Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients

Abstract

Immunological mechanisms and therapy approaches in psychotic syndromes were recently supported by the discovery of autoantibody-associated limbic and non-limbic encephalitis. However, how clinical diagnostic procedures in psychiatry should be adapted to these new insights is still unclear. In this study, we analyzed the cerebrospinal fluid (CSF) and neuroimmunological alterations and their association with cerebral MRI (cMRI) and electroencephalographic (EEG) findings. From 2006 to 2013, we acquired 180 CSF samples from psychotic patients. Between 2006 and 2009, CSF examinations were only performed in cases in which organic brain disease was suspected. Since then, this procedure has been integrated into our routine diagnostic workup. CSF basic diagnostics were supplemented by measuring antineuronal antibodies against intracellular synaptic antigens, antibodies against intracellular onconeural antigens, antibodies against neuronal cell surface antigens and thyroid antibodies. In addition, cMRIs and EEGs were conducted. We found white cell counts elevated in 3.4% of the cases, albumin quotient elevated in 21.8%, and protein concentration elevated in 42.2%. Evidence of intrathecal immunoglobulin synthesis was found in 7.2% of the cases. Antibodies measured against neuronal cell surface antigens were positive in 3.2%. Reactivity on antibodies against intracellular onconeural antigens were detected in 3.5%. Serum thyroid antibodies were elevated in 24.7%. Abnormalities were found in 39.5% of cMRIs and in 34.3% of EEGs. The main finding of our study was the high prevalence of CSF and autoantibody abnormalities in 54.4% of psychotic patients. In combination with cMRIs and EEGs, 75.6% showed abnormal findings. Our results are discussed with regard to the concept of immunological encephalopathy. Future studies should analyze the efficacy of immunomodulatory therapies.

Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders

“…To date, four studies that have screened individuals with schizophrenia spectrum disorders for the aforementioned antibodies have included CSF findings [10, 16, 29, 40], and three have yielded positive results [10, 16, 40]. The methodological details of these studies are outlined in Table 1.…”

Autoantibodies in Neuropsychiatric Disorders

“…IgGs against the GluN1a subunit were described in two first episode catatonic schizophrenic patients (probably misdiagnosed NMDA-R encephalitis), while two other paranoid schizophrenia patients presented IgGs against GluN1a/2b, in lower titers, which declined during remission also shown in other studies [115,141,145]. Curiously, only the two patients with anti-GluN1 IgG autoantibodies presented IgG positive titers in CSF, a controversial result based on the 3.2% reactivity to neuronal surface antigens in CSF found in a psychotic disorder cohort (0.8% to NMDA-R and 2.4% to VGKC complex) [144]. Another study showed GluN1 IgG autoantibodies in 5 out of 43 children with a first episode of acute psychosis, screened by a more objective variety of the CBA using flow cytometry [160].…”

“…The frequency of autoantibodies to NMDA-R and VGKC complex in different studies ranged from 0% to 10% in cohorts of first-episode psychosis or schizophrenia [38,122,144,159,161,162]. Nevertheless, the results are controversial, since a number of other studies did not find autoantibodies in neuropsychiatric cohorts [146,159,162,163] or not specific to the disease [45,122].…”

“…Autoantibodies to GAD have been studied in a schizophrenia cohort where no autoantibodies were found in any of the 180 CSF samples [144]. Only a single case has been reported, where a schizophrenia patient presented elevated serum titers against GAD [154].…”

“…Presumably, a number of antigens involved in neuropsychiatric disorders are still not well understood demanding further work to identify novel autoantibody targets and help to better diagnose autoimmune patients' subgroups and understand disease mechanisms. n/a n/a HTR-1A + [148] n/a n/a n/a mAChR + [147,148] + [147,164] n/a n/a nAChR + [149] n/a n/a n/a GAD +/´ [144,154]´ [99] n/a + [154] FR + [202,212] n/a n/a n/a…”