Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABAA receptor encephalitis.

Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABAA-R) is a rare form of autoimmune encephalitis. The pathogenesis is still unknown but autoimmune mechanisms were surmised. Here we identified a strongly expanded B cell clone in the cerebrospinal fluid of a patient with GABAA-R encephalitis. We expressed the antibody produced by it and showed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry that it recognizes the GABAA-R. Patch-clamp recordings revealed that it tones down inhibitory synaptic transmission and causes increased excitability of hippocampal CA1 pyramidal neurons. Thus, the antibody likely contributed to clinical disease symptoms. Hybridization to a protein array revealed the cross-reactive protein LIM-domain-only protein 5 (LMO5), which is related to cell-cycle regulation and tumor growth. We confirmed LMO5 recognition by immunoprecipitation and ELISA and showed that cerebrospinal fluid samples from two other patients with GABAA-R encephalitis also recognized LMO5. This suggests that cross-reactivity between GABAA-R and LMO5 is frequent in GABAA-R encephalitis and supports the hypothesis of a paraneoplastic etiology.

COVID-19 Pandemic and Dysbiosis: Can the Ivermectin Hysteria Lead to an Increase of Autoimmune Neuroinflammatory Diseases?

The pandemic caused by the SARS-CoV-2 has made new treatments a goal for the scientific community. One of these treatments is Ivermectin. Here we discuss the hypothesis of dysbiosis caused by the use of Ivermectin and the possible impacts on neuroinflammatory diseases after the end of the pandemic.

New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.

The 2019 new coronavirus (SARS-CoV-2) is a novel respiratory virus which has increasingly spread all over the world. Although the predominant clinical presentation is represented by respiratory symptoms, neurological manifestation of SARS-CoV-2 is being increasingly recognized. In the present report, we present a case of post SARS-CoV-2 autoimmune encephalitis associated with a new-onset refractory status epilepticus (NORSE).

Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation.

Autoreactive inflammatory CD4+ T cells, such as T helper (Th)1 and Th17 subtypes, have been found to associate with the pathogenesis of autoimmune disorders. On the other hand, CD4+ Foxp3+ T regulatory (Treg) cells are crucial for the immune tolerance and have a critical role in the suppression of the excessive immune and inflammatory response promoted by these Th cells. In contrast, dendritic cells (DCs) and macrophages are immune cells that through their inflammatory functions promote autoreactive T-cell responses in autoimmune conditions. In recent years, there has been increasing attention to exploring effective immunomodulatory or anti-inflammatory agents from the herbal collection of traditional medicine. Berberine, an isoquinoline alkaloid, is one of the main active ingredients extracted from medicinal herbs and has been shown to exert various biological and pharmacological effects that are suggested to be mainly attributed to its anti-inflammatory and immunomodulatory properties. Several lines of experimental study have recently investigated the therapeutic potential of berberine for treating autoimmune conditions in animal models of human autoimmune diseases. Here, we aimed to seek mechanisms underlying immunomodulatory and anti-inflammatory effects of berberine on autoreactive inflammatory responses in autoimmune conditions. Reported data reveal that berberine can directly suppress functions and differentiation of pro-inflammatory Th1 and Th17 cells, and indirectly decrease Th cell-mediated inflammation through modulating or suppressing other cells assisting autoreactive inflammation, such as Tregs, DCs and macrophages.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Treatments in Aicardi-Goutières syndrome.

Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.

The kaleidoscope of neurological manifestations in primary Sjögren's syndrome.

Neurologic involvement is a common extraglandular manifestation of primary Sjögren's syndrome (pSS), is varied and can be divided anatomically into 3 categories: central nervous system, peripheral neuropathies and autonomous nervous system manifestations. According to different study cohorts, neurological manifestations can occur in 18-45% of pSS patients, with the peripheral nervous system being the most frequent site of involvement compared to the central nervous system and autonomic system. Some neurologic complications share convergent pathophysiology, although the pathological basis of other conditions, namely cognitive impairment in pSS, is less clear. The heterogeneity of neurologic manifestations in pSS complicates the diagnosis and approach to treatment, which should be directed toward the underlying neuro-pathologic mechanism. The diagnosis and treatment of these manifestations must be optimised in order to avoid severe disability. However, for the majority of the complications, evidence for treatment efficacy is limited and requires further investigation.

