Encefalomielite aguda disseminada com provável etiologia de Bartonella henselae / Acute disseminated encephalomyelitis with probable Bartonella henselae etiology

RESUMO A encefalomielite aguda disseminada é uma doença rara, aguda, inflamatória e desmielinizante do sistema nervoso central, presumivelmente associada, em mais de três quartos dos casos, a infecções (virais, bacterianas ou inespecíficas) e imunizações ou sem qualquer antecedente indentificável. Habitualmente, apresenta um curso monofásico com início de sintomas inespecíficos na fase prodrómica, podendo evoluir com alterações neurológicas multifocais e até à perda total da acuidade visual. Descrevemos o caso de um menino de 9 anos com quadro inicial de edema de papila causado por encefalomielite aguda disseminada devido a Bartonella henselae. Apesar da gravidade da doença, o diagnóstico e o tratamento precoce proporcionaram bons desfechos.

ABSTRACT Acute disseminated encephalomyelitis is a rare, acute, inflammatory, and demyelinating disease of the central nervous system. Presumably associated in more than three quarters of cases by infections (viral, bacterial, or nonspecific) and immunizations or without any identifiable antecedent. It usually presents a monophasic course with onset of nonspecific symptoms in the prodromal phase and may evolve with multifocal neurological changes and even visual acuity loss. We describe a case of a 9-year-old boy with an initial picture of papillary edema caused by acute disseminated encephalomyelitis due to Bartonella henselae. Despite the severity of the disease, early diagnosis and treatment provided good outcomes.

Clinical spectrum of myelin oligodendrocyte glycoprotein antibody-associated disease in Brazil: a single-center experience / Espectro clínico de doença associada com anticorpos contra a glicoproteína de oligodendrócito de mielina no Brasil: uma experiencia de centro único

Abstract Background Anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibody-associated disease (MOGAD) is an immune-mediated neurological disorder with a broad spectrum of clinical presentation that is often difficult to distinguish from other demyelinating diseases, such as multiple sclerosis and neuromyelitis optica spectrum disorder. Objective To describe the clinical and paraclinical characteristics of MOGAD in a Brazilian tertiary center. Methods We retrospectively reviewed the records of adult and pediatric patients who tested positive for anti-MOG antibodies and presented with clinical and radiological diseases compatible with MOGAD. Results Forty-one patients (10 children) were included: 56% female, 58% Caucasian, mean age at onset 31 years (range 6-64), with a mean disease duration of 59.6 months (range 1-264 months). The most frequent onset presentation was optic neuritis (68%), acute disseminated encephalomyelitis (ADEM, 12%), and myelitis (10%). A monophasic disease course was observed in 49%. EDSS median was 2.1 at the last visit. Most patients (83%) were under continuous immunosuppressive treatment. Azathioprine was the first-line treatment in 59%. In all ADEM cases, conus, and root involvement was radiologically observed on MRI. Conclusion Brazilian MOGAD patients presented with a similar spectrum of previously reported MOGAD phenotypes. Conus and spinal root involvement seems to be frequently present in MOGAD-ADEM and could serve as radiologic characteristics of this clinical entity.

Resumo Antecedentes A doença associada ao anticorpo da glicoproteína da mielina de oligodendrócitos (anti-MOG; MOGAD) é uma doença neurológica imunomediada com um amplo espectro de apresentações clínicas que muitas vezes é difícil de distinguir de outras doenças desmielinizantes, como a esclerose múltipla e o distúrbio do espectro da neuromielite óptica. Objetivo Descrever as características clínicas e paraclínicas da MOGAD em um centro terciário brasileiro. Métodos Revisamos retrospectivamente os prontuários dos pacientes adultos e pediátricos que testaram positivos para anticorpos anti-MOG e apresentaram um quadro clínico e radiológico compatível com MOGAD. Resultados Quarenta e um pacientes (10 crianças) foram incluídos: 56% do sexo feminino, 58% caucasianos, idade média de início da doença foi 31 anos (intervalo de 6-64), com duração média da doença de 59,6 meses (intervalo de 1-264 meses). A apresentação inicial mais frequente foi neurite óptica (68%), seguida pela encefalomielite disseminada aguda (ADEM, 12%) e mielite (10%). Um curso monofásico da doença foi observado em 49%. EDSS foi de 2,1 na última visita. A maioria dos pacientes (83%) estava sob tratamento imunossupressor contínuo. Azatioprina foi o tratamento de primeira linha em 59%. Em todos os casos de ADEM, o envolvimento do cone medular e das raízes espinhais foi observado radiologicamente na ressonância magnética. Conclusão Os pacientes brasileiros com MOGAD apresentam um espectro clínico e radiológico semelhante aos fenótipos de MOGAD relatados anteriormente. O envolvimento do cone e das raízes espinhais parece estar frequentemente presente no MOGAD-ADEM e poderia servir como característica radiológica nesta entidade.

