Impact of T cells on neurodegeneration in anti-GAD65 limbic encephalitis.

OBJECTIVE: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. METHODS: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long-standing GAD65-LE compared to controls in a cross-sectional manner. These data were related to each other within the GAD65-LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full-resolution human leukocyte antigen (HLA) genotyping of all patients was performed. RESULTS: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen-experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin-expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide-spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA-A*02:01 allele known to present the immunodominant GAD65114-123 peptide in humans. INTERPRETATION: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long-standing GAD65-LE.

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis.

OBJECTIVES: To report the neuropsychiatric features and frequency of NMDA receptor (NMDAR) and other neuronal immunoglobulin G antibodies in patients with first episode psychosis (FEP) and to assess the performance of reported warning signs and criteria for autoimmune psychosis (AP). METHODS: This was a prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed. RESULTS: One hundred five patients were included; their median age was 30 (range 14-75) years, and 44 (42%) were female. None had neuronal antibodies. Two of 105 (2%) had CSF pleocytosis, 4 of 100 (4%) had brain MRI abnormalities, and 3 of 73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled 2 sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and nonpsychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1,159 reported patients with FEP, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features). CONCLUSIONS: 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 neurologic symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.

Prognostic value of acute cerebrospinal fluid abnormalities in antibody-positive autoimmune encephalitis.

OBJECTIVE: To examine the prognostic value of CSF abnormalities in seropositive autoimmune encephalitis (AE). METHODS: We retrospectively studied 57 cases of seropositive AE. Primary outcomes were mortality and modified Rankin Scale, while secondary outcomes were first line treatment failure, ICU admission and relapse. Regression analysis was performed. RESULTS: CSF white cell count (WCC) was higher in the NMDAR group, while elevated protein was more common amongst other subtypes. We found an association between WCC >5 cells/mm3 and treatment failure (OR 16.0, p = 0.006)), and between WCC >20 cells/mm3 and ICU admission (OR 19.3, p = 0.026). CONCLUSIONS: Different subsets of AE have characteristic CSF abnormalities, which may aid recognition during early evaluation. CSF WCC had prognostic significance in our study.

Uncommon manifestations of a rare disease: a case of autoimmune GFAP astrocytopathy.

BACKGROUND: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported. CASE PRESENTATION: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition. CONCLUSION: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.

Case Report: Anti-LGI1 Encephalitis Following COVID-19 Vaccination.

Anti-leucine rich glioma inactivated 1 (LGI1) autoimmune encephalitis (AE) is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, faciobrachial dystonic seizures (FBDS) and refractory hyponatremia. Since December 2020, millions of people worldwide have been vaccinated against COVID-19. Several soft neurological symptoms like pain, headache, dizziness, or muscle spasms are common and self-limited adverse effects after receiving the COVID-19 vaccine. However, several major neurological complications, despite the unproven causality, have been reported since the introduction of the COVID-19 vaccine. Herein, we describe a 48 years old man presenting with rapidly progressive cognitive decline and hyponatremia diagnosed with anti LGI1 AE, occurring shortly after the second dose of mRNA COVID -19 vaccine and possibly representing a severe adverse event related to the vaccination. Response to high dose steroid therapy was favorable. As millions of people worldwide are currently receiving COVID-19 vaccinations, this case should serve to increase the awareness for possible rare autoimmune reactions following this novel vaccination in general, and particularly of anti-LGI1 AE.

Clinical features of nine cases of leucine-rich glioma inactivated 1 protein antibody-associated encephalitis.

