and 3 T brain MRI. Twelve antibody-positive (ab+) and 26 antibody-negative (ab-) patients consented to follow-up. Ab+ patients had more severe symptoms of depression (p = 0.03), psychoticism (p = 0.04) and agitation (p = 0.001) compared to ab- patients. There were no differences in CSF analysis (n = 6 ab+/12 ab-), EEG (n = 7 ab+/19 ab-) or brain MRI (n = 7 ab+/17 ab-) between the groups. In conclusion, anti-neuronal ab+ status during index admission was associated with more severe symptoms of depression, psychoticism and agitation at three-year follow-up. This supports the hypothesis that anti-neuronal antibodies may be of clinical significance in a subgroup of psychiatric patients.

Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains.

OBJECTIVE: To identify the specific domains of the presynaptic protein synapsin targeted by recently described autoantibodies to synapsin. METHODS: Sera of 20 and CSF of two patients with different psychiatric and neurological disorders previously tested positive for immunoglobulin (Ig)G antibodies to full-length synapsin were screened for IgG against synapsin I domains using HEK293 cells transfected with constructs encoding different domains of rat synapsin Ia. Additionally, IgG subclasses were determined using full-length synapsin Ia. Serum and CSF from one patient were also screened for IgA autoantibodies to synapsin I domains. Sera from nine and CSF from two healthy subjects were analyzed as controls. RESULTS: IgG in serum from 12 of 20 IgG synapsin full-length positive patients, but from none of the healthy controls, bound to synapsin domains. Of these 12 sera, six bound to the A domain, five to the D domain, and one to the B- (and possibly A-), D-, and E-domains of synapsin I. IgG antibodies to the D-domain were also detected in one of the CSF samples. Determination of IgG subclasses detected IgG1 in two sera and one CSF, IgG2 in none of the samples, IgG3 in two sera, and IgG4 in eight sera. One patient known to be positive for IgA antibodies to full-length synapsin had IgA antibodies to the D-domain in serum and CSF. CONCLUSIONS: Anti-synapsin autoantibodies preferentially bind to either the A- or the D-domain of synapsin I.

Disease trajectories in behavioural variant frontotemporal dementia, primary psychiatric and other neurodegenerative disorders presenting with behavioural change.

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.

Elevated levels of 8-oxoGuo and 8-oxodG in individuals with severe mental illness - An autopsy-based study.

Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (N = 107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (r = 0.50, P < 0.001), a similar correlation was not evident for 8-oxoGuo (r = 0.15, P = 0.16). Additionally, the two r-values were significantly different (P < 0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.

The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis.

Some patients with primary central nervous system lymphoma (PCNSL) may initially present with similar clinical, magnetic resonance imaging, and routine cerebrospinal fluid (CSF) findings as those observed in multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, appears to be the most specific CSF marker for MS. This study aimed to determine whether a positive MRZR and other routine CSF markers help differentiate between MS and PCNSL. Data regarding brain biopsy, CSF routine tests, cytopathological examination and immunophenotyping of CSF cells were assessed in 68 PCNSL patients. MRZR was determined, as possible, in PCNSL patients (n = 37) and in those with MS (n = 74; age and sex matched to PSCNL patients) and psychiatric disorders (PD; n = 78). Two stringency levels for a positive antibody index (AI) evaluation (AI ≥ 1.5 and 2.0) were applied, and MRZR was considered positive in cases with ≥ 2 positive AIs (MRZR-2). Using the common AI threshold of ≥ 1.5, MS patients exhibited positive MRZR-2 (58.1%) more frequently than PCNSL (8.1%) and PD patients (2.6%; p < 0.0001 for each comparison with the MS group) corresponding to a positive predictive value (PPV) of 89.6% and a negative predictive value (NPV) of 78.0%. On applying the stricter AI threshold of ≥ 2.0, 37.8% of MS patients were MRZR-2 positive; however, all patients with PCNSL and PD were MRZR-2 negative (p < 0.0001 for each comparison with the MS cohort) resulting in a PPV of 100% and an NPV of 71.4%. Consequently, a positive MRZR-2 result may contribute toward the distinction between MS and PCNSL owing to its high specificity and PPV for MS in the context of the present study. Among the other CSF parameters only a quantitative intrathecal IgG synthesis (present in 49.3% of MS patients but in none of the PCNSL or PD patients; p < 0.0001 for each comparison with the MS group) reliably indicated MS rather than PCNSL.

Psychiatric syndromes other than dementia.

