RESUMO
BACKGROUND: Definitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP)). METHODS: We recruited 77 patients with relapsing-remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse. RESULTS: After adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.00008; pcNfL = 0.004) as well as the presence of infratentorial lesions on MRI (psNfL = 0.0003; pcNfL < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.001), presence of more than 20 T2-lesions (psNfL = 0.049) as well as the presence of infratentorial lesions on MRI (psNfL = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.011) and presence of more than 20 T2-lesions (psNfL = 0.029). CONCLUSIONS: Among proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone.
Assuntos
Biomarcadores , Proteína Glial Fibrilar Ácida , Imageamento por Ressonância Magnética , Proteínas de Neurofilamentos , Humanos , Masculino , Feminino , Adulto , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Estudos Transversais , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/patologia , Pessoa de Meia-Idade , Adulto Jovem , Axônios/patologia , Neuroglia/patologia , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/sangueRESUMO
BACKGROUND: Serum neurofilament light (sNfL) reflects neuroaxonal damage and is now used as an outcome in treatment trials of relapsing-remitting multiple sclerosis (RRMS). However, the diagnostic properties of sNfL for monitoring disease activity in individual patients warrant further investigations. METHOD: Patients with suspected relapse and/or contrast-enhancing lesions (CELs) were consecutively included and performed magnetic resonance imaging (MRI) of the brain at baseline and weeks 28 and 48. Serum was obtained at baseline and 2, 4, 8, 16, 24, and 48 weeks. Neurofilament light concentration was measured using Single molecule array technology. RESULTS: We included 44 patients, 40 with RRMS and 4 with clinically isolated syndrome. The median sNfL level peaked at 2 weeks post-baseline (14.6 ng/L, interquartile range (IQR); 9.3-31.6) and reached nadir at 48 weeks (9.1 ng/L, IQR; 5.5-15.0), equivalent to the median sNfL of controls (9.1 ng/L, IQR; 7.4-12). A baseline Z-score of more than 1.1 (area under the curve; 0.78, p < 0.0001) had a sensitivity of 81% and specificity of 70% to detect disease activity. CONCLUSION: One out of five patients with relapse and/or CELs did not change significantly in post-baseline sNfL levels. The utility of repeated sNfL measurements to monitor disease activity is complementary rather than a substitute for clinical and MRI measures.
Assuntos
Biomarcadores , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente , Proteínas de Neurofilamentos , Humanos , Feminino , Proteínas de Neurofilamentos/sangue , Masculino , Adulto , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Estudos Prospectivos , Pessoa de Meia-Idade , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagemRESUMO
Importance: Myelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct central nervous system-demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur. Objective: To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center. Design, Setting, and Participants: This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded. Main Outcomes and Measures: Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed. Results: A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P < .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%. Conclusions and Relevance: This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Imunoglobulina G/sangue , Glicoproteína Mielina-Oligodendrócito/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Pré-Escolar , Técnicas e Procedimentos Diagnósticos/normas , Feminino , Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Adulto JovemRESUMO
It is unclear whether brain atrophy in multiple sclerosis (MS) is associated with not only neuroinflammation but also systemic inflammation. Here we found that systemic inflammatory marker serum amyloid A (SAA) was moderately correlated with cortical volume in the patients with clinically isolated syndrome (CIS) and MS (r = -0.41, p = 0.019). SAA was also significantly correlated with T2 lesion volume (T2LV) even after adjusting for age, disease duration, and disease modifying therapy (p = 0.0050). Thus, systemic inflammation may be associated with cortical atrophy, possibly via an increase in the T2LV in patients with CIS/MS.
Assuntos
Encéfalo/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/patologia , Proteína Amiloide A Sérica/metabolismo , Adulto , Atrofia , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/análiseRESUMO
Anti-myelin oligodendrocyte glycoprotein antibodies have been associated with a wide range of clinical presentations including monophasic and relapsing disease courses. Lack of a definitive marker for predicting further relapses and the final diagnoses complicates the clinical follow-up and treatment decisions for patients with the first episode. This study retrospectively analyzed the clinical spectrum, treatment protocols and outcome of nine children with MOG antibody-associated demyelinating disease. Diagnoses at first presentation were acute disseminated encephalomyelitis (ADEM) in six cases (67%), optic neuritis in two cases (22%), and clinically isolated syndrome in one case (11%). The disease remained monophasic in five (56%) cases. All cases with a monophasic disease course were negative for anti-MOG antibody titers in the third month. The initial diagnosis of all relapsing cases was ADEM. Three of the four cases with a relapsing disease course were available for anti-MOG antibody testing at the third month and all were positive, however, antibody titers at the sixth month were inconsistent. Cases with a relapsing disease course had no further attacks after monthly intravenous immunoglobulin treatment. Relapsing disease course is not rare in childhood MOG-antibody associated demyelinating disease. Monthly IVIG treatment may be a good alternative for the long-term treatment of relapsing cases with a low side effect profile. Anti-MOG antibody serostatus at remission periods should be interpreted cautiously. Further studies are needed to better understand and predict the clinical course of pediatric patients with MOG-antibody associated diseases.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Glucocorticoides/uso terapêutico , Glicoproteína Mielina-Oligodendrócito/sangue , Centros de Atenção Terciária , Criança , Pré-Escolar , Doenças Desmielinizantes/tratamento farmacológico , Feminino , Seguimentos , Glucocorticoides/farmacologia , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Aim: Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (RIS) population. The aim of this study was to assess signatures of circulating miRNAs in those patients according to their conversion status after 5 years of follow-up. Patients & methods: OpenArray plates assessing 216 miRNA candidates were run in 15 RIS patients, and their relative abundances were analyzed. Results: A specific profile of deregulated circulating miRNAs (miR-144-3p, miR-448 and miR-653-3p in cerebrospinal fluid and miR-142-3p, miR-338-3p, miR-363-3p, miR-374b-5p, miR-424-5p, miR-483-3p in plasma) differentiated individuals who remained as RIS after 5 years of follow-up. Conclusion: Circulating miRNAs might be used as prognostic biomarkers for RIS patients.
