Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

Effect of eccentric fixation on the steady-state pattern electroretinogram.

PURPOSE: The steady-state pattern electroretinogram (ssPERG) is used to assess retinal ganglion cell function in a variety of research contexts and diagnostic applications. In certain groups of patients or study participants, stable central fixation of the stimulus is not guaranteed. The present study aimed at assessing the effects of misfixation on the ssPERG response to checkerboard reversal stimuli. METHODS: Using two check sizes (0.8° and 15°), we compared ssPERG responses for several amounts of fixation deviation, ranging from 0° to 19° horizontally and from 0° to 14° diagonally. The stimulus area extended to 15° eccentricity, stimulus reversal rate was 15/s. RESULTS: Up to around 7° eccentricity, there was no sizable effect of fixation deviation under most conditions. Effects were somewhat larger for nasal than for temporal deviation, in particular for small checks. Diagonal deviation was associated with a response to luminance onset/offset at 7.5 Hz (subharmonic of the reversal rate), most prominently when the interior of a large check was fixated. CONCLUSION: Generally, moderate inaccuracies of fixation do not have a sizable effect on ssPERG amplitude. However, with large checks, the luminance response has to be considered.

Cerebrospinal fluid findings in patients with obsessive-compulsive disorder, Tourette syndrome, and PANDAS: A systematic literature review.

BACKGROUND: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS. METHODS: A systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool. RESULTS: Meta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies. CONCLUSIONS: This systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

Increased cerebral lactate levels in adults with autism spectrum disorders compared to non-autistic controls: a magnetic resonance spectroscopy study.

INTRODUCTION: Autism spectrum disorder (ASD) encompasses a heterogeneous group with varied phenotypes and etiologies. Identifying pathogenic subgroups could facilitate targeted treatments. One promising avenue is investigating energy metabolism, as mitochondrial dysfunction has been implicated in a subgroup of ASD. Lactate, an indicator of energy metabolic anomalies, may serve as a potential biomarker for this subgroup. This study aimed to examine cerebral lactate (Lac+) levels in high-functioning adults with ASD, hypothesizing elevated mean Lac+ concentrations in contrast to neurotypical controls (NTCs). MATERIALS AND METHODS: Magnetic resonance spectroscopy (MRS) was used to study cerebral Lac+ in 71 adults with ASD and NTC, focusing on the posterior cingulate cortex (PCC). After quality control, 64 ASD and 58 NTC participants remained. Lac+ levels two standard deviations above the mean of the control group were considered elevated. RESULTS: Mean PCC Lac+ levels were significantly higher in the ASD group than in the NTC group (p = 0.028; Cohen's d = 0.404), and 9.4% of the ASD group had elevated levels as compared to 0% of the NTCs (p = 0.029). No significant correlation was found between blood serum lactate levels and MRS-derived Lac+ levels. LIMITATIONS: A cautious interpretation of our results is warranted due to a p value of 0.028. In addition, a higher than anticipated proportion of data sets had to be excluded due to poor spectral quality. CONCLUSION: This study confirms the presence of elevated cerebral Lac+ levels in a subgroup of adults with ASD, suggesting the potential of lactate as a biomarker for mitochondrial dysfunction in a subgroup of ASD. The lower-than-expected prevalence (20% was expected) and moderate increase require further investigation to elucidate the underlying mechanisms and relationships with mitochondrial function.

Altered markers of mitochondrial function in adults with autism spectrum disorder.

