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1.
Front Immunol ; 13: 953993, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958613

RESUMO

Background: Immunotherapy has been shown to reduce relapses in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder (MOG-AD); however, the superiority of specific treatments remains unclear. Aim: To identify the efficacy and tolerability of different treatments for MOG-AD. Methods: Systematic search in Pubmed, Embase, Web of Science, and Cochrane Library databases from inception to March 1, 2021, were performed. Published articles including patients with MOG-AD and reporting the efficacy or tolerability of two or more types of treatment in preventing relapses were included. Reported outcomes including incidence of relapse, annualized relapse rate (ARR), and side effects were extracted. Network meta-analysis with a random-effect model within a Bayesian framework was conducted. Between group comparisons were estimated using Odds ratio (OR) or mean difference (MD) with 95% credible intervals (CrI). Results: Twelve studies that compared the efficacy of 10 different treatments in preventing MOG-AD relapse, including 735 patients, were analyzed. In terms of incidence of relapse, intravenous immunoglobulins (IVIG), oral corticosteroids (OC), mycophenolate mofetil (MMF), azathioprine (AZA), and rituximab (RTX) were all significantly more effective than no treatment (ORs ranged from 0.075 to 0.34). On the contrary, disease-modifying therapy (DMT) (OR=1.3, 95% CrI: 0.31 to 5.0) and tacrolimus (TAC) (OR=5.9, 95% CrI: 0.19 to 310) would increase the incidence of relapse. Compared with DMT, IVIG significantly reduced the ARR (MD=-0.85, 95% CrI: -1.7 to -0.098). AZA, MMF, OC and RTX showed a trend to decrease ARR, but those results did not reach significant differences. The combined results for relapse rate and adverse events, as well as ARR and adverse events showed that IVIG and OC were the most effective and tolerable therapies. Conclusions: Whilst DMT should be avoided, IVIG and OC may be suited as first-line therapies for patients with MOG-AD. RTX, MMF, and AZA present suitable alternatives.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Imunoglobulinas Intravenosas , Azatioprina/efeitos adversos , Teorema de Bayes , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Ácido Micofenólico/efeitos adversos , Metanálise em Rede , Recidiva , Rituximab/efeitos adversos
2.
Mult Scler Relat Disord ; 68: 104141, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36037757

RESUMO

BACKGROUND: Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs) following vaccination. METHODS: We prospectively collected cases of new-onset CNS-IDDs with a temporal relationship between disease onset and COVID-19 vaccination and investigated their proportion among newly registered cases of CNS-IDD over the past year. RESULTS: Among 117 cases, 10 (8.5%) had their first disease manifestation within one month following COVID-19 vaccination: 2 multiple sclerosis, 2 neuromyelitis optica spectrum disorder, 3 MOG antibody-associated disease, and 3 unclassified CNS-IDDs. CONCLUSION: This observation suggests that COVID-19 vaccination may trigger the onset of various CNS-IDDs in susceptible individuals.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Doenças do Sistema Nervoso Central , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Humanos , Autoanticorpos , Sistema Nervoso Central , Doenças do Sistema Nervoso Central/etiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/etiologia , Neuromielite Óptica
3.
Mult Scler Relat Disord ; 59: 103662, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35149394

RESUMO

Inflammatory demyelinating diseases of the central nervous system (CNS) in childhood include clinically and radiologically defined diseases such as acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). Differentiation between these phenotypes can be difficult and cases not meeting established diagnostic criteria may remain without any specific diagnosis for months. Laboratory markers can assist in the diagnosis and management of these diseases. Previous studies suggest serum kynurenine-tryptophan pathway products and serum neopterin as biomarkers for CNS autoimmune diseases. Because urine is a reliable and repeatable source for analysis of these products with the additional advantage of easy sampling, we measured neopterin concentrations in serum and urine samples, urinary biopterin and serum kynurenine-tryptophan levels in autoimmune demyelinating diseases of CNS: pediatric multiple sclerosis (pMS, n = 27), MOGAD (n = 10), NMOSD (n = 5) patients and a control group consisting of healthy children or children with non-inflammatory diseases (n = 13), total 55 children. Methods were high performance liquid chromatography (HPLC) for neopterin, biopterin and creatinine in urine and kynurenine and tryptophan in serum; ELISA was used for serum neopterin. Comparison for biomarkers between all diagnostic groups showed urinary neopterin values were significantly higher in the pMS group (p = 0.002). The cut-off point determined by ROC analysis indicated urinary neopterin >167.75 µmol/mol creatinine could distinguish the patients from the controls with a sensitivity of 71% and specificity of 90%. The most significant difference was between the pMS and control groups (p = 0.002) while no difference was observed between pMS patients who were in relapse or stable state. Therefore, urinary neopterin appeared as a potential marker that could differentiate pMS from other demyelinating patient groups MOGAD and NMOSD as well as from controls. The fact that pteridine pathway products had not been studied in urine and serum in children with demyelinating disease before highlights the novelty of this study. If further research in larger samples confirm the present results, these molecules might assist the differential diagnosis of pMS from other demyelinating CNS diseases.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Encefalomielite Aguda Disseminada , Esclerose Múltipla , Neuromielite Óptica , Autoanticorpos , Criança , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Diagnóstico Diferencial , Encefalomielite Aguda Disseminada/diagnóstico , Humanos , Neopterina
4.
Mult Scler Relat Disord ; 59: 103689, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35183817