Mycophenolate mofetil in paediatric autoimmune or immune-mediated diseases of the central nervous system: clinical experience and recommendations.

AIM: To gather data on mycophenolate mofetil (MMF) in paediatric autoimmune/immune-mediated central nervous system (CNS) conditions, focusing on safety and factors that may affect MMF efficacy. METHOD: Retrospective, multicentre study based on four paediatric neurology centres. RESULTS: Forty-four children were included (30 females, 14 males): 19 had proven/suspected autoimmune encephalitis, 14 had inflammatory demyelinating CNS diseases, and 11 had other autoimmune/immune-mediated CNS conditions. Before MMF, all received first-line immune therapies, and 17 had second-line rituximab and/or cyclophosphamide. MMF was started at a median of 9.5 months from disease onset (range 1-127mo) (median age 9y 4mo, range 1y 5mo-16y 5mo), and was used for median 18 months (range 0.3-73mo). On MMF, 31 patients were relapse-free, whereas eight relapsed (excluding patients with chronic-progressive course). Relapses on MMF were associated with medication weaning/cessation, or with suboptimal MMF dosage/duration. Adverse events of MMF occurred in eight patients: six moderate (gastrointestinal, movement disorder, dermatological) and two severe (infectious). INTERPRETATION: MMF use in paediatric neuroimmunology is heterogeneous, although relatively safe. We have identified factors that may affect MMF efficacy and provide recommendations on MMF usage. WHAT THIS PAPER ADDS: Mycophenolate mofetil (MMF) use was heterogeneous with relatively common adverse events, although mostly not severe. MMF treatment reduced median annualized relapse rate, although 20% of patients relapsed on MMF. A high relapse rate pre-MMF and late MMF start were associated with higher probability of relapsing on MMF. Most relapses were associated with suboptimal MMF dosage, short MMF duration, or concurrent medication weaning/discontinuation.

MICOFENOLATO DE MOFETILO EN ENFERMEDADES PEDIÁTRICAS AUTOINMUNES O INMUNO-MEDIADAS DEL SISTEMA NERVIOSO CENTRAL: EXPERIENCIA CLÍNICA Y RECOMENDACIONES: OBJETIVO: Recolectar información sobre el uso de Micofenolato de mofetilo (MMF) en enfermedades pediátricas del sistema nervioso central (SNC) autoinmunes o inmuno-mediadas, focalizando en la seguridad y otros factores que pudieran afectar la eficacia del MMF. MÈTODO: Estudio retrospectivo, multicéntrico, con base en cuatro centros de neurología infantil. RESULTADOS: Se incluyeron 44 niños (30 sexo femenino, 14 masculino): 19 de ellos tuvieron encefalitis autoimmune confirmada / sospechada, 14 tuvieron enfermedades inflamatorias desmielinizantes del SNC y 11 tuvieron otras condiciones autoinmunes o inmuno-mediadas del SNC. Previo al MMF todos recibieron terapias inmunológicas de primera línea, y 17 recibieron como segunda línea rituximab y / o ciclofosfamida. MMF fue iniciada a una mediana de 9.5 meses desde el comienzo de la enfermedad (rango 1-127 meses) (edad mediana 9 años y 4 meses, rango 1 año y 5 meses a 16 años y 5 meses), y fue utilizada por un tiempo mediana de 18 meses (rango 0.3 a 73 meses). Bajo MMF, 31 pacientes estuvieron libres de recidivas, mientras que 8 recidivaron (excluyendo aquellos con un curso crónico-progresivo). Las recaídas bajo el MMF estuvieron asociadas a suspensión/cese, o dosis de MMF o duración de tratamiento subóptimos. En ocho pacientes se observaron reacciones adversas al MMF: seis moderados (gastrointestinales, trastornos de movimiento o dermatológicos) y dos severos (infecciones). INTERPRETACIÓN: El uso de MMF en neuroinmunología pediátrica es heterogéneo, aunque relativamente seguro. Identificamos factores que pueden afectar la eficacia del MMF y proponemos recomendaciones sobre su uso.