Acute abducens nerve palsy with acute disseminated encephalomyelitis-like presentation following COVID-19 vaccination

We report two adult cases of abducens nerve palsy presenting immediately (within weeks) after they received the first dose of Covishield vaccination. Magnetic resonance imaging (MRI) of the brain obtained after the onset of diplopia demonstrated demyelinating changes. The patients had associated systemic symptoms. Post-vaccination demyelination typically known as acute disseminated encephalomyelitis (ADEM) associated with several vaccines is more common in children. Although the mechanism of the nerve palsy remains unclear, it is suspected to be related to the post-vaccine neuroinflammatory syndrome. Cranial nerve palsies and ADEM-like presentations may represent part of the neurologic spectrum following COVID-vaccination in adults, and ophthalmologists should be aware of these sequelae. Although cases of sixth nerve palsy following COVID vaccination are already reported, associated MRI changes have not been reported from India.

Study on the mechanism of Yishen daluo decoction in alleviating nervous system inflammation in EAE model mice / 中国药房

OBJECTIVE To study the effects of Yishen daluo decoction on inflammatory factors and cyclic adenosine monophosphate（cAMP）/protein kinase A （PKA）/cAMP response element binding protein （CREB） signal pathway in experimental autoimmune encephalomyelitis （EAE） model mice by inhibiting the expressions of β-arrestin1， and to explore the mechanism of Yishen daluo decoction in the treatment of EAE. METHODS Sixty mice were randomly divided into normal group， model group， TCM group （Yishen daluo decoction 20 g/kg）， positive control group （prednisone acetate 3.9 mg/kg）， β-arrestin1 siRNA adeno- associated virus （AAV-β） group， AAV-β+TCM group， with 10 mice in each group. Except for normal group， EAE model was made in other groups. AAV-β group and AAV-β+TCM group were injected with AAV-β via tail vein to interfere with the expression of β -arrestin1 protein. Starting from the 8th day of modeling， they were given corresponding drug solution/normal saline intragastrically， once a day， for consecutive 14 days. The neurological function score of mice was detected； the pathological and morphological changes were observed in the brain and spinal cord tissues of mice； the serum levels of inflammatory factors [interleukin-2 （IL-2）， IL-23， interferon-γ （IFN-γ）] in mice were determined； the expressions of β-arrestin1， cAMP， PKA and CREB in brain and spinal cord were detected. RESULTS Compared with normal group， neurological function scores， serum levels of inflammatory factors， and protein expressions of β-arrestin1 in brain and spinal cord were significantly increased （P＜0.05 or P＜ 0.01）； protein expressions of PKA， CREB and cAMP in brain and spinal cord were decreased significantly（P＜0.05 or P＜0.01）. The deep staining of cellular shrinkage and aggregation of inflammatory cells were observed in most neurons of the brain and spinal cord， with varying degrees of demyelinating. Compared with model group， the neurological function scores， pathological changes in brain and spinal cord tissues， and most indicators （except for CREB and cAMP proteins in the brain tissue of AAV-β group） were significantly reversed （P＜0.05 or P＜0.01）.Compared with AAV- β group， the neurological function scores， the levels of IFN-γ in serum and β-arrestin1 in spinal cord were significantly decreased （P＜0.05 or P＜0.01）， PKA and cAMP in brain and spinal cord tissues were significantly increased in AAV- β +TCM group （P＜0.05 or P＜0.01）. CONCLUSIONS Yishen daluo decoction can inhibit the expression of β-arrestin1 in the central nervous system thus activating the cAMP/PKA/CREB signaling pathway， relieving nervous system inflammation， and ultimately alleviates the symptoms of EAE.

Improvement effect and mechanism of matrine on experimental autoimmune encephalomyelitis mice / 中国药房

OBJECTIVE To investigate whether matrine exerts improvement effect on experimental autoimmune encephalomyelitis （EAE） mice by regulating ferroptosis pathway. METHODS Totally 30 female C57BL/6 mice were randomly assigned into normal group， model group and matrine group， with 10 mice in each group. Model group and matrine group were given antigen emulsion containing inactivated Mycobacterium tuberculosis and MOG35-55 to induce EAE model. Matrine group was injected with Matrine injection （50 mg/kg） intraperitoneally since the 7th day after immunization； normal group and model group were given constant volume of normal saline intraperitoneally， once a day， since 18th day after immunization. The neurofunctional score of mice was recorded， and hematoxylin and eosin staining and Luxol fast blue staining were used to observe inflammatory cell infiltration and demyelination in spinal cord tissue. The quantitative reverse transcription PCR and Western blot assay were performed to determine the mRNA expressions of transferrin receptor 1 （TFR1）， nuclear receptor coactivator 4 （NCOA4） and hephaestin （Heph）， and the protein expressions of system Xc－ （xCT） and glutathione peroxidase 4 （GPx4）. RESULTS Compared with normal group， accumulative neurofunctional score was significantly increased in model group （P＜0.01）； inflammatory cell infiltration and demyelination were obvious in spinal cord tissue， and related scores were increased significantly （P＜0.01）. The mRNA expressions of TFR1 and NCOA4 in myelin tissue were up-regulated significantly， while the mRNA expression of Heph and the protein expressions of xCT and GPx4 were down-regulated significantly （P＜0.05 or P＜0.01）. Compared with model group， above indexes of matrine group were all improved significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Matrine can improve EAE mice， the mechanism of which may be associated with regulating iron metabolism pathway and xCT/GPx4 pathway in ferroptosis.