RESUMO

INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies are identified in approximately 30-50% of youth with pediatric-onset acquired demyelinating syndromes. Little is known about the cognitive sequelae of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with onset in childhood or adolescence.Overall, adults had 41% more risk than children to relapse over the whole disease course Overall, adults had 41% more risk than children to relapse over the whole disease course OBJECTIVE: To compare cognitive performance in participants with pediatric-onset relapsing MOGAD, pediatric-onset multiple sclerosis (POMS), and age-matched healthy controls. METHODS: The Penn Computerized Neurocognitive Battery (PCNB) was administered to 12 individuals with relapsing MOGAD (age = 16.3 ± 4.8 years; 75% female; disease duration = 8.1 ± 2.7 years), 68 individuals with POMS (age = 18.3 ± 4.0 years; 72% female; disease duration = 3.8 ± 3.9 years), and 108 healthy controls (age = 17.0 ± 4.9 years; 68.5% female). Accuracy was assessed on four domains: Executive Function, Episodic Memory, Complex Cognition, Social Cognition; and overall response time (RT) and RT across three factors (i.e., Time Constrained, Open-Window, Memory). Global performance was determined by a composite score. Multiple linear regression was used to examine group differences on PCNB domain and factor z-scores, controlling for age and sex. We also covaried disease duration for relapsing MOGAD vs. POMS analyses. RESULTS: Relative to healthy controls, relapsing MOGAD participants were less accurate on the Complex Cognition domain (B=-0.28, SE=0.11, p=.02), and had slower overall response time (B=-0.16, SE=0.07, p=.02). Relative to POMS, relapsing MOGAD participants were more accurate on the Executive Function domain (B = 0.70, SE=0.30, p=.02) and on the battery overall (B = 0.41, SE=0.18, p=.02). Relative to controls, overall PCNB score was significantly lower in the POMS group (B=-0.28, SE=0.06, p<.001) whereas the relapsing MOGAD participants did not differ from controls (p=.06) on the overall PCNB score. CONCLUSIONS: The relapsing MOGAD group demonstrated reduced reasoning skills and slower overall response time, relative to controls. A broad pattern of deficits was observed among POMS participants relative to controls. Overall, cognitive difficulties in the MOGAD group were milder relative to the POMS group.


Assuntos
Cognição , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Adolescente , Autoanticorpos , Criança , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Feminino , Humanos , Masculino , Memória Episódica , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito , Recidiva , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-35091466

RESUMO

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.


Assuntos
Doença de Alzheimer , Córtex Cerebral/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Encefalite , Peptídeos e Proteínas de Sinalização Intracelular , Mesencéfalo/metabolismo , Putamen/metabolismo , Adolescente , Adulto , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Autoanticorpos , Córtex Cerebral/diagnóstico por imagem , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Eletroencefalografia , Encefalite/diagnóstico por imagem , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Seguimentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Estudos Retrospectivos , Adulto Jovem
6.
J Neuroimmunol ; 364: 577812, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35063726