To investigate clinical features of leucine-rich glioma inactivated 1 protein (LGI1) antibody-associated autoimmune encephalitis (AE). The clinical data were collected and analyzed in nine patients with LGI1 AE. All nine patients (100%) presented acute/subacute onset, had seizures, cognitive impairment, mental/behavioral abnormalities, six had sleep disorders and seven showed hyponatremia. Seizures manifested in three types: faciobranchial dystonia seizure (FBDS) (44%), mesial temporal lobe epilepsy (MTLE)-like seizure (66%), and focal to bilateral tonic-clonic seizure (FBTCS) (77%). Six of nine cases (66%) showed abnormalities in brain MRI, among them four showed high T2/flair signal on unilateral/bilateral hippocampus, two showed high T1/T2 signal on unilateral basal ganglia. All nine patients (100%) showed abnormalities in EEG, among them 1 (11%) showed diffuse slow waves, 8 (88%) showed focal slow waves; 6 (66%) revealed interictal epileptic discharges; ictal EEG was recorded in five patients, two were FBDS, three were MTLE-like seizure.LGI1 antibodies in serum and cerebrospinal fluid were both positive. No signs of tumor were found in all patients. Eight of nine patients received immunotherapy and antiepileptic drug (AED) treatment, one only treated with AED without immunotherapy. Eight patients improved significantly with seizure-free after immunotherapy, only one still had FBDS after immunotherapy and AED treatment. In LGI1 AE hippocampus and basal ganglia were two main targets, the corresponding seizure type was MTLE-like seizure and FBDS respectively. Diagnosis depended on detection of LGI1 antibodies in CSF. The incidence of tumor was low. The effect of immunotherapy was good and AEDs should be considered as add-on symptomatic treatment.

Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates.

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of 'neurological' autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or 'onconeuronal' ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB+, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB- patients (n = 199) were positive (screening+), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB+ with neuroAB-/screening+ patients than with neuroAB-/screening- patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB+ individuals were virtually indistinguishable from neuroAB-/screening+ patients in several major clinical features. In contrast, neuroAB-/screening- TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis.

Changes in levels of cytokines or soluble receptors in biological fluids may provide information on immunological pathomechanisms underlying the respective diseases. Here, we studied cytokine patterns of patients with autoimmune encephalitis (AE) before and after immunosuppressive treatment in order to identify possible biomarker candidates and to look for putatively involved pathomechanisms. We performed measurements in Cerebrospinal fluid (CSF) and serum of 7 patients suffering from AE with antibodies (ab) against Leucine-rich glioma-inactivated-protein 1 (LGI1) and 9 AE patients with Contactin-associated protein-like 2 (Caspr2) ab recruited from two tertiary AE centers in Magdeburg and Berlin, Germany. In the Magdeburg samples before and after treatment were available for the measurements and in the Berlin cohort samples were collected after treatment was initiated. First, we used a human cytokine array comprising 36 cytokines or soluble receptors to screen for biomarkers in CSF samples of 8 AE (before and after treatment), 4 herpes-simplex virus meningoencephalitis patients and 4 controls without neuroinflammation. Next, CCL2, CXCl10, CXCl13, Il -6 and sICAM1 were chosen as candidates and measured in CSF and serum with specific ELISA systems in all 16 AE patients, 14 controls without neuroinflammation and 7 herpes-simplex virus meningitis patients. Clinical outcome was assessed via modified Rankin scale. LGI1 and Caspr2 abs from the Magdeburg cohort were purified by chromatography. IgG subclasses of these LGI1 or Caspr2 abs were identified by immunoblot analysis. The levels of most candidate parameters were higher in the CSF of Caspr2 than of LGI1 AE patients and controls, but there were no significant changes of cytokine concentrations before and after initiating treatment. Thus, these parameters seem unsuited as surrogate biomarkers of disease. Significantly higher levels were observed in the CSFs of Caspr2 AE patients (CXCL13 and sICAM1) as well as in the serum of Caspr2 (CXCL10) and LGI1 AE patients (CXCL13) in comparison to control samples. These results suggest that neuro-immunological pathomechanisms may differ between Caspr2 and LGI1 AE patients. Caspr2 AE seems to elicit a higher immune response than LGI1 AE, which has no correlation to the respective IgG subclass combination of AE specific abs involved in each type of disease.

Presence of anti-neuronal antibodies in children with neurological disorders beyond encephalitis.