Progress in Mechanism of Astragalus membranaceus and Its Chemical Constituents on Multiple Sclerosis / 中国结合医学杂志

The primary chemical components of Astragalus membranaceus include polysaccharides, saponins, flavonoids, and amino acids. Recent studies have shown that Astragalus membranaceus has multiple functions, including improving immune function and exerting antioxidative, anti-radiation, anti-tumor, antibacterial, antiviral, and hormone-like effects. Astragalus membranaceus and its extracts are widely used in clinical practice because they have obvious therapeutic effects against various autoimmune diseases and relatively less adverse reaction. Multiple sclerosis (MS) is an autoimmune disease of central nervous system (CNS), which mainly caused by immune disorder that leads to inflammatory demyelination, inflammatory cell infiltration, and axonal degeneration in the CNS. In this review, the authors analyzed the clinical manifestations of MS and experimental autoimmune encephalomyelitis (EAE) and focused on the efficacy of Astragalus membranaceus and its chemical components in the treatment of MS/EAE.

Clinical analysis and follow-up study of 32 children with first diagnosed acute disseminated encephalomyelitis / 国际儿科学杂志

Objective:To analyze the clinical features, risk factors of the prognosis and recurrence of first diagnosed acute disseminated encephalomyelitis(ADEM)in children.Methods:The clinical characteristics of 32 children with first diagnosed ADEM who were treated in the Department of Neurology of Shanghai Children′s Medical Center from January 1, 2012 to January 31, 2022 were analyzed retrospectively and followed up.Results:After follow-up, 27 of the 32 patients were diagnosed as ADEM and 4 were diagnosed as multiphasic disseminated encephalomyelitis(MDEM), 1 was diagnosed as ADEM followed by optic neuritis(ADEM-ON).Among the 27 patients diagnosed with ADEM, most of them were girls, 3~8 years old, had a history of infection before onset, occurred in summer and autumn.Common clinical symptoms included disturbance of consciousness or mental and behavior disorders(27/27, 100.0%), fever(13/27, 48.1%), paralysis(13/27, 48.1%), abnormal defecation(7/27, 25.9%), decreased vision(7/27, 25.9%)and so on.Brain MRI mainly involved subcortical white matter(20/27, 74.1%), cerebellum(10/27, 37.0%), deep nuclei such as thalamus and basal ganglia(7/27, 25.9%)and brainstem(3/27, 11.1%).In 10 cases, myelin oligodendrocyte glycoprotein(MOG)antibody tests showed positive results in 3(30.0%)and negative results in 7(70.0%).There were no significant differences in gender, age, history of infection before onset, season of onset, clinical symptoms, peripheral WBC, CRP, erythrocyte sedimentation rate, levels of WBC and protein in cerebrospinal fluid, electroencephalogram, brain and spinal cord MRI, treatment and prognosis between the MOG antibody positive and negative children(all P>0.05).16 cases (59.3%)were recovery completely, 11 cases (40.7%)were not, the rate of the infection before onset of the former was higher than the latter( P<0.05).27 cases (84.4%)had monophasic course and 5 cases (15.6%)had non-monophasic course, more of the nonmonophasic children′s brain MRI show multiple abnormal signals in the brain than the monophasic children( P<0.05). Conclusion:Children with first diagnosed ADEM require long-term clinical follow-up, and brain MRI show a higher risk of recurrence of multiple abnormal signals in the brain.The prognosis of ADEM children with a history of infection before onset is relatively good.