Previous research suggests potential mitochondrial dysfunction and changes in fatty acid metabolism in a subgroup of individuals with autism spectrum disorder (ASD), indicated by higher lactate, pyruvate levels, and mitochondrial disorder prevalence. This study aimed to further investigate potential mitochondrial dysfunction in ASD by assessing blood metabolite levels linked to mitochondrial metabolism. Blood levels of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, pyruvate, free and total carnitine, as well as acylcarnitines were obtained in 73 adults with ASD (47 males, 26 females) and compared with those of 71 neurotypical controls (NTC) (44 males, 27 females). Correlations between blood parameters and psychometric ASD symptom scores were also explored. Lower CK (pcorr = 0.045) levels were found exclusively in males with ASD compared to NTC, with no such variation in females. ALT and AST levels did not differ significantly between both groups. After correction for antipsychotic and antidepressant medication, CK remained significant. ASD participants had lower serum lactate levels (pcorr = 0.036) compared to NTC, but pyruvate and carnitine concentrations showed no significant difference. ASD subjects had significantly increased levels of certain acylcarnitines, with a decrease in tetradecadienoyl-carnitine (C14:2), and certain acylcarnitines correlated significantly with autistic symptom scores. We found reduced serum lactate levels in ASD, in contrast to previous studies suggesting elevated lactate or pyruvate. This difference may reflect the focus of our study on high-functioning adults with ASD, who are likely to have fewer secondary genetic conditions associated with mitochondrial dysfunction. Our findings of significantly altered acylcarnitine levels in ASD support the hypothesis of altered fatty acid metabolism in a subset of ASD patients.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting as cortisone sensible psychosis with reversible leukoencephalopathy.

INTRODUCTION: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a frequently discussed neuropsychiatric syndrome with elevated thyroid antibodies in the context of various clinical neuropsychiatric phenotypes. MRI abnormalities are usually nonspecific and treatment can be complex. CASE STUDY: We present a case of a woman in her sixties with SREAT whose psychosis kept worsening under cortisone tapering. After three years with cortisone side effects, therapy was changed to plasmapheresis and rituximab treatment with an excellent initial response, subacute unexplained deterioration with extensive leukoencephalopathy on MRI shortly after, and full recovery with regression of leukoencephalopathy afterwards. DISCUSSION: SREAT varies in clinical and diagnostic presentation. Its precise pathophysiology is unknown, as are the best treatment protocols. The case illustrates that some patients with SREAT syndrome might end up in constellations, in which it proves difficult to wean off steroid treatment and illustrates treatment alternatives such as plasmapheresis and/or rituximab. In addition, it highlights leukoencephalopathy as possible MRI finding in the context of SREAT. Further research is necessary to fully comprehend the (potentially different) pathomechanisms and courses of SREAT.

Autoantibodies in patients with obsessive-compulsive disorder: a systematic review.

Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are high. Emerging evidence suggests that biological components, especially autoimmune processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. The following search strategy was used to search PubMed: "(OCD OR obsessive-compulsive OR obsessive OR compulsive) AND (antib* OR autoantib* OR auto-antib* OR immunoglob* OR IgG OR IgM OR IgA)". Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2], paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and "anti-brain" structures) and four with autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome, one with neuropsychiatric lupus, and one with anti-phospholipid autoantibodies). Six patients (67%) benefited from immunotherapy. In addition, eleven cross-sectional studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with inconsistent results, but in six studies an association between autoantibodies and OCD was suggested. In summary, the available case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with OCD compared with healthy controls are needed.

Deep clinical phenotyping of patients with obsessive-compulsive disorder: an approach towards detection of organic causes and first results.

In the revised diagnostic classification systems ICD-11 and DSM-5, secondary, organic forms of obsessive-compulsive disorder (OCD) are implemented as specific nosological entities. Therefore, the aim of this study was to clarify whether a comprehensive screening approach, such as the Freiburg-Diagnostic-Protocol for patients with OCD (FDP-OCD), is beneficial for detecting organic OCD forms. The FDP-OCD includes advanced laboratory tests, an expanded magnetic resonance imaging (MRI) protocol, and electroencephalography (EEG) investigations as well as automated MRI and EEG analyses. Cerebrospinal fluid (CSF), [18F]fluorodeoxyglucose positron emission tomography, and genetic analysis were added for patients with suspected organic OCD. The diagnostic findings of the first 61 consecutive OCD inpatients (32 female and 29 male; mean age: 32.7 ± 12.05 years) analyzed using our protocol were investigated. A probable organic cause was assumed in five patients (8%), which included three patients with autoimmune OCD (one patient with neurolupus and two with specific novel neuronal antibodies in CSF) and two patients with newly diagnosed genetic syndromes (both with matching MRI alterations). In another five patients (8%), possible organic OCD was detected (three autoimmune cases and two genetic cases). Immunological serum abnormalities were identified in the entire patient group, particularly with high rates of decreased "neurovitamin" levels (suboptimal vitamin D in 75% and folic acid in 21%) and increased streptococcal (in 46%) and antinuclear antibodies (ANAs; in 36%). In summary, the FDP-OCD screening led to the detection of probable or possible organic OCD forms in 16% of the patients with mostly autoimmune forms of OCD. The frequent presence of systemic autoantibodies such as ANAs further support the possible influence of autoimmune processes in subgroups of patients with OCD. Further research is needed to identify the prevalence of organic OCD forms and its treatment options.