BACKGROUND: Anti-neuronal autoantibodies have been reported as the cause of several neurologic disorders other than encephalitis. Unfortunately, data are mostly based on serum analysis. Predictions about pathogenicity are thus limited. To determine the presence of so far unidentified autoantibody-derived neuroreactivity we analyzed cerebrospinal fluid (CSF) of children with neurological disorders other than encephalitis. PATIENTS AND METHODS: We did a retrospective analysis of CSF from 254 children with various neurologic diseases other than encephalitis and searched for reactivity against neuronal surface antigens by immunofluorescence on unfixed murine brain sections (tissue-based assay, TBA) and by commercial cell-based assays (CBA). A semi-quantitative fluorescence score classified our results and we described the clinical course of all positive patients with strong neuroreactivity. RESULTS: Strong anti-neuronal IgG immunoreactivity of unknown antigen specificity was detected in CSF samples of 10 pediatric patients (4%, n = 10/254) with unsolved neurological disorders. CSF inflammatory markers were elevated. Most patients did not or only partly recover. Five screening-positive patients presented with a combination of headache and visual impairment due to optic nerve atrophy. Our data suggest to consider inflammatory, autoantibody-related etiologies, especially in cases without definite diagnoses. CONCLUSIONS: We present an overview of CSF neuroreactivity in children with neurological disorders other than encephalitis, indicating the presence of unidentified anti-neuronal autoantibodies. As TBA enables screening for unknown autoantibodies, we suggest this method as a second step if commercial CBAs do not yield a result. Further studies are necessary to characterize such antibodies, evaluate pathogenicity, and answer the question whether positive CSF neuroreactivity should prompt an immunotherapeutic approach.

Low CSF CD4/CD8+ T-cell proportions are associated with blood-CSF barrier dysfunction in limbic encephalitis.

PURPOSE: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE. METHODS: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry. RESULTS: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05). CONCLUSIONS: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.

Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis.

BACKGROUND: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. METHODS: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. RESULTS: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. CONCLUSIONS: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Similarity of autoimmune diseases based on the profile of immune complex antigens.

Since immune complexes (IC) are a direct product of immune response through the binding between antigen and antibody, the profile of antigen-associated ICs may depend on each autoimmune disease. In this report, we examined the similarity of four neurological autoimmune diseases, Alzheimer's disease and healthy donors, and seven connective tissue diseases based on the profiling of IC-associated antigens which were previously or recently identified by immune complexome analysis of cerebrospinal fluid (CSF) or serum samples. The similarity between each pair of two diseases was assessed by correlation coefficients as distance matrix with the use of detection frequency (i.e., the percentage of patients who were positive for a certain antigen in each disease) of each IC-associated antigen in a certain disease. Among 15 pairs of five diseases and healthy control examined by the analysis of CSF samples, only 1 pair of neuropsychiatric systemic lupus erythematosus and multiple sclerosis corresponds to the higher correlation value (r = 0.73) than 0.7. On the other hand, among seven connective tissue diseases examined by the analysis of serum samples, 12 of 21 pairs show high correlation value (r > 0.70). Our finding suggested that the profile of IC-associated antigens identified by immune complexome analysis of CSF samples can be useful for evaluating the similarity of neurological autoimmune diseases; however, not by that of serum samples.

Autoimmune glial fibrillary acidic protein astrocytopathy in Chinese patients: a retrospective study.

BACKGROUND AND PURPOSE: The aim was to describe the clinical, radiological and pathological features of an autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. METHODS: Data from 19 patients with positive GFAP-immunoglobulin G in cerebrospinal fluid (CSF) were retrospectively analyzed. RESULTS: The main disease manifestations included myelitis (68.4%), headache (63.2%), abnormal vision (63.2%), fever (52.6%), ataxia (36.8%), psychosis (31.6%), dyskinesia (15.8%), dementia (15.8%) and seizure (10.5%). Seventeen patients had brain abnormalities (89.5%), of which eight (42.1%) revealed the characteristic radial enhancing and laminar patterns. Cortical abnormalities were found in four patients (21.1%). Other abnormalities were found in the hypothalamus, midbrain, pons, medulla cerebellum, meninges and skull. Eleven patients had longitudinally extensive spinal cord lesions. CSF abnormalities were detected in all patients. Pathological examinations of four patients revealed extensive inflammation, with prominent perivascular B cells and T cells. Abundant antibody-secreting cells were noted in the interstitial and perivascular spaces. Immunohistochemical analysis showed loss of astrocytes and neurons. CONCLUSION: The present patients with positive GFAP-immunoglobulin G are highly similar to autoimmune GFAP astrocytopathy, described in a recent report. The features of the neuropathology and immunopathology of GFAP astrocytopathies were perivascular inflammation and loss of astrocytes and neurons.