Effect of Yishen Daluo Prescription on Rho/ROCK Signaling Pathway in EAE Mice Based on Silencing of β-arrestin1 / 中国实验方剂学杂志

ObjectiveTo investigate the effects of Yishen Daluo prescription （YSDL） on Ras homolog（Rho）/Rho-associated coiled-coil containing protein kinase（ROCK）signaling pathway in mice with experimental autoimmune encephalomyelitis （EAE） based on the silencing of β-arrestin1 gene. MethodSixty C57BL/6 female mice were randomly divided into a blank group， a model group， a virus group， a YSDL group， a virus + YSDL group， and a prednisone acetate group （hormone group）. The EAE model was induced in mice except for those in the normal group. Adeno-associated virus（AAV）solution （150 μL， 1×1011 vg·mL-1） was injected into the tail vein of each mouse in the virus group and the virus + YSDL group on the 4th day of immunization. Drugs were administered on the 8th day of modeling. Specifically， normal saline was given to the mice in the normal group，the model group，and the virus group at 10 mL∙kg-1， prednisone acetate suspension to those in the hormone group at 3.9 g∙kg-1，and YSDL to those in other groups at 20 g∙kg-1 for 14 consecutive days. The mice were weighed and scored every day. The neurological function scores of mice in each group were recorded every day after immunization. Hematoxylin-eosin （HE） staining was used to determine the inflammatory response and lesion location in the brain tissues and spinal cord tissues of mice. The protein expression of β-arrestin1，Ras homolog gene family member A（RhoA）， and Rho-associated coiled-coil forming protein kinase Ⅰ（ROCK Ⅰ） in spinal cord and brain tissues of EAE mice was determined by Western blot. ResultCompared with the model group， the virus group and the virus + YSDL group showed decreased neurological function scores （P<0.01），and the YSDL group also showed decreased neurological function scores（P<0.05）. HE results showed that there was obvious inflammatory reaction in the central nervous system （CNS） of the model group， which was alleviated to varying degrees in other groups compared with the model group. Western blot results showed that compared with the blank group， the model group showed increased protein expression levels of β-arrestin1， RhoA， and ROCK Ⅰ in the spinal cord tissues （P<0.01）. Compared with the model group， the virus group， the YSDL group， the virus + YSDL group， and the hormone group showed decreased protein expression levels of β-arrestin1， RhoA， and ROCKⅠ in the spinal cord tissues （P<0.01）. Compared with the blank group， the model group showed increased protein expression levels of β-arrestin1， RhoA， and ROCK Ⅰ in the brain tissues （P<0.01）. Compared with the model group， the virus group， the YSDL group， the virus + YSDL group， and the hormone group showed decreased protein expression level of β-arrestin1 in the brain tissues （P<0.01）， and the virus group and the YSDL group showed decreased protein expression levels of RhoA， and ROCKⅠ in the brain tissues （P<0.05）. Additionally， the virus + YSDL group and the hormone group showed decreased protein expression levels of RhoA and ROCKⅠ in the brain tissues （P<0.01）. ConclusionYSDL can improve the clinical symptoms of EAE mice and improve the inflammatory response of CNS. The mechanism is presumably attributed to the fact that YSDL inhibits the expression of β-arrestin1 in CNS，thereby reducing the expression of Rho/ROCK signaling pathway. Furthermore， YSDL may have a synergistic effect with the inhibition of β-arrestin1 gene expression.

Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells / 中国结合医学杂志

OBJECTIVE@#To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action.@*METHODS@#This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 β (IL-1 β), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively.@*RESULTS@#GSE reduced the secretion of TNF-α, IL-1 β and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 β, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05).@*CONCLUSION@#GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.

Progressive encephalomyelitis with rigidity and myoclonus: a case report / 中华神经科杂志

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a specific subtype of the stiff-person syndrome, which is rare and difficult to diagnose clinically. A case of PERM in a 66-year-old female with a fluctuating progressive course was reported in this article. She had increased facial muscle tone, pruritus and sensory hypersensitivity mainly in the head and neck, medullary involvement syndrome and bilateral lower limb rigidity as the main clinical manifestations, and a previous history of pulmonary malignancy, thymoma, typeⅠ diabetes and Hashimoto′s thyroiditis. The patient′s serum and cerebrospinal fluid were positive for anti-glutamic acid decarboxylase antibody. The electromyogram showed a large number of motor unit potentials in the trunk and proximal extremities in the quiet state, which were significantly enhanced during spastic episodes, consistent with the electromyographic manifestations of stiff-person syndrome. The final diagnosis was PERM, and immunotherapy including gamma globulin and hormone responded well. PERM is a rare neurological autoimmune disease with atypical early symptoms, which can be easily misdiagnosed, and it requires attention to avoid delaying the diagnosis.

Clinical and radiological manifestations of acute disseminated encephalomyelitis associated with the main arboviruses / Manifestaciones clínicas y radiográficas de la encefalomielitis aguda diseminada asociada a los principales Arbovirus

