Structural and functional retinal alterations in patients with paranoid schizophrenia.

Ophthalmological methods have increasingly raised the interest of neuropsychiatric specialists. While the integrity of the retinal cell functions can be evaluated with the electroretinogram (ERG), optical coherence tomography (OCT) allows a structural investigation of retinal layer thicknesses. Previous studies indicate possible functional and structural retinal alterations in patients with schizophrenia. Twenty-five patients with paranoid schizophrenia and 25 healthy controls (HC) matched for age, sex, and smoking status participated in this study. Both, ERG and OCT were applied to obtain further insights into functional and structural retinal alterations. A significantly reduced a-wave amplitude and thickness of the corresponding para- and perifoveal outer nuclear layer (ONL) was detected in patients with paranoid schizophrenia with a positive correlation between both measurement parameters. Amplitude and peak time of the photopic negative response (PhNR) and thickness of the parafoveal ganglion cell layer (GCL) were decreased in patients with schizophrenia compared to HC. Our results show both structural and functional retinal differences between patients with paranoid schizophrenia and HC. We therefore recommend the comprehensive assessment of the visual system of patients with schizophrenia, especially to further investigate the effect of antipsychotic medication, the duration of illness, or other factors such as inflammatory or neurodegenerative processes. Moreover, longitudinal studies are required to investigate whether the functional alterations precede the structural changes.

Spectrum of Novel Anti-Central Nervous System Autoantibodies in the Cerebrospinal Fluid of 119 Patients With Schizophreniform and Affective Disorders.

BACKGROUND: Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies, such as those against the NMDA receptor. However, the presence of additional anti-central nervous system (CNS) autoantibodies in these patients has not been systematically assessed. METHODS: Serum and cerebrospinal fluid (CSF) from patients with schizophreniform and affective syndromes were analyzed for immunoglobulin G anti-CNS autoantibodies using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue as part of an extended routine clinical practice. After an initial assessment of patients with red flags for autoimmune psychosis (n = 30), tissue-based testing was extended to a routine procedure (n = 89). RESULTS: Based on the findings from all 119 patients, anti-CNS immunoglobulin G autoantibodies against brain tissue were detected in 18% (n = 22) of patients (serum 9%, CSF 18%) following five principal patterns: 1) against vascular structures, most likely endothelial cells (serum 3%, CSF 8%); 2) against granule cells in the cerebellum and/or hippocampus (serum 4%, CSF 6%); 3) against myelinated fibers (serum 2%, CSF 2%); 4) against cerebellar Purkinje cells (serum 0%, CSF 2%); and 5) against astrocytes (serum 1%, CSF 1%). The patients with novel anti-CNS autoantibodies showed increased albumin quotients (p = .026) and white matter changes (p = .020) more frequently than those who tested negative for autoantibodies. CONCLUSIONS: The study demonstrates five novel autoantibody-binding patterns on brain tissue of patients with schizophreniform and affective syndromes. CSF yielded positive findings more frequently than serum analysis. The frequency and spectrum of autoantibodies in these patient groups may be broader than previously thought.

Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases.

BACKGROUND: Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. METHODS: The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. RESULTS: We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. 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.

Probable Autoimmune Depression in a Patient With Multiple Sclerosis and Antineuronal Antibodies.

BACKGROUND: In a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed. CASE PRESENTATION: The authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement. CONCLUSION: The present patient suffered from a probable "autoimmune depression" in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

Psychiatric Manifestation of Anti-LGI1 Encephalitis.

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is typically characterized by limbic encephalitis, faciobrachial dystonic seizures and hyponatremia. The frequency with which milder forms of anti-LGI1 encephalitis mimic isolated psychiatric syndromes, such as psychoses, or may lead to dementia if untreated, is largely unknown. CASE PRESENTATION: Here, the authors present a 50-year-old patient who had suffered from neurocognitive deficits and predominant delusions for over one and a half years. He reported a pronounced feeling of thirst, although he was drinking 10-20 liters of water each day, and he was absolutely convinced that he would die of thirst. Due to insomnia in the last five years, the patient took Z-drugs; later, he also abused alcohol. Two years prior to admission, he developed a status epilepticus which had been interpreted as a withdrawal seizure. In his serum, anti-LGI1 antibodies were repeatedly detected by different independent laboratories. Cerebrospinal fluid analyses revealed slightly increased white blood cell counts and evidence for blood-brain-barrier dysfunction. Magnetic resonance imaging showed hyperintensities mesio-temporally and in the right amygdala. In addition, there was a slight grey-white matter blurring. A cerebral [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) examination of his brain showed moderate hypometabolism of the bilateral rostral mesial to medial frontal cortices. Treatment attempts with various psychotropic drugs remained unsuccessful in terms of symptom relief. After the diagnosis of probable chronified anti-LGI1 encephalitis was made, two glucocorticoid pulse treatments were performed, which led to a slight improvement of mood and neurocognitive deficits. Further therapy was not desired by the patient and his legally authorized parents. 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. Based on this case, the authors advocate the concept-long established in many chronic inflammatory diseases in rheumatology-of distinguishing between an "acute inflammatory state" and a "state of organ damage" in autoimmune psychosis resembling neurodegenerative mechanisms.