MICOFENOLATO MOFETIL EM DOENÇAS PEDIÁTRICAS AUTO-IMUNES OU IMUNO-MEDIADAS DO SISTEMA NERVOSO CENTRAL: EXPERIÊNCIA CLÍNICA E RECOMENDAÇÕES: OBJETIVO: Reunir dados do micofenolato mofetil (MMF) em condições pediátricas auto-imunes ou imuno-mediadas do sistema nervoso central (SNC), com foco na segurança e nos fatores que podem afetar a eficácia do MMF. MÉTODO: Estudo restrospectivo multicêntrico baseado em quatro centros de neurologia pediátrica. RESULTADOS: Quarenta e quatro crianças foram incluídas (30 do sexo feminino, 14 do sexo masculino): 19 tiveram encefalite auto-imune comprovada/suspeita, 14 tiveram doenças inflamatórias desmielinizantes do SNC, e 11 tiveram outras condições auto-imunes ou imuno-mediadas do SNC. Antes do MMF, todas receberam imuno-terapias de primeira linha, e 17 tiveram rituximab e/ou ciclofosfamida de segunda linha. O MMF foi iniciado em uma mediana de 9.5 meses após o início da doença (variação de 1-127 meses) (idade mediana 9a 4m, variação 1a 5m a 16a 5m), e foi utilizado por uma mediana de 18 meses (variação 0.3-73m). Com MMF, 31 pacientes ficaram livres de recidivas, enquanto oito tiveram recidivas (excluídos os pacientes com curso crônico-progressivo). As recidivas com MMF forma associadas com desmame/descontinuidade da medicação, ou com dosagem/duração do MMF sub-ótimas. Efeitos adversos do MMF ocorreram em oito pacientes: seis moderados (gastrointestinal, desordem motora, dermatológico) e dois severos (infeccioso). INTERPRETAÇÃO: O uso de MMF em neuroimunologia pediátrica é heterogêneo, embora relativamente seguro. Identificamos fatores que podem afetar a eficácia do MMF e fornecemos recomendações sobre o uso de MMF.

Impacts of microbiome metabolites on immune regulation and autoimmunity.

A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro-inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T-cells (Treg), contributing to immune suppression. Short-chain fatty acids may induce Treg either by G-protein-coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T-cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long-chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host-microbiota interaction and the immune system with a special focus on MS as a prototype T-cell-mediated autoimmune disease of the CNS.

A comprehensive analysis and immunobiology of autoimmune neurological syndromes during the Zika virus outbreak in Cúcuta, Colombia.

We have focused on the epidemiology and immunobiology of Zika virus (ZIKV) infection and factors associated with the development of Guillain-Barré syndrome (GBS) and other neurological syndromes in Cúcuta, the capital of North Santander department, Colombia. Data of patients with ZIKV disease reported to the national population-based surveillance system were used to calculate the basic reproduction number (R0) and the attack rates (ARs) as well as to develop epidemiological maps. Patients with neurological syndromes were contacted and their diagnoses were confirmed. A case-control study in which 29 patients with GBS associated with ZIKV compared with 74-matched control patients with ZIKV infection alone was undertaken. Antibodies against arboviruses and other infections that may trigger GBS were evaluated. The estimated value of R0 ranged between 2.68 (95% CI 2.54-2.67) to 4.57 (95% CI 4.18-5.01). The sex-specific ARs were 1306 per 100,000 females, and 552 per 100,000 males. A non-linear interaction between age and gender on the ARs was observed. The incidence of GBS in Cúcuta increased 4.41 times secondary to ZIKV infection. The lag time between ZIKV infection and neurological symptoms was 7 days (interquartile range 2-14.5). Patients with GBS appeared to represent a lower socioeconomic status and were living near to environmentally contaminated areas. All GBS patients were positive for IgG antibodies against both ZIKV and Dengue virus, and 69% were positive for Chikungunya virus. Noteworthy, GBS was associated with a previous infection with M. pneumoniae (OR: 3.95; 95% CI 1.44-13.01; p = 0.006). No differences in antibody levels against C. jejuni, Epstein-Barr virus and cytomegalovirus were observed. High rates of cranial nerves involvement and dysautonomia were present in 82% and 75.9%, respectively. Intensive care unit (ICU) admission was necessary in 69% of the GBS patients. Most of the patients disclosed a high disability condition (Hughes grade 4). Dysautonomia was the main risk factor of poor GBS prognosis (i.e., ICU admission and disability). Thirteen patients were diagnosed with other neurological syndromes different to GBS (6 with transverse myelitis, 3 with encephalitis, 3 with peripheral facial palsy and one with thoraco-lumbosacral myelopathy). Our data confirm an increased transmission of ZIKV in Cúcuta, and provide support to the view that severe neurological syndromes are related to ZIKV disease. The complex ways by which previous infections and socioeconomic status interact to increase the risk of GBS in people infected by ZIKV should be further investigated.