ABSTRACT Introduction: Acute disseminated encephalomyelitis (ADEM) is an acute and inflammatory neuropathic disease that causes demyelination, predominantly affecting the white matter. Clinical manifestations of ADEM may be associated with the arboviruses zika fever, dengue fever, and chikungunya. Objective: The aim of the present study was to carry out a bibliographical survey about the clinical manifestations and radiological findings of ADEM after infection with dengue, zika, and chikungunya viruses, as well as their correlation. Methods: MEDLINE, LILACS, Web of Science, and Scopus databases were searched for articles published between 2010 and 2020, written in English, Spanish, and Portuguese, about the occurrence of ADEM in patients affected by zika fever, dengue fever, or chikungunya. The search yielded articles that demonstrated the occurrence of five cases of ADEM associated with zika fever, ten cases post-infection with the dengue virus cases, and two cases related to chikungunya. Conclusions: The most common initial clinical presentations of ADEM were fever, nausea and/or vomiting, myalgia, headache, skin rashes, and arthralgia. The main neurological symptoms reported were changes in the level of consciousness, pyramidal signs, tonic-clonic seizures, visual changes, and urinary disorders. The most common radiological findings were T2/FLAIR hyperintense lesions on magnetic resonance imaging (MRI), affecting mainly the subcortical and central white matter. It is highlighted the importance of monitoring patients with dengue fever, zika fever, or chikungunya to identify clinical manifestations of ADEM that may contribute to an early and correct diagnosis of this encephalomyelitis, and, consequently, to intervene and obtain better patient prognosis.

RESUMEN Introducción: La encefalomielitis diseminada aguda (EMDA) es una enfermedad neuropática aguda e inflamatoria que provoca desmielinización, y afecta predominantemente la materia blanca. Las manifestaciones clínicas de la EMDA pueden estar asociadas a los arbovirus Zika, dengue y chikungunya. Objetivo: Realizar una encuesta bibliográfica sobre las manifestaciones clínicas y los hallazgos radiográficos de la EMDA después de la infección por los virus del dengue, del Zika y del chikungunya, así como su correlación. Métodos: Se realizó una búsqueda, en las bases de datos MEDLINE, LILACS, Web of Science y Scopus, de artículos publicados entre 2010 y 2020, escritos en inglés, español y portugués, sobre la aparición de EMDA en pacientes afectados por la fiebre del Zika, la fiebre del dengue o del chikungunya. Se hallaron artículos que demostraron la ocurrencia de cinco casos de EMDA asociados con la fiebre del Zika, diez casos posteriores a la infección por el virus del dengue y dos casos relacionados con el chikungunya. Conclusiones: Las presentaciones clínicas iniciales más comunes de EMDA fueron fiebre, náuseas o vómitos, mialgia, dolor de cabeza, erupciones cutáneas y artralgia. Los principales síntomas neurológicos reportados fueron cambios en el nivel de conciencia, signos piramidales, convulsiones tónico-clónicas, cambios visuales y trastornos urinarios. Los hallazgos radiográficos más comunes fueron lesiones hiperintensas T2/FLAIR en imágenes de resonancia magnética. Estas lesiones afectaron principalmente la subcortical y la materia blanca central. Se destaca la importancia de la vigilancia de los pacientes con dengue, Zika o chikungunya para identificar las manifestaciones clínicas de la EMDA que puedan contribuir a un diagnóstico precoz y correcto de esta encefalomielitis y, por consiguiente, para intervenir y obtener un mejor pronóstico del paciente.

Cornuside ameliorated experimental autoimmune encephalomyelitis by limiting the recruitment of CD4+ T lymphocytes in the spinal cord

We conducted this study to determine whether cornuside could improve the neurological deficit symptoms of experimental autoimmune encephalomyelitis (EAE) rats, as well as determine the potential involvement of CD4+ T lymphocytes, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor-α (TNF-α). Altogether, 32 Lewis rats were randomly divided into control, EAE, EAE/prednisolone, and EAE/cornuside, wherein their neurological function was assessed every day. CD4+ T lymphocyte recruitment into the spinal cord (SC) was evaluated using immunohistochemistry. The VCAM-1, ICAM-1 and TNF-α mRNA expressions in the SC were determined by real-time quantitative PCR, and the VCAM-1 and ICAM-1 proteins were determined by western blotting. Compared to the control group, the EAE group rats with neurological deficits had enhanced CD4+ T lymphocyte infiltration and higher expression levels of VCAM-1, ICAM-1, and TNF-α in the SC. Meanwhile, compared with the EAE group, the EAE/cornuside and EAE/prednisolone groups had lower neurological scores, less CD4+ T lymphocyte infiltrations, and lower expression levels of VCAM-1, ICAM-1, and TNF-α in the SC. Thus, cornuside ameliorated EAE, which could be owed to the inhibition of CD4+ T lymphocyte recruitment and VCAM-1, ICAM-1, and TNF-α expressions in the SC

The dual effect of acetate on microglial TNF-α production

Abstract Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases. HIGHLIGHTS Acetate was able to exacerbate the production of TNF-α in microglia. Acetate administered as pre-treatment to LPS acts as an anti-inflammatory. Histone deacetylase decreased TNF-α production in Acetate- and LPS-treated cells. Depending on the time of administration, Acetate modulates microglia's activation. Acetate may threaten neurodegenerative and neuropsychiatric diseases.