Multiple sclerosis, and other demyelinating and autoimmune inflammatory diseases of the central nervous system.

Multiple sclerosis (MS) is characterized by a substantial degree of heterogeneity in relation to clinical manifestations, disease course, radiologic findings, histopathologic characteristics of brain lesions, and response to treatment. In this scenario, there is a strong need in MS for biomarkers that reliably capture these diverse aspects of disease heterogeneity and assist, for instance, in disease diagnosis and stratification, in the prediction of disease course, or in the identification of new and effective therapies for the disease. Due to its close proximity to sites of inflammatory lesions, biomarkers measured in cerebrospinal fluid (CSF) are likely to be more informative compared to other body fluid sources such as peripheral blood or urine. This chapter will review the current knowledge existing on CSF molecular biomarkers in MS and also neuromyelitis optica, a pathologic condition originally considered to be a form of MS, following a classification of biomarkers based on the predominant pathophysiologic processes taking place in these two diseases: activation/inflammatory biomarkers; oxidative stress biomarkers; neuroaxonal damage biomarkers; and remyelination and demyelination biomarkers.

CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment.

Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types.

In parallel to the detection of new neuronal autoantibodies, the diagnosis of non-infectious limbic encephalitis has risen. Given that cerebral imaging studies show highly variable results, the present retrospective study investigates imaging findings in association with autoantibody type. An institutional database search identified 18 patients with non-infectious limbic encephalitis who had undergone [18F] fluorodeoxyglucose positron emission tomography (FDG-PET). Sixteen of these patients also underwent magnetic resonance imaging (MRI). MRI and FDG-PET images were categorized as follows: normal (0); mesiotemporal abnormality (1); normal mesiotemporal finding but otherwise abnormal (2). Neuronal autoantibodies were determined in serum and/or CSF. Autoantibodies were grouped according to the cellular localization of their target antigen: antibodies against surface antibodies (i.e., VGKC, NMDAR): 9; antibodies against intracellular antigens (i.e., Hu, Ri, GAD): 4; no autoantibodies: 5. The fraction of abnormal scans was lower for MRI (10/16) than for FDG-PET (14/18). There was a significant association between PET findings and autoantibody type: All patients with autoantibodies against intracellular antigens showed mesiotemporal findings on FDG-PET. In turn, only 2/9 patients with autoantibodies against surface antigens displayed mesiotemporal hypermetabolism. In the remaining seven patients, four scans were rated as normal and three only showed findings outside the mesiotemporal region. A similar association was found using MRI, although this did not reach statistical significance. Autoantibody type was found to be associated with FDG-PET and, to a lesser extent, with MRI imaging results. Our observations may explain the heterogeneity of imaging data in LE and based on in vivo findings support the assumption of different patho mechanisms underlying LE due to antibodies against surface and intracellular antigens, respectively.

[Proteasomes and their role in the extracellular space].

The presented review concerns the intracellular proteasome and their possible functions. The ubiquitin-proteasome system (UPS) is responsible for the common regulated proteolysis in the cell. 26S proteasome is a central proteolytic unit of UPS and is a multisubunit protein complex consisting of a core catalytic complex, called 20S proteasome, capped at one or both ends by 19S regulatory complex. Proteasomes have been shown in the extracellular space: in alveolar and cerebrospinal fluids, blood plasma. Extracellular proteasomes are intact intracellular particles that exhibit three types of specific peptidase activity. Extracellular proteasomes have been detected in both healthy people and patients with different diseases. Its concentration has been found to be increased in patients suffering from autoimmune diseases, malignant tumors, trauma or sepsis and to correlate with the disease progression, which has both diagnostic and prognostic value.