Autoimmune choreas.

Chorea, a movement disorder characterised by a continuous flow of unpredictable muscle contractions, has a myriad of genetic and non-genetic causes. Although autoimmune processes are rare aetiology of chorea, they are relevant both for researchers and clinicians. The aim of this article is to provide a review of the epidemiology, clinical and laboratory features, pathogenesis and management of the most common autoimmune causes of chorea. Emphasis is given particularly to Sydenham's chorea, systemic lupus erythematosus, primary antiphospolipid antibody syndrome, paraneoplastic chorea and anti-N-methyl-d-aspartate receptor encephalitis.

Autoimmune Encephalitis at the Neurological Intensive Care Unit: Etiologies, Reasons for Admission and Survival.

BACKGROUND: Early recognition and treatment of autoimmune encephalitis (AE) has become an essential issue in clinical practice. However, little is known about patients with deteriorating conditions and the need for intensive care treatment. Here, we aimed to characterize underlying aetiologies, clinical symptoms, reasons for intensive care admission, and mortality of critically ill patients with AE. METHODS: We conducted a retrospective chart review of all patients with "definite" or "probable" diagnoses of AE treated at our neurological intensive care unit between 2002 and 2015. We collected and analyzed clinical, paraclinical, laboratory findings and assessed the mortality at last follow-up based on patient records. RESULTS: Twenty-seven patients [median age 55 years (range 25-87), male = 16] were included. Thirteen (48%) had "definite" AE. The most common reasons for admission were status epilepticus (7/27, 26%) and delirium (4/27, 15%). One-year survival was 82%, all five deceased were male, and 3 (60%) of them had "probable" disease. The non-survivors (median follow-up 1 year) were more likely to have underlying cancer and higher need for respiratory support compared to the survivors (p < 0.041, and p = 0.004, respectively). CONCLUSIONS: Clinical presentations and outcomes in critically ill patients with AE are diverse, and the most common leading cause for intensive care unit admission was status epilepticus. The association of comorbid malignancy and the need for mechanical ventilation with mortality deserves further attention.

[Pachymeningitis associated with IgG4 disease]. / Paquimeningitis asociada a enfermedad por IgG4.

Hypertrophic pachymeningitis is an infrequent disorder. It can be idiopathic or secondary to infectious, autoimmune or neoplastic disease. The recently described 〈IgG4-related disease〉 could be the origin of many cases considered cryptogenic. We present the case of a 60-year-old man, with a history of headache and episcleritis in both eyes, with partial response to corticoid therapy. The brain MR study with gadolinium showed enhancement and thickening of the dura mater, extending from lateral wall of left temporal and occipital lobes to ipsilateral tentorium. Meningeal biopsy showed fibrosis and lymphoplasmacytic infiltrate, with more than 10 IgG4+ plasma cells per high power field. After treatment with rituximab there was clinical improvement accompanied by the virtual disappearance of the alterations detected in neuroimaging. Hypertrophic pachymeningitis as a manifestation of IgG4-related disease can be based on MRI findings if plasma IgG4 are elevated.