LncRNA Gm13568 regulates the activation of A1 astrocytes and affects the EAE process in mice / 中华微生物学和免疫学杂志

Objective:To investigate the effects of long non-coding RNA (lncRNA) Gm13568 on the activation of A1 astrocytes and the progress of experimental autoimmune encephalomyelitis (EAE) in mice.Methods:A recombinant lentiviral vector (LV-Inhibit-Gm13568) carrying astrocyte-specific promoter of glial fibrillary acidic protein (GFAP) was established to inhibit the function of endogenous Gm13568. A control vector (LV-ctrl) was established as well. The recombinant vectors were packaged. C57BL/6 mice were injected with 1×10 7 transforming units of viral suspension via the tail vein and 7 d after the injection, myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55) was used to establish the mouse model of EAE. Four groups, PBS group, EAE group, LV-ctrl+ EAE group and LV-Inhibit-Gm13568+ EAE group, were included in this study. Clinical signs of the mice were monitored daily in a double-blinded manner. The mice were sacrificed 23 d after the EAE model was established and the spinal cord tissues were collected. The expression of Serping 1, C3, Srgn and H2-T23 at mRNA level was detected by real-time PCR. Changes in the expression of IL-6, TNF-α, macrophage chemotactic protein-1 (MCP-1) and interferon-inducible protein-10 (IP-10) were measured. Western blot was used to investigate the expression of GFAP and Notch1 in spinal cord tissues and the phosphorylation of signal transduction and transcription activator 3 (STAT3). The expression of Notch1 intracellular domain (NICD) and GFAP in spinal cord tissues was detected by immunofluorescence. Furthermore, the infiltration of inflammatory cells and the demyelination of spinal cord were observed using HE and Luxol fast blue (LFB) staining methods. Results:Compared with PBS group, A1 astrocytes were activated and Notch1 expression was significantly up-regulated in EAE group and LV-ctrl+ EAE group. The clinical score of mice in LV-Inhibit-Gm13568+ EAE group was decreased from an average score of 3.5 to less than 1 on 23 d after antigen induction and the clinical symptoms were alleviated as compared with the mice in LV-ctrl+ EAE group. Meanwhile, the activation of A1 astrocytes was down-regulated, and the production of inflammatory cytokines and chemokines was also reduced. The expression of Notch1, GFAP and NICD at protein level and the phosphorylation of STAT3 were significantly reduced. Moreover, the infiltration of inflammatory cells and demyelination of spinal cord tissues were alleviated significantly.Conclusions:LncRNA Gm13568 might regulate the activation of A1 astrocytes via the Notch1/STAT3 pathway, thus affecting the production of inflammatory cytokines and chemokines and participating in the process of EAE.

Lowered serum cesium levels in schizophrenia: association with immune-inflammatory biomarkers and cognitive impairments

Objectives: A previous study has shown that schizophrenia (SCZ) is accompanied by lowered levels of trace/metal elements, including cesium. However, it is not clear whether changes in cesium, rubidium, and rhenium are associated with activated immune-inflammatory pathways, cognitive impairments, and the symptomatology of SCZ. Methods: This study measured cesium, rubidium, and rhenium, cognitive impairments (using the Brief Assessment of Cognition in Schizophrenia [BACS]), and the levels of cytokines/chemokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and eotaxin (CCL11) in 120 patients with SCZ and 54 healthy controls. Severity of illness was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale, and the Hamilton Depression Rating Scale (HAM-D). Results: Serum cesium was significantly lower in patients with SCZ as compared with controls. Further, serum cesium was significantly and inversely associated with CCL11 and TNF-α, but not IL-1β, in patients with SCZ; significant inverse associations were also noted between serum cesium levels and BPRS, FF, HAM-D, and SANS scores. Finally, cesium was positively correlated with neurocognitive probe results including the Tower of London, Symbol Coding, Controlled Word Association, Category Instances, Digit Sequencing Task, and List Learning tests. Conclusion: The results suggest that lowered serum cesium levels may play a role in the pathophysiology of SCZ, contributing to specific symptom domains including negative, depressive and fatigue symptoms, neurocognitive impairments (spatial working, episodic, and semantic memory and executive functions), and neuroimmune pathways.

Encefalomielitis tóxica por anestesia espinal. Presentación de un caso / Toxic encefphalomyelitis due to spinal anesthesia. Presentation of a case