Left insular cortical thinning differentiates the inattentive and combined subtype of adult attention-deficit/hyperactivity disorder.

BACKGROUND: Neuroimaging studies in attention-deficit/hyperactivity disorder (ADHD) demonstrated decreased global gray matter volume. In terms of surface parameters, most investigations focused on cortical thickness with a multi-center MEGA-analysis indicating cortical thinning in children, but not in adults with ADHD. In this single-scanner study, for the first time in adult ADHD, we additionally examined metrics beyond cortical thickness and surface area, namely sulcal depth and fractal dimension as measures of cortical alteration and complexity. Unlike most previous studies, ADHD subtypes were considered. METHODS: As part of the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS), surface parameters were analyzed in 131 adults with ADHD (66 combined, 60 inattentive and 5 hyperactive/impulsive subtype) and 95 healthy controls with the Computational Anatomy Toolbox (CAT12) using Statistical Parametric Mapping Software (SPM). RESULTS: Neither at the vertex- nor at the region of interest-level, the ADHD and control group differed significantly with regard to cortical thickness, gyrification index, sulcal depth or fractal dimension. Contrasting the combined and the inattentive subtype, patients of the combined subtype showed a significant thinning of the left anterior insular cortex. Thinner left pars opercularis cortical thickness was associated with symptoms of hyperactivity/restlessness. CONCLUSIONS: Resembling previous findings of a correlation of the left anterior insular gray matter volume with oppositional symptoms in adolescents with ADHD, we detected left anterior insular cortical thinning in the ADHD combined subtype. Left insular cortical thickness could represent a potential marker to distinguish the predominantly inattentive and the combined ADHD subtype in adulthood.

Cerebrospinal fluid findings in adult patients with obsessive-compulsive disorder: A retrospective analysis of 54 samples.

OBJECTIVES: Obsessive-compulsive disorder (OCD) can rarely be associated with immunological aetiologies, most notably in Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections and possibly in autoimmune encephalitis. As cerebrospinal fluid (CSF) analysis is a sensitive method for assessing neuroinflammation, this retrospective study analysed basic CSF parameters and well-characterised as well as novel neuronal autoantibodies in OCD to screen for signs of autoimmunity. METHODS: Basic CSF findings of 54 adult OCD patients suspected of an organic aetiology were retrospectively compared to a control group of mentally healthy patients (N = 39) with idiopathic intracranial hypertension. Further subgroup analysis included testing for well-characterised neuronal IgG autoantibodies and tissue-based assays using indirect immunofluorescence to screen for novel brain autoantibodies. RESULTS: Elevated protein in the CSF of OCD patients compared to the control group (p = 0.043) was identified. Inflammatory markers (pleocytosis/oligoclonal bands/increased IgG-index) were detected in 7% of all patients with OCD. Well-characterised neuronal autoantibodies were not found in any OCD patient, whereas 6/18 (33%) CSF samples showed binding on mouse brain sections in tissue-based assays (binding to neuropil in the basal ganglia/brainstem, cilia of granule cells, blood vessels, nuclear/perinuclear structures). CONCLUSIONS: While elevated CSF protein is merely a weak indicator of blood CSF barrier dysfunction, the presence of inflammatory CSF changes and novel brain autoantibodies in CSF may indicate OCD subtypes with inflammatory pathomechanism and supports the hypothesis of a rare "autoimmune OCD" subtype.