There is wide variability in how psychiatry guidelines and textbooks address the question of cerebrospinal fluid (CSF) diagnostics in the screening of psychiatric disorders. A United States-based textbook confirms that there is no consensus about which laboratory investigation should be routinely performed in psychiatric patients, but with respect to CSF diagnostics, the differences are even more striking. A survey among European experts showed a wide variety of opinions regarding clinical use and criteria in various countries of Europe and worldwide: some psychiatrists, mostly university hospital-based, recommended performing CSF diagnostics in every patient first experiencing severe mental illness (SMI), but especially in patients from the schizophrenia spectrum, whereas others almost never perform CSF examinations themselves and usually refer patients to neurology departments if necessary. Minor neurologic signs are generally frequent in SMI, mainly in affective and schizophrenic disorders. Even with neurologic signs present, there are no clear guidelines regarding CSF evaluation, leaving doctors with experience-based decision making. However, the field is evolving. A recent review provides helpful yellow and red flags for differential diagnosis of SMI from autoimmune encephalitis; interestingly, minor CSF abnormalities are considered a red flag, suggesting that CSF should be routinely performed in acute psychiatric patients. There are reports of single cases identified as an established neurologic disorder: patients within affective and schizophrenic spectrum disorders systematically underwent CSF examination, and were rediagnosed based on CSF results. This was often to the surprise of the psychiatric doctors. Overall, an increasing number of psychiatrists believe that CSF is too rarely examined in psychiatric patients. This chapter provides an overview of differential diagnostic issues in SMI, particularly for new-onset cases. The general recommendations regarding CSF examination procedures can be found in other chapters of this book. Here we focus on specific aspects of differential diagnosis in SMI. Also, there will be an overview of admittedly limited CSF research efforts in psychiatric disorders, focusing on more recent CSF studies. CSF studies in SMI performed with state-of-the-art methods, for example proteomics or assessments of cytokines, were intriguing but difficult to interpret and required critical considerations regarding respective methodology, an undertaking which is outside the scope of this chapter.

Comparisons between Psychiatric Symptoms of Patients with Anti-NMDAR Encephalitis and New-Onset Psychiatric Patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially lethal autoimmune disease. Early diagnosis and immunotherapy can improve prognosis; however, early prominent psychiatric symptoms have led to misdiagnosis in numerous cases, delaying diagnosis and treatment. This study aimed to explore the clinical features and psychiatric symptoms of anti-NMDAR encephalitis and the association between antibody titers and psychiatric symptoms. METHODS: In this retrospective study, 43 patients with anti-NMDAR encephalitis and 70 new-onset psychiatric patients were enrolled. Psychiatric symptoms were assessed by trained psychiatrists using the Positive and Negative Syndrome Scale. RESULTS: There were significant differences in psychiatric symptoms between the antibody-positive and antibody-negative groups. The item scores for poor rapport (p < 0.01), difficulty in abstract thinking (p < 0.01), lack of spontaneity and flow of conversation (p < 0.01), unusual thought content (p < 0.01), and disorientation (p < 0.01) were significantly higher in the antibody-positive group, while the item scores for delusions (p < 0.01) were significantly higher in the antibody-negative group. These differences all remained significant after Holm-Bonferroni correction. In the antibody-positive group, scores for each item, subscale, and factor increased with increases in antibody titer, particularly for delusions (p < 0.05) and hallucinatory behavior (p < 0.01). Thereafter, only hallucinatory behavior remained significant. CONCLUSIONS: Patients with anti-NMDAR encephalitis with initial psychiatric symptoms may have the following characteristics: poor rapport, difficulty in abstract thinking, lack of spontaneity and flow of conversation, unusual thought content, and disorientation. Furthermore, antibody titer may be associated with psychiatric symptom severity, especially in hallucinatory behavior.

What is the significance of onconeural antibodies for psychiatric symptomatology? A systematic review.

BACKGROUND: Patients with intracellular onconeural antibodies may present with neuro-psychiatric syndromes. We aimed to evaluate the evidence for an association between well-characterized onconeural antibodies and psychiatric symptoms in patients with and without paraneoplastic central nervous system syndromes. METHODS: Eligible studies were selected from 1980 until February 2017 according to standardized review criteria and evaluated using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). We included studies describing the psychiatric symptomatology of onconeural antibody positive patients and the prevalence of onconeural antibodies in patients with psychiatric disorders. RESULTS: Twenty-seven studies met the inclusion criteria. Six studies reported on the prevalence of well-characterized onconeural antibodies in patients with different psychiatric disorders, ranging from 0% to 4.9%. Antibody prevalence in controls was available from three studies, ranging from 0% to 2.8%. Data heterogeneity precluded a meta-analysis. Two cerebrospinal fluid studies found well-characterized onconeural antibodies in 3.5% and 0% of patients with psychotic and depressive syndromes, respectively. CONCLUSIONS: The available evidence suggests that the prevalence of well-characterized onconeural antibodies in patients with psychiatric disorders is generally low. However, the question whether onconeural antibodies are important in select patients with a purely psychiatric phenotype needs to be addressed by appropriately designed studies in the future.