RESUMEN: Introducción: Las complicaciones neurológicas como consecuencia de anestesia espinal se han reportado frecuentemente debido al amplio uso de dicha anestesia, la cual puede ocasionar una mielopatía tóxica. Presentación del Caso Paciente de 26 de edad con antecedentes de salud, fue ingresada en el Hospital Clínico Quirúrgico Freyre de Andrade 24 horas después de operada por hemorroides con anestesia espinal (lidocaína hiperbárica). Comienza con ptosis palpebral derecha y dificultad para la marcha. Es egresada y dos días después ingresa en obnubilación y rigidez de nuca con LCR (Líquido Cefalorraquídeo) - positivo y sospecha de meningoencefalitis. Evoluciona en coma sin respuesta satisfactoria a antibióticos durante 14 días. Se constata edema cerebral, trastornos autonómicos, hemiparesia alterna y paraplejía fláccida. Se retira antibiótico y se trata con betametasona parenteral durante dos meses más fisioterapia durante 10 meses. Tuvo mejoría progresiva y recuperación casi total. Todos los estudios microbiológicos fueron normales en suero y líquido cefalorraquídeo Discusión: Se han reportado disímiles lesiones neurológicas por anestesia espinal que incluyen 3 síndromes: meningoencefalitis, lesión de pares craneales y paraparesia(plejía). El caso que presentamos presentó los 3 tipos de lesiones más edema cerebral. Conclusiones: Es infrecuente la asociación de los tres síndromes pues no encontramos caso igual en bases de datos. La resolución con betametasona es un aspecto terapéutico a considerar ante casos similares.

Abstract: Introduction: Neurological complications as a consequence of spinal anesthesia have been frequently reported due to its extensive use, which can cause toxic myelopathy. Case Presentation A 26-years-old patient with a health history was admitted to the Freyre de Andrade Clinical Surgical Hospital 24 hours after surgery for hemorrhoids with spinal anesthesia (hyperbaric lidocaine). It begins with right palpebral ptosis and difficulty walking. She was discharged and two days later she was admitted with drowsiness and stiff neck with positive CSF and suspected meningoencephalitis. She evolves into a coma with no satisfactory response to antibiotics for 14 days. Cerebral edema, autonomic disorders, alternating hemiparesis, and flaccid paraplegia are noted. The antibiotic was withdrawn and she was treated with parenteral betamethasone for two months plus physiotherapy for 10 months. She had progressive improvement and almost total recovery. All serum and cerebrospinal fluid microbiological studies were normal. Discussion: Dissimilar neurological injuries have been reported by spinal anesthesia that include 3 syndromes: meningoencephalitis, cranial nerve injury and paraparesis (plegia). This case had 3 types of lesions plus cerebral edema. Conclusions: The association of the three syndromes is infrequent since we did not find the same case in databases. Resolution with betamethasone is a therapeutic aspect to consider in similar cases

Encefalomielitis aguda diseminada: simulando enfermedad cerebrovascular en un adolescente / Acute disseminated encephalomyelitis: simulating cerebrovascular disease in an adolescent

RESUMEN La encefalomielitis aguda diseminada (ADEM) es una enfermedad desmielinizante del sistema nervioso central (SNQ, de baja prevalencia, con predominio de presentación en población pediátrica. Describir y revisar la presentación clínica de un paciente con ADEM, su proceso diagnóstico y el manejo terapéutico, de acuerdo con la evidencia disponible. Adolescente masculino de 17 años, sin antecedentes de importancia, con cuadro de cefalea hemicraneal derecha, tipo punzada, de alta intensidad, dos semanas de evolución y posterior compromiso agudo neurológico multifocal con encefalopatía, hemiparesia y diplopía. Se realiza estudio con resonancia de cerebro contrastada que pone en evidencia lesiones hiperintensas a nivel de tallo, cerebelo y ganglios basales. Estas lesiones son asimétricas, unilaterales y agudas y siguen el trayecto vascular de la arteria cerebelosa posteroinferior (PICA), sin restricción a la difusión o cambios en mapa ADC. Inicialmente se sospecha evento cerebrovascular (ECV) y se estudia con angiorresonancia normal, ayudas diagnósticas para causas cardioembólicas y trombofilias negativas. Al considerar lesiones no se sugieren cambios de origen isquémico, pero si desmielinizantes. Se inicia manejo con pulsos de metilprednisolona con resolución de hemiparesia y encefalopatía. En seguimiento a 18 meses, el paciente no ha presentado nuevos eventos clínicos o radiológicos. La ADEM es una patología infrecuente en la edad pediátrica, con un diagnóstico basado en la clínica y hallazgos imagenológicos en resonancia magnética. Su presentación clínica puede ser inespecífica y como en este caso simular enfermedad cerebrovascular, y el tratamiento se basa en inmunomoduladores, principalmente corticoides, con una tasa de recuperación favorable en las series previamente reportadas.