Psychiatric Presentation of Anti-NMDA Receptor Encephalitis.

Background: Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is an autoimmune condition characterized by neuropsychiatric symptoms, including epileptic seizures, movement disorders, autonomic instability, disturbances of consciousness, paranoia, delusions, and catatonia. Ovarian teratomas and viral infections, typically Herpes simplex viruses, have previously been demonstrated to precipitate anti-NMDA receptor encephalitis, but in many cases, the trigger remains unclear. The detection of anti-NMDA receptor antibodies in cerebrospinal fluid (CSF), in combination with other CSF, electroencephalography (EEG), or magnetic resonance imaging (MRI) abnormalities, typically leads to diagnostic clarification. Case Presentation: We present the case of a 22-year-old female patient who developed an acute polymorphic psychotic episode 3 days after receiving a booster vaccination against tetanus, diphtheria, pertussis, and polio (Tdap-IPV). Her psychiatric symptoms were initially diagnosed as a primary psychiatric disorder. Her MRI, EEG, and CSF results were non-specific. Anti-NMDA receptor IgG antibodies against the GluN1 subunit were detected in her serum (with a maximum titer of 1:320), but not in her CSF. [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) showed pronounced relative hypermetabolism of her association cortices and a relative hypometabolism of the primary cortices, on the basis of which an anti-NMDA receptor encephalitis diagnosis was made, and treatment with a steroid pulse was initiated. The treatment led to fast and convincing clinical improvement with normalization of neuropsychological findings, considerable improvement of FDG-PET findings, and decreasing antibody titers. Conclusion: The patient's psychiatric symptoms were most likely caused by anti-NMDA receptor encephalitis. Her polymorphic psychotic symptoms first occurred after she had received a Tdap-IPV booster vaccination. Although the vaccination cannot have caused the initial antibody formation since IgG serum antibodies were detected only 3 days after administration of the vaccine, the vaccine may have exerted immunomodulatory effects. MRI, EEG, and CSF findings were non-specific; however, FDG-PET identified brain involvement consistent with anti-NMDA receptor encephalitis. This case shows the importance of implementing a multimodal diagnostic work-up in similar situations. The negative CSF antibody finding furthermore fits to the hypothesis that the brain may act as an immunoprecipitator for anti-NMDA receptor antibodies.

New Variant of MELAS Syndrome With Executive Dysfunction, Heteroplasmic Point Mutation in the MT-ND4 Gene (m.12015T>C; p.Leu419Pro) and Comorbid Polyglandular Autoimmune Syndrome Type 2.

Background: Mitochondrial diseases are caused by dysfunctions in mitochondrial metabolic pathways. MELAS syndrome is one of the most frequent mitochondrial disorders; it is characterized by encephalopathy, myopathy, lactic acidosis, and stroke-like episodes. Typically, it is associated with a point mutation with an adenine-to-guanine transition at position 3243 of the mitochondrial DNA (mtDNA; m.3243A>G) in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene. Other point mutations are possible and the association with polyglandular autoimmune syndrome type 2 has not yet been described. Case presentation: We present the case of a 25-year-old female patient with dysexecutive syndrome, muscular fatigue, and continuous headache. Half a year ago, she fought an infection-triggered Addison crisis. As the disease progressed, she had two epileptic seizures and stroke-like episodes with hemiparesis on the right side. Cerebral magnetic resonance imaging showed a substance defect of the parieto-occipital left side exceeding the vascular territories with a lactate peak. The lactate ischemia test was clearly positive, and a muscle biopsy showed single cytochrome c oxidase-negative muscle fibers. Genetic testing of blood mtDNA revealed a heteroplasmic base exchange mutation in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4) gene (m.12015T>C; p.Leu419Pro; heteroplasmy level in blood 12%, in muscle tissue: 15%). The patient suffered from comorbid autoimmune polyglandular syndrome type 2 with Hashimoto's thyroiditis, Addison's disease, and autoimmune gastritis. In addition, we found increased anti-glutamic acid decarboxylase 65, anti-partial cell, anti-intrinsic factor, and anti-nuclear antibodies. Conclusion: We present an atypical case of MELAS syndrome with predominant symptoms of a dysexecutive syndrome, two stroke-like episodes, and fast-onset fatigue. The symptoms were associated with a not yet described base and aminoacid exchange mutation in the MT-ND4 gene (m.12015T>C to p.Leu419Pro). The resulting changed protein complex in our patient is part of the respiratory chain multicomplex I and might be the reason for the mitochondriopathy. However, different simulations for pathogenetic relevance are contradictory and rather speak for a benign variant. To our knowledge this case report is the first reporting MELAS syndrome with comorbid polyglandular autoimmune syndrome type 2. Screening for autoimmune alterations in those patients is important to prevent damage to end organs.

Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by difficulties in social communication, unusually restricted, repetitive behavior and interests, and specific abnormalities in language and perception. The precise etiology of ASD is still unknown and probably heterogeneous. In a subgroup of patients, toxic environmental exposure might lead to an imbalance between oxidative stress and anti-oxidant systems. Previous serum and postmortem studies measuring levels of glutathione (GSH), the main cellular free radical scavenger in the brain, have supported the hypothesis that this compound might play a role in the pathophysiology of autism. METHODS: Using the method of single-voxel proton magnetic resonance spectroscopy (MRS), we analyzed the GSH signal in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) of 24 ASD patients with normal or above average IQs and 18 matched control subjects. We hypothesized that we would find decreased GSH concentrations in both regions. RESULTS: We did not find overall group differences in neurometabolites including GSH, neither in the dorsal ACC (Wilks' lambda test; p = 0.429) nor in the DLPFC (p = 0.288). In the dACC, we found a trend for decreased GSH signals in ASD patients (p = 0.076). CONCLUSIONS: We were unable to confirm our working hypothesis regarding decreased GSH concentrations in the ASD group. Further studies combining MRS, serum, and cerebrospinal fluid measurements of GSH metabolism including other regions of interest or even whole brain spectroscopy are needed.

Hypoglutamatergic state is associated with reduced cerebral glucose metabolism in anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first described in 2005 in association with ovarian teratoma. The diagnostic workup of this common autoimmune encephalitis includes cerebrospinal fluid analysis, electroencephalography, magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET). In addition to standard diagnostics, we performed metabolic investigations using proton magnet resonance spectroscopy ((1)H-MRS). CASE PRESENTATION: We describe the case of a non-limbic anti-NMDAR encephalitis with a long course of disease (21 months). Laboratory diagnostics showed antibodies against NMDAR; an MRI revealed unspecific findings. (1)H-MRS indicated a hypoglutamatergic state in the left prefrontal cortex associated with a left hemispherical hypometabolism on FDG-PET. Despite the long course of disease, immunosuppressive therapy with methylprednisolone and azathioprine led to almost complete remission of clinical symptoms. Clinical improvement developed in parallel with remarkable normalization of cerebral glucose metabolism on FDG-PET. CONCLUSION: This case of long-lasting extra-limbic anti-NMDAR encephalitis is of high clinical relevance. First, it illustrates that a very good outcome is possible even if adequate therapy is started only 21 months after the onset of severe symptoms. Second, it provides valuable insights into the pathophysiology of such anti-NMDAR encephalitis; these insights prove that anti-NMDAR encephalitis is linked not only to hyperglutamatergic signals but also to hypoglutamatergic states. These findings, contradictory at first glance, can be integrated within the model of excitatory/inhibitory imbalance and local area network inhibition.

Analysis of pure tar substances (polycyclic aromatic hydrocarbons) in the gas stream using ultraviolet visible (UV-Vis) spectroscopy and multivariate curve resolution (MCR).