Neurodegeneration Markers in the Cerebrospinal Fluid of 100 Patients with Schizophrenia Spectrum Disorder.

BACKGROUND: Schizophrenia spectrum disorders (SSD) can be associated with neurodegenerative processes causing disruption of neuronal, synaptic, or axonal integrity. Some previous studies have reported alterations of neurodegenerative markers (such as amyloid beta [Aß], tau, or neurofilaments) in patients with SSD. However, the current state of research remains inconclusive. Therefore, the rationale of this study was to investigate established neurodegenerative markers in the cerebrospinal fluid (CSF) of a large group of patients with SSD. STUDY DESIGN: Measurements of Aß1-40, Aß1-42, phospho- and total-tau in addition to neurofilament light (NFL), medium (NFM), and heavy (NFH) chains were performed in the CSF of 100 patients with SSD (60 F, 40 M; age 33.7 ± 12.0) and 39 controls with idiopathic intracranial hypertension (33 F, 6 M; age 34.6 ± 12.0) using enzyme-linked immunoassays. STUDY RESULTS: The NFM levels were significantly increased in SSD patients (P = .009), whereas phospho-tau levels were lower in comparison to the control group (P = .018). No other significant differences in total-tau, beta-amyloid-quotient (Aß1-42/Aß1-40), NFL, and NFH were identified. CONCLUSIONS: The findings argue against a general tauopathy or amyloid pathology in patients with SSD. However, high levels of NFM, which has been linked to regulatory functions in dopaminergic neurotransmission, were associated with SSD. Therefore, NFM could be a promising candidate for further research on SSD.

Altered cytokine levels in the cerebrospinal fluid of adult patients with autism spectrum disorder.

BACKGROUND: Despite intensive research, the etiological causes of autism spectrum disorder (ASD) remain elusive. Immunological mechanisms have recently been studied more frequently in the context of maternal autoantibodies and infections, as well as altered cytokine profiles. For the detection of immunological processes in the central nervous system, analyses of cerebrospinal fluid (CSF) are advantageous due to its proximity to the brain. However, cytokine studies in the CSF of ASD patients are sparse. METHODS: CSF was collected from a patient sample of 24 adults (m = 16, f = 8, age: 30.3 ± 11.6 years) with ASD and compared to a previously published mentally healthy control sample of 39 neurological patients with idiopathic intracranial hypertension. A magnetic bead multiplexing immunoassay was used to measure multiple cytokines in CSF. RESULTS: Significantly decreased interferon-γ-induced protein-10 (p = 0.001) and monocyte chemoattractant protein-1 (p = 0.041) levels as well as significantly higher interleukin-8 levels (p = 0.041) were detected in patients with ASD compared with the control group. CONCLUSION: The main finding of this study is an altered cytokine profile in adult patients with ASD compared to the control group. This may indicate immune dysregulation in a subgroup of adult ASD patients. Further studies in larger cohorts that examine a broader spectrum of chemokines and cytokines in general are needed to detect possible specific immune signatures in ASD.

Obsessive-compulsive symptoms in two patients with chromosomal disorders involving the X chromosome.

INTRODUCTION: The etio-pathophysiology of obsessive-compulsive disorder (OCD) can be explained using a biopsychosocial model. Little is known about obsessive-compulsive symptoms (OCS) in the context of chromosomal disorders involving the X chromosome. METHODS: Case studies of two patients with chromosomal disorders involving the X chromosome (Patient 1 with a variant of Turner syndrome and Patient 2 with triple X syndrome). RESULTS: Both patients were treated due to severe OCS. In the research MRI analysis, the most pronounced MRI change in both patients was a gray matter volume loss in the orbitofrontal cortex. Patient 1 additionally showed left mesiotemporal changes. Patient 2 presented with global gray matter volume reduction, slowing in EEG, and a reduced intelligence quotient. DISCUSSION: OCS could occur in the context of Turner syndrome or triple X syndrome. The detected MRI changes would be compatible with dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD pathophysiology. Further studies with larger patient groups should investigate whether this association can be validated.