RESUMO

INTRODUCTION: Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-associated disorders (MOGAD) is neuroimmunological disorder manifesting as episodes of ADEM, optic neuritis, transverse myelitis, brainstem encephalitis, and other CNS manifestations and notably, distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Current treatment strategy is high-dose intravenous methylprednisolone followed by maintenance immunotherapy for relapse prevention. The purpose of this study is to systematically create compelling evidence addressing the role of rituximab in relapse prevention among patient with MOGAD. METHODS: This study follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. We searched PubMed, Embase, and Google Scholar for English language papers published between 2010 and 2021. Individual study proportions were meta-analyzed to yield the pooled relapse-free patient proportion. Individual studies' mean pre- and post-treatment annualized relapse ratio (ARR) and Expanded Disability Status Scale (EDSS) were used to calculate the overall mean difference. RESULTS: Our meta-analysis includes 13 studies with 238 subjects. After rituximab treatment, 55% (95% CI: 0.49-0.61) of MOGAD patients remained relapse-free. Our study found that after rituximab therapy, ARR was lowered by 1.36 (95% CI 1.02-1.71, p < 0.001). Similarly, we detected a 0.52 (95% CI: 0.08 to 0.96, p = 0.02) difference in EDSS score after starting rituximab medication. Because only a handful of the included studies documented adverse events, the safety profile of rituximab for the treatment of MOGAD could not be effectively determined. CONCLUSION: Our meta-analysis shows that rituximab effectively prevents relapses in MOGAD patients.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Humanos , Imunoglobulina G/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Recidiva
7.
JAMA Netw Open ; 5(1): e2142780, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-35006246

RESUMO

Importance: Longer-term outcomes and risk factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well established. Objective: To investigate longer-term risk of relapse and factors associated with this risk among patients with MOGAD. Design, Setting, and Participants: This large, single-nation, prospective cohort study was conducted among 276 patients with MOGAD at 5 health care centers in the UK. Data from January 1973 to March 2020 were collected from 146 patients at Oxford and its outreach sites, 65 patients at Liverpool, 32 patients at a children's hospital in Birmingham, 22 patients at a children's hospital in London, and 11 patients at Cardiff, Wales. Data were analyzed from April through July 2020. Main Outcomes and Measures: Risk of relapse and annualized relapse rate were evaluated according to different baseline features, including onset age, onset phenotype, and incident vs nonincident group, with the incident group defined as patients diagnosed with antibodies against myelin oligodendrocyte glycoprotein before a second attack. Time to next relapse among patients experiencing relapse was measured and compared between the maintenance therapy subgroup and each first-line treatment group. The no-treatment group was defined as the off-treatment phase among patients who were relapsing, which could occur between any attack or between the last attack and last follow-up. Results: Among 276 patients with MOGAD, 183 patients were identified as being part of the incident group. There were no differences in mean (SD) onset age between total and incident groups (26.4 [17.6] years vs 28.2 [18.1] years), and female patients were predominant in both groups (166 [60.1%] female patients vs 106 [57.9%] female patients). The most common presentation overall was optic neuritis (ON) (119 patients among 275 patients with presentation data [43.3%]), while acute disseminated encephalomyelitis (ADEM), brain, or brainstem onset was predominant among 69 patients aged younger than 12 years (47 patients [68.1%]), including 41 patients with ADEM (59.4%). In the incident group, the 8-year risk of relapse was 36.3% (95% CI, 27.1%-47.5%). ON at onset was associated with increased risk of relapse compared with transverse myelitis at onset (hazard ratio [HR], 2.66; 95% CI, 1.01-6.98; P = .047), but there was no statistically significant difference with adjustment for a follow-on course of corticosteroids. Any TM at onset (ie, alone or in combination with other presentations [ie, ON or ADEM, brain, or brain stem]) was associated with decreased risk of relapse compared with no TM (HR, 0.41; 95% CI, 0.20-0.88; P = .01). Young adult age (ie, ages >18-40 years) was associated with increased risk of relapse compared with older adult age (ie, ages >40 years) (HR, 2.71; 95% CI, 1.18-6.19; P = .02). First-line maintenance therapy was associated with decreased risk of relapse when adjusted for covariates (prednisolone: HR, 0.33; 95% CI, 0.12-0.92; P = .03; prednisolone, nonsteroidal immunosuppressant, or combined: HR, 0.51; 95% CI, 0.28-0.92; P = .03) compared with the no-treatment group. Conclusions and Relevance: The findings of this cohort study suggest that onset age and onset phenotype should be considered when assessing subsequent relapse risk and that among patients experiencing relapse, prednisolone, first-line immunosuppression, or a combination of those treatments may be associated with decreased risk of future relapse by approximately 2-fold. These results may contribute to individualized treatment decisions.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Adulto , Idade de Início , Idoso , Autoanticorpos , Criança , Pré-Escolar , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Reino Unido , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-34955459