The analysis of tar, mostly characterized as polycyclic aromatic hydrocarbons (PAHs), describes a topic that has been researched for years. An online analysis of tar in the gas stream in particular is needed to characterize the tar conversion or formation in the biomass gasification process. The online analysis in the gas is carried out with ultraviolet-visible (UV-Vis) spectroscopy (190-720 nm). This online analysis is performed with a measuring cell developed by the Fraunhofer Institute for Chemical Technology (ICT). To this day, online tar measurements using UV-Vis spectroscopy have not been carried out in detail. Therefore, PAHs are analyzed as follows. The measurements are split into different steps. The first step to prove the online method is to vaporize single tar substances. These experiments show that a qualitative analysis of PAHs in the gas stream with the used measurement setup is possible. Furthermore, it is shown that the method provides very exact results, so that a differentiation of various PAHs is possible. The next step is to vaporize a PAH mixture. This step consists of vaporizing five pure substances almost simultaneously. The interpretation of the resulting data is made using a chemometric interpretation method, the multivariate curve resolution (MCR). The verification of the calculated results is the main aim of this experiment. It has been shown that the tar mixture can be analyzed qualitatively and quantitatively (in arbitrary units) in detail using the MCR. Finally it is the main goal of this paper to show the first steps in the applicability of the UV-Vis spectroscopy and the measurement setup on online tar analysis in view of characterizing the biomass gasification process. Due to that, the gasification plant (at the laboratory scale), developed and constructed by the Fraunhofer ICT, has been used to vaporize these substances. Using this gasification plant for the experiments enables the usage of the measurement setup also for the spectroscopic analysis of the tar formation during the biomass gasification.

The NF-kappaB signalling pathway is involved in the LPS/IL-2-induced upregulation of FoxP3 expression in human CD4+CD25high regulatory T cells.

Regulatory T cells (Treg) have been found to be central for host defense regulation against microbial antigens, the prevention of allergic and autoimmune diseases and the suppression of effective tumor immune responses. However, the influence of the microenvironment and the mechanisms leading to their activation in the periphery still remain unclear. In vitro infection models revealed that survival and suppressive function of Treg is improved when they are confronted with lipopolysaccharide (LPS). Because LPS initiates signalling via the receptor Toll-like receptor 4 (TLR4) and the consequent activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we investigated TLR4 expression and NF-kappaB regulation in human Treg. We demonstrated that LPS in combination with IL-2 induces human CD25(+)FoxP3(+) T cells in vitro. FoxP3 expression of purified natural Treg increased and suppressive capacity was markedly improved compared with unstimulated Treg upon stimulation with LPS/IL-2. Furthermore, blockade of the NF-kappaB pathway by a selective inhibitor of IkappaB kinase (IKK)beta abrogated the upregulation of FoxP3 expression. Taken together, our results suggest an important role of the NF-kappaB signalling pathway for the induction and modulation of suppressive function of natural Treg, if they are confronted with TLR4-stimulating agents such as Gram-negative bacteria.

Long-Chain Polyphosphates Inhibit Growth of Clostridium tyrobutyricum in Processed Cheese Spreads.

The effect of novel food-grade long-chain polyphosphate formulations (JOHA HBS sodium polyphosphate glassy, 69 ± 1% P2O5, and two similar salts (HBS-1 and HBS-9) on the growth of Clostridium tyrobutyricum ATCC 25755 in liquid culture and in pasteurized, processed cheese spreads was evaluated. In broth, 0.1 % polyphosphate was sufficient to inhibit vegetative growth of the organism. In addition, a panel of 21 other gram-positive and 11 gram-negative bacteria were tested for their sensitivity against the polyphosphates. Whereas 17 of the gram-positives could be inhibited by 0.05 to 0.3% polyphosphate, none of the tested gram-negatives were affected. Two different cheese spread formulations (cheese blend A: 55% moisture, 47.2% fat in dry matter; cheese blend B: 55% moisture, 57% fat in dry matter) were fortified with 0.1 % to 1.0% polyphosphates, inoculated with 5 × 105 (cheese blend A) or 2.5 × 106 (cheese blend B) C. tyrobutyricum spores per gram, and incubated at 35°C for up to 7 weeks. Determination of viable cell counts was carried out at days 1, 9, 19, and 49 (cheese blend A) and 8, 16, 27, 35, and 50 (cheese blend B). While 0.1 % polyphosphate had little effect, higher concentrations were increasingly inhibitory to growth from a spore inoculum, to cell multiplication, and to gas formation. With 0.5% polyphosphate, onset of growth was delayed for about 3 weeks in cheese blend A, while this concentration was able to inhibit the organism in cheese blend B. In view of the experimental parameters selected (high initial contamination level; intrinsic and extrinsic parameters optimized for growth of clostridia), 0.5% polyphosphate may be sufficient to control C. tyrobutyricum growth under "normal" conditions, where initial spore counts are rather low, and storage temperatures are usually at or below 20°C. Moreover, clostridia were completely inhibited by 1.0% polyphosphate, which clearly indicated the usefulness of these polyphosphates for prevention of butyric blowing in pasteurized processed cheese spreads.