SUMMARY Acute disseminated encephalomyelitis (ADEM) is a low-prevalence demyelinating disease of the central nervous system (CNS) with a predominance of presentation in the pediatric population. To describe and review the clinical presentation of a patient with ADEM, its diagnostic process and therapeutic management according to the available evidence. A 17-year-old male adolescent, with a 2-week history of high-intensity right-sided headache, stitching type, subsequent acute multifocal neurological compromise with encephalopathy, hemiparesis, and diplopia. A contrast-enhanced brain resonance study with evidence of hyperintense lesions at the level of the stem, cerebellum, and basal ganglia, asymmetric, unilateral, acute, following the vascular path of the posteroinferior cerebellar artery (PICA), but without restriction to diffusion or changes on the ADC map, so that an initial suspicion of cerebrovascular event (CVD) is made, studying with normal angioresonance, diagnostic aids for negative cardioembolic causes and thrombophilias. Considering that lesions do not suggest changes of ischemic origin, but if they are demyelinating, management with methylprednisolone pulses with resolution of hemiparesis and encephalopathy is initiated. In the 18-month follow-up, the patient has not presented new clinical or radiological events. ADEM, is an infrequent pathology in pediatric age, with a diagnosis based on the clinic and magnetic resonance imaging findings, its clinical presentation may be nonspecific and as in this case simulate cerebrovascular disease, the treatment is based on immunomodulatory treatment, mainly corticosteroids, with a favorable recovery rate in the previously reported series.

Relief of HHV-6 Encephalomyelitis-induced Electric Shock-like Pain with Levetiracetam after Blood Stem Cell Transplantation

We encountered a case of HHV-6 encephalomyelitis following blood stem cell transplantation. A woman in her 30’s suffered from paroxysmal electric shock-like pain, itching, tremor of lower limbs and excessive sweating on the 15th day after cord blood transplantation. Urinary retention also occurred. Pregabalin and opioid administration was started, and foscarnet was administered after a finding of HHV-6DNA positive in cerebrospinal fluid. Combined use of levetiracetam 1000 mg per day decreased both frequency and intensity of the electric shock-like pain. In a week before the negative results of HHV-6 amplification, she became excessively drowsy. With withdrawal of levetiracetam, her consciousness returned to be clear. The main symptoms on discharge were pain and itching with numbness around the anus, and were well controlled with oxycodone 15 mg, pregabalin 225 mg, and lorazepam 0.5 mg per day. In our case of HHV-6 encephalomyelitis after cord blood transplantation, levetiracetam was effective in suppressing electric shock-like pain.

Cornuside alleviates experimental autoimmune encephalomyelitis by inhibiting Th17 cell infiltration into the central nervous system / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The present study was conducted to clarify the therapeutic effect of cornuside on experimental autoimmune encephalomyelitis (EAE) and its influence on T helper 17 (Th17) cell and regulatory T (Treg) cell infiltration into the central nervous system. Rats were randomly placed into four treatment groups: control, EAE, EAE+cornuside, and EAE+prednisolone. The neurological function scores of rats were assessed daily. On the second day after EAE rats began to show neurological deficit symptoms, the four groups were treated with normal saline, normal saline, cornuside (150 mg/kg), and prednisolone (5 mg/kg), respectively. The treatment was discontinued after two weeks, and the spinal cord was obtained for hematoxylin and eosin (H&E) and luxol fast blue staining, as well as retinoic acid receptor-related orphan receptor γ (RORγ) and forkhead box protein P3 (Foxp3) immunohistochemical staining. Blood was collected for Th17 and Treg cell flow cytometry testing, and the serum levels of interleukin (IL)-17A, IL-10, transforming growth factor-β (TGF-β), IL-6, IL-23, and IL-2 were measured via enzyme-linked immunosorbent assay (ELISA). Compared with rats in the EAE group, rats in the EAE+cornuside and EAE+prednisolone groups began to recover from neurological deficits earlier, and had a greater degree of improvement of symptoms. Focal inflammation, demyelination, and RORγ-positive cell infiltration were reduced by cornuside or prednisolone treatment, whereas the Foxp3-positive cell numbers were not significantly different. Meanwhile, the number of Th17 cells and the IL-17A, IL-6, and IL-23 levels were lower in the blood after cornuside or prednisolone treatment, whereas the number of Treg cells or the levels of IL-10, TGF-β, and IL-2 were not markedly different. Cornuside can alleviate symptoms of EAE neurological deficits through its anti-inflammatory and immunosuppressive effects, and Th17 cells may be one of its therapeutic targets.

Pharmacological insights into autophagy modulation in autoimmune diseases

As a cellular bulk degradation and survival mechanism, autophagy is implicated in diverse biological processes. Genome-wide association studies have revealed the link between autophagy gene polymorphisms and susceptibility of autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD), indicating that autophagy dysregulation may be involved in the development of autoimmune diseases. A series of autophagy modulators have displayed protective effects on autoimmune disease models, highlighting the emerging role of autophagy modulators in treating autoimmune diseases. This review explores the roles of autophagy in the autoimmune diseases, with emphasis on four major autoimmune diseases [SLE, rheumatoid arthritis (RA), IBD, and experimental autoimmune encephalomyelitis (EAE)]. More importantly, the therapeutic potentials of small molecular autophagy modulators (including autophagy inducers and inhibitors) on autoimmune diseases are comprehensively analyzed.