RESUMO

The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Avaliação de Resultados em Cuidados de Saúde , Transtornos da Visão/diagnóstico , Testes Visuais , Vias Visuais/diagnóstico por imagem , Humanos
10.
Artigo em Inglês | MEDLINE | ID: mdl-34785575

RESUMO

BACKGROUND AND OBJECTIVES: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Aquaporina 4/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Avaliação de Resultados em Cuidados de Saúde , Prevenção Secundária , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-34711644

RESUMO

BACKGROUND AND OBJECTIVE: To investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort. METHODS: In this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD. RESULTS: Nineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins. DISCUSSION: CSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.


Assuntos
Autoanticorpos/líquido cefalorraquidiano , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/sangue , Pessoas com Deficiência , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
J Neuroimmunol ; 362: 577765, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34839149

RESUMO

BACKGROUND: Since the emergency use approval of different types of COVID-19 vaccines, several safety concerns have been raised regarding its early and delayed impact on the nervous system. OBJECTIVE: This study aims to systematically review the reported cases of CNS demyelination in association with COVID-19 vaccination, which has not been performed, to our knowledge. METHODS: A systematic review was performed by screening published articles and preprints of cases of CNS demyelination in association with COVID-19 vaccines in PubMed, SCOPUS, EMBASE, Google Scholar, Ovid and medRxiv databases, until September 30, 2021. This study followed PRISMA guidelines. Descriptive findings of reported cases were reviewed and stratified by demographic and clinical findings, diagnostic work-up, management, and overall outcome. RESULTS: A total of 32 cases were identified, with female predominance (68.8%) and median age of 44 years. Eleven cases were reported after Pfizer vaccine, 8 following AstraZeneca vaccine, 6 following Moderna, 5 following Sinovac/ Sinopharm vaccines, and one following each of Sputnik and Johnson&Johnson vaccines. The majority of cases (71.8%) occurred after the first dose of the vaccine, with neurological symptoms manifesting after a median of 9 days. The most common reported presentations were transverse myelitis (12/32) and MS-like pictures (first diagnosis or a relapse) in another 12/32 cases, followed by ADEM- like (5/32), and NMOSD- like (3/32) presentations. History of a previous immune-mediated disease was reported in 17/32 (53.1%) cases. The mRNA-based vaccines resulted in the greatest number of demyelinating syndromes (17/32), followed by viral vector vaccines (10/32), and inactivated vaccines (5/32). Most MS-like episodes (9/12) were triggered by mRNA-based vaccines, while TM occurred following both viral vector and mRNA-based vaccines. Management included high dose methylprednisolone, PLEX, IVIg, or a combination of those, with a favorable outcome in the majority of case; marked/complete improvement (25/32) or stabilized/ partial recovery in the remaining cases. CONCLUSION: This systematic review identified few cases of CNS demyelination following all types of approved COVID-19 vaccines so far. Clinical presentation was heterogenous, mainly following the first dose, however, half of the reported cases had a history of immune-mediated disease. Favorable outcome was observed in most cases. We suggest long-term post-marketing surveillance for these cases, to assess for causality, and ensure the safety of COVID-19 vaccines.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/induzido quimicamente , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/etiologia , Humanos , SARS-CoV-2
13.
J Neurol ; 269(3): 1641-1650, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34383114

RESUMO

BACKGROUND: We aimed to compare the clinical data, laboratory findings, and imaging characteristics of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and aquaporin 4 antibody (AQP4)-positive neuromyelitis optica spectrum disorder (NMOSD), as detailed comparative analyses of laboratory data for both diseases are rare. METHODS: Our retrospective study compared the clinical data, laboratory findings, and imaging characteristics of 118 AQP4-positive patients with first-episode NMOSD and 25 patients with first-episode MOGAD. Logistic regression was used to determine the factors that differentiated MOGAD and AQP4-positive NMOSD. RESULTS: There were significant differences in age, symptoms, recurrence rate, laboratory indicators, and imaging examinations between patients with MOGAD and patients with AQP4-positive NMOSD. Patients with MOGAD were younger and had higher levels of uric acid than those with AQP4-positive NMOSD. The proportion of cortical gray matter/juxtacortical white matter lesions was significantly higher in the MOGAD group than in the NMOSD group. Logistic regression revealed that young age [odds ratio (OR) = 0.947, 95% confidence interval (CI) = 0.905-0.99], high uric acid level (OR = 1.016, 95% CI = 1.006-1.027), and cortical gray matter/juxtacortical white matter involvement (OR = 3.889, 95% CI = 1.048-14.442) were significantly related to MOGAD. CONCLUSION: The multivariate analysis of the present study demonstrated that age, uric acid level, and the presence of lesions in the cortical gray matter/juxtacortical white matter can aid in distinguishing patients with AQP4-positive NMOSD from those with MOGAD. These factors may also aid in determining which patients should be tested for antibodies.