[Autoimmune factors and epilepsy].

Epilepsy is a common chronic brain disorder with multiple causes, and now autoimmune factors are believed to be an independent cause for epilepsy. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Moreover, systemic autoimmune diseases and epilepsy co-occur frequently. Neural specific autoantibodies can also mediate the process of seizures through different pathways. The diagnosis of autoimmune epilepsy is based on frequency of antiepileptic drug-resistant seizures, the presence of neural specific autoantibodies, inflammatory changes in serum or spinal fluid or on magneticresonanceimaging, the change in electroencephalogram, a personal or family history of autoimmunity. Once autoimmune epilepsy is diagnosed, the immunotherapy is required. Early immunotherapy is crucial for improving the prognosis of the patients.

Neuronal central nervous system syndromes probably mediated by autoantibodies.

In the last few years, a rapidly growing number of autoantibodies targeting neuronal cell-surface antigens have been identified in patients presenting with neurological symptoms. Targeted antigens include ionotropic receptors such as N-methyl-d-aspartate receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, metabotropic receptors such as mGluR1 and mGluR5, and other synaptic proteins, some of them belonging to the voltage-gated potassium channel complex. Importantly, the cell-surface location of these antigens makes them vulnerable to direct antibody-mediated modulation. Some of these autoantibodies, generally targeting ionotropic channels or their partner proteins, define clinical syndromes resembling models of pharmacological or genetic disruption of the corresponding antigen, suggesting a direct pathogenic role of the associated autoantibodies. Moreover, the associated neurological symptoms are usually immunotherapy-responsive, further arguing for a pathogenic effect of the antibodies. Some studies have shown that some patients' antibodies may have structural and functional in vitro effects on the targeted antigens. Definite proof of the pathogenicity of these autoantibodies has been obtained for just a few through passive transfer experiments in animal models. In this review we present existing and converging evidence suggesting a pathogenic role of some autoantibodies directed against neuronal cell-surface antigens observed in patients with central nervous system disorders. We describe the main clinical symptoms characterizing the patients and discuss conflicting arguments regarding the pathogenicity of these antibodies.

In vivo imaging in autoimmune diseases in the central nervous system.

Intravital imaging is becoming more popular and is being used to visualize cellular motility and functions. In contrast to in vitro analysis, which resembles in vivo analysis, intravital imaging can be used to observe and analyze cells directly in vivo. In this review, I will summarize recent imaging studies of autoreactive T cell infiltration into the central nervous system (CNS) and provide technical background. During their in vivo journey, autoreactive T cells interact with many different cells. At first, autoreactive T cells interact with endothelial cells in the airways of the lung or with splenocytes, where they acquire a migratory phenotype to infiltrate into the CNS. After arriving at the CNS, they interact with endothelial cells of the leptomeningeal vessels or the choroid plexus before passing through the blood-brain barrier. CNS-infiltrating T cells become activated by recognizing endogenous autoantigens presented by local antigen-presenting cells (APCs). This activation was visualized in vivo by using protein-based sensors. One such sensor detects changes in intracellular calcium concentration as an early marker of T cell activation. Another sensor detects translocation of Nuclear factor of activated T-cells (NFAT) from cytosol to nucleus as a definitive sign of T cell activation. Importantly, intravital imaging is not just used to visualize cellular behavior. Together with precise analysis, intravital imaging deepens our knowledge of cellular functions in living organs and also provides a platform for developing therapeutic treatments.

[Ovarian teratomas as the cause of diseases of the nervous, endocrine and haematology system].

Teratomas are the most common tumors of the ovary occurring in girls and young women. Derived from primordial germ cell and embryonic gonads have the ability to differentiate into the three germ layers. In about 95% of cases are benign, and their most common form is a dermoid cyst of the ovary. This paper aims to present the relationship described tumors of autoimmune hemolytic anemia, anti-NMDA-dependent autoimmune inflammation of the brain and thyroid disease. It reminds us that teratomas are not always insulated disease entities and may have a significant impact on the course of coexisting diseases and their treatment.