Assuntos
Aquaporina 4 , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Neuromielite Óptica , Aquaporina 4/imunologia , Autoanticorpos , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Glicoproteína Mielina-Oligodendrócito , Neuromielite Óptica/diagnóstico por imagem , Estudos Retrospectivos
14.
Exp Neurol ; 347: 113895, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34653510

RESUMO

Injury of oligodendrocytes (OLs) induces demyelination, and patients with neurodegenerative diseases exhibit demyelination concomitantly with neurological deficit and cognitive impairment. Oligodendrocyte progenitor cells (OPCs) are present in the adult central nervous system (CNS), and they can proliferate, differentiate, and remyelinate axons after damage. However, remyelination therapies are not in clinical use. Multiple sclerosis (MS) is a major demyelinating disease in the CNS. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic promise in animal models and in clinical trials of MS. Exosomes are nanoparticles generated by nearly all cells and they mediate cell-cell communication by transferring cargo biomaterials. Here, we hypothesize that exosomes harvested from MSCs have a similar therapeutic effect on enhancement of remyelination as that of MSCs. In the present study we employed exosomes derived from rhesus monkey MSCs (MSC-Exo). Two mouse models of demyelination were employed: 1) experimental autoimmune encephalomyelitis (EAE), an animal model of MS; and 2) cuprizone (CPZ) diet model, a toxic demyelination model. MSC-Exo or PBS were intravenously injected twice a week for 4 weeks, starting on day 10 post immunization in EAE mice, or once a week for 2 weeks starting on the day of CPZ diet withdrawal. Neurological and cognitive function were tested, OPC differentiation and remyelination, neuroinflammation and the potential underlying mechanisms were investigated using immunofluorescent staining, transmission electron microscopy and Western blot. Data generated from the EAE model revealed that MSC-Exo cross the blood brain barrier (BBB) and target neural cells. Compared with the controls (p < 0.05), treatment with MSC-Exo: 1) significantly improved neurological outcome; 2) significantly increased the numbers of newly generated OLs (BrdU+/APC+) and mature OLs (APC+), and the level of myelin basic protein (MBP); 3) decreased amyloid-ß precursor protein (APP)+ density; 4) decreased neuroinflammation by increasing the M2 phenotype and decreasing the M1 phenotype of microglia, as well as their related cytokines; 5) inhibited the TLR2/IRAK1/NFκB pathway. Furthermore, we confirmed that the MSC-Exo treatment significantly improved cognitive function, promoted remyelination, increased polarization of M2 phenotype and blocked TLR2 signaling in the CPZ model. Collectively, MSC-Exo treatment promotes remyelination by both directly acting on OPCs and indirectly by acting on microglia in the demyelinating CNS. This study provides the cellular and molecular basis for this cell-free exosome therapy on remyelination and modulation of neuroinflammation in the CNS, with great potential for treatment of demyelinating and neurodegenerative disorders.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Exossomos/transplante , Células-Tronco Mesenquimais/metabolismo , Doenças Neuroinflamatórias/patologia , Remielinização , Animais , Feminino , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Remielinização/fisiologia
15.
Ann Clin Transl Neurol ; 8(12): 2252-2269, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34889081

RESUMO

OBJECTIVE: To examine the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS). METHODS: We compared stool-derived microbiota of Canadian Pediatric Demyelinating Disease Network study participants ≤21 years old, with MS (disease-modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset <18 years), and unaffected controls. All were ≥30 days without antibiotics or corticosteroids. V4 region 16S RNA gene-derived amplicon sequence variants (Illumina MiSeq) were assessed using negative binomial regression and network analyses; rate ratios were age- and sex-adjusted (aRR). RESULTS: Thirty-two MS, 41 monoADS (symptom onset [mean] = 14.0 and 6.9 years) and 36 control participants were included; 75%/56%/58% were female, with mean ages at stool sample = 16.5/13.8/15.1 years, respectively. Nine MS cases (28%) were DMD-naïve. Although microbiota diversity (alpha, beta) did not differ between participants (p > 0.1), taxa-level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6-11.2, p = 0.004, Q = 0.01), and lower abundances of short-chain fatty acid (SCFA)-producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q < 0.05). DMD-naïve MS cases were depleted for Clostridiales vadin-BB60 (unnamed species) versus either DMD-exposed, controls (p, Q < 0.01), or monoADS (p = 0.001, Q = 0.06) and exhibited altered community connectedness (p < 10-9 Kruskal-Wallis), with SCFA-producing taxa underrepresented. Consistent taxa-level findings from an independent US Network of Pediatric MS Centers case/control (n = 51/42) cohort included >eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8-12.8, p < 0.05) in MS cases and 72%-80% lower abundance of SCFA-producing Ruminococcaceae-NK4A214 (aRR = 0.38-0.2, p ≤ 0.01). INTERPRETATION: Gut microbiota community structure, function and connectivity, and not just individual taxa, are of likely importance in MS.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/microbiologia , Microbioma Gastrointestinal , Esclerose Múltipla/microbiologia , Adolescente , Canadá , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Biologia Computacional , Feminino , Humanos , Masculino , RNA Ribossômico 16S
16.
BMJ Open ; 11(11): e055392, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34848526

RESUMO

OBJECTIVE: To identify factors predictive of relapse risk and disability in myelin oligodendrocyte glycoprotein associated disease (MOGAD). SETTING: Patients were seen by the neuromyelitis optica spectrum disorders (NMOSD) service in Liverpool, UK, a national referral centre for adult patients with MOGAD, NMOSD and related conditions. PARTICIPANTS: Patients with MOGAD=76 from England, Northern Ireland and Scotland were included in this cohort study. RESULTS: Relapsing disease was observed in 55% (42/76) of cases. Steroid treatment >1 month (OR 0.2, 95% CI 0.05 to 0.80; p=0.022), transverse myelitis (TM) at first attack (OR 0.03, 95% CI 0.004 to 0.23; p=0.001) and male sex (OR 0.16, 95% CI 0.04 to 0.68; p=0.014) were associated with monophasic disease (area under the curve=0.85). Male sex (HR 0.46, 95% CI 0.24 to 0.89; p=0.011) and TM at disease onset (HR 0.42, 95% CI 0.22 to 0.82; p=0.011) were also associated with an increased latency to first relapse. 45% (32/71) of patients became MOG-antibody negative and in relapsing patients negative seroconversion was associated with a lower relapse risk (relative risk 0.11 95% CI 0.05 to 0.26; p<0.001). No specific factors were predictive of visual or overall disability. CONCLUSIONS: Male patients with spinal cord involvement at disease onset have a lower risk of relapsing disease and longer latency to first relapse. Steroid treatment for at least 1 month at first attack was also associated with a monophasic disease course. MOG-antibody negative seroconversion was associated with a lower risk of relapse and may help inform treatment decisions and duration.


Assuntos
Aquaporina 4 , Autoanticorpos , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Estudos de Coortes , Inglaterra , Feminino , Humanos , Masculino , Glicoproteína Mielina-Oligodendrócito , Irlanda do Norte , Recidiva , Escócia
17.
JAMA Neurol ; 78(12): 1441-1442, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724032
18.
J Neuroimmunol ; 361: 577747, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34715592

RESUMO

Immune-mediated myelopathy (IMM) diagnosis is challenging, and its etiology may remain unclear despite extensive investigation. We evaluated diagnostic changes in IMM patients during follow-up. We included 80 patients, 61.3% female, with median follow-up time 62.5 months. Diagnoses at discharge were: 48.8% Multiple Sclerosis-IMM (MS-IMM), 32.5% I-IMM, 11.3% Neuromyelitis Optica Spectrum Disorders-IMM (NMOSD-IMM), 1.3% MOG encephalomyelitis (MOGAD), and 6.2% Others IMM (O-IMM). Twenty-two  patients (27.5%) changed diagnosis (median 15.5  months): 68.8% MS-IMM, 12.5%  NMOSD-IMM, 3.8% MOGAD, 10.0% I-IMM, and 5.0% O-IMM. Most patients that changed diagnosis were I-IMM. Predictive factors for diagnostic change in I-IMM were: autonomous gait (p = 0.029), lesions suggestive of MS (p = 0.039), higher number of lesions (p = 0.043), lesions length < 3 vertebral bodies (p = 0.033), cervical involvement (p = 0.038), and lower EDSS at admission (p = 0.013). Etiologic reclassifications in IMM are common, therefore patients require an appropriate follow-up time to increase diagnostic accuracy.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Mielite/etiologia , Adulto , Encéfalo/patologia , Diagnóstico Tardio , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/complicações , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Diagnóstico Diferencial , Feminino , Seguimentos , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielite/epidemiologia , Mielite/imunologia , Neuroimagem , Admissão do Paciente , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Medula Espinal/patologia , Adulto Jovem
19.
J Neuroimmunol ; 361: 577725, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34610502

RESUMO

The acquired chronic demyelinating neuropathies include a growing number of disease entities that have characteristic, often overlapping, clinical presentations, mediated by distinct immune mechanisms, and responding to different therapies. After the discovery in the early 1980s, that the myelin associated glycoprotein (MAG) is a target antigen in an autoimmune demyelinating neuropathy, assays to measure the presence of anti-MAG antibodies were used as the basis to diagnose the anti-MAG neuropathy. The route was open for describing the clinical characteristics of this new entity as a chronic distal large fiber sensorimotor neuropathy, for studying its pathogenesis and devising specific treatment strategies. The initial use of chemotherapeutic agents was replaced by the introduction in the late 1990s of rituximab, a monoclonal antibody against CD20+ B-cells. Since then, other anti-B cells agents have been introduced. Recently a novel antigen-specific immunotherapy neutralizing the anti-MAG antibodies with a carbohydrate-based ligand mimicking the natural HNK-1 glycoepitope has been described.


Assuntos
Autoantígenos/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Glicoproteína Associada a Mielina/imunologia , Polirradiculoneuropatia/imunologia , Adenina/análogos & derivados , Adenina/uso terapêutico , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Antígenos CD57/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Epitopos/imunologia , Transtornos Neurológicos da Marcha/imunologia , Humanos , Imunossupressores/uso terapêutico , Imunoterapia , Lenalidomida/uso terapêutico , Mamíferos , Camundongos , Mimetismo Molecular , Bainha de Mielina/química , Bainha de Mielina/imunologia , Bainha de Mielina/ultraestrutura , Fibras Nervosas Mielinizadas/imunologia , Fibras Nervosas Mielinizadas/patologia , Doença Autoimune do Sistema Nervoso Experimental/imunologia , Paraproteinemias/imunologia , Paraproteínas/imunologia , Piperidinas/uso terapêutico , Troca Plasmática , Polirradiculoneuropatia/diagnóstico , Polirradiculoneuropatia/terapia , Nós Neurofibrosos/química , Nós Neurofibrosos/imunologia , Ratos , Rituximab/uso terapêutico
20.
J Neuroimmunol ; 361: 577742, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34655992

RESUMO

Neuromyelitis Optica spectrum disorders (NMOSD) are autoimmune inflammatory central nervous system diseases. NMOSD patients typically have recurrent attacks of severe optic neuritis or/and myelitis with majority of them having autoantibodies against the aquaporin-4 (AQP4). In the recent past, a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations had been demonstrated. MOG-IgG antibody associated disease (MOGAD) is now considered as a disease entity in its own right, distinct from classic MS and from AQP4-IgG-positive NMOSD. Here, we compared the clinical, laboratory, radiological features and treatment outcomes of patients with Aquaporin-4-IgG seropositive NMOSD and MOGAD. Relatively younger age at onset, lesser number of relapses, better response to treatment and favorable clinical outcomes were found in MOGAD group in comparison to AQP4-IgG-positive NMOSD group.


Assuntos
Aquaporina 4/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Imunoglobulina G/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/epidemiologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idade de Início , Antirreumáticos/uso terapêutico , Autoanticorpos/sangue , Criança , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Feminino , Hospitais de Ensino , Humanos , Imunossupressores/uso terapêutico , Masculino , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/terapia , Fenótipo , Prognóstico , Estudos Prospectivos , Recidiva , Rituximab/uso terapêutico , Convulsões/etiologia , Centros de Atenção Terciária , Resultado do Tratamento , Adulto Jovem
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