Assuntos
MicroRNA Circulante/sangue , MicroRNA Circulante/líquido cefalorraquidiano , Doenças Desmielinizantes , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Prognóstico , SíndromeRESUMO
The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood-brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.
Assuntos
Aquaporina 4/genética , Doenças Desmielinizantes/genética , Inflamação/genética , Bainha de Mielina/genética , Neuromielite Óptica/genética , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/sangue , Lesões Encefálicas/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Esclerose Múltipla/sangue , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Neuromielite Óptica/sangue , Neuromielite Óptica/patologiaRESUMO
Objective: Early and accurate diagnosis of multiple sclerosis (MS) remains a clinical challenge. The main objective is to evaluate the diagnostic and prognostic value of the routinely performed immunoglobulin G (IgG) index for MS patients in the Asian population. Methods: A retrospective study was conducted among a cohort of clinically isolated syndrome (CIS) patients in China with known oligoclonal band (OCB) status and IgG index at baseline. We first evaluated the predictive value of IgG index for OCB status. Secondly, the diagnostic utility and prognostic value of IgG index alone were tested. Lastly, we incorporated IgG index into the 2017 McDonald criteria by replacing OCB with either "IgG index or OCB" (modified criteria 1), "IgG index and OCB" (modified criteria 2), or "IgG index" (modified criteria 3). The diagnostic utility of different criteria was calculated and compared. Results: In a CIS cohort in China (n = 105), IgG index > 0.7 forecasted OCB positivity (X2 = 22.90, P < 0.001). An elevated IgG index was highly prognostic of more clinical relapses [1-year adjusted odds ratio [OR] = 1.32, P = 0.015; 2-years adjusted OR = 1.69, P = 0.013] and Expanded Disability Status Scale worsening (1-year adjusted OR = 1.76, P = 0.040; 2-years adjusted OR = 1.85, P = 0.032). Under the 2017 McDonald criteria (Positive Likelihood Ratio = 1.54, Negative Likelihood Ratio = 0.56), an IgG index > 0.7 in CIS patients increased the likelihood of developing MS within 2 years, either when OCB status was unknown (Positive Likelihood Ratio = 2.11) or with OCB positivity (Positive Likelihood Ratio = 2.11) at baseline; An IgG index ≤ 0.7, along with a negative OCB, helped rule out the MS diagnosis (Negative Likelihood Ratio = 0.53). Conclusions: IgG index > 0.7 predicts OCB positivity at the initial attack of MS and is prognostic of early disease activity. IgG index serves as an easily-obtainable and accurate OCB surrogate for MS diagnosis in the Asian population.
Assuntos
Doenças Desmielinizantes/diagnóstico , Imunoglobulina G/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , China , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/imunologia , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Bandas Oligoclonais/líquido cefalorraquidiano , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos RetrospectivosAssuntos
Aquaporina 4/biossíntese , Doenças Desmielinizantes/sangue , Regulação Neoplásica da Expressão Gênica , Gamopatia Monoclonal de Significância Indeterminada/sangue , Proteínas de Neoplasias/biossíntese , Síndromes Paraneoplásicas do Sistema Nervoso/sangue , Doença Aguda , Doenças Desmielinizantes/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/patologia , Síndromes Paraneoplásicas do Sistema Nervoso/patologiaRESUMO
Paroxysmal dysarthria and ataxia (PDA) syndrome constitutes a rare neurological disorder, and is generally reported in cases of multiple sclerosis (MS) involving the midbrain. We present an illustrative case of 32-year-old female who developed clinically isolated syndrome manifested paroxysmal dysarthria, ataxia, ptosis and diplopia, coexisting with anti-N-methyl-d-aspartate receptor antibodies. We review the literature and identify 23 other cases with brain MRI examinations to summarize the lesion locations and clinical characteristics of PDA syndrome, and ultimately provide a new framework for understanding this rare condition. The current case expands the spectrum of symptoms in PDA syndrome, which was including but not limited to dysarthria and ataxia. Caudal paramedian midbrain lesions involving decussation of the superior cerebellar peduncles appear to be critical for PDA syndrome.
Assuntos
Ataxia/diagnóstico por imagem , Autoanticorpos , Doenças Desmielinizantes/diagnóstico por imagem , Disartria/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Receptores de N-Metil-D-Aspartato , Adulto , Ataxia/sangue , Ataxia/complicações , Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/complicações , Disartria/sangue , Disartria/complicações , Feminino , Humanos , Receptores de N-Metil-D-Aspartato/sangue , SíndromeRESUMO
RATIONALE: There is an increasing and compelling need for early recognition of features of osmotic demyelination syndrome (ODS), and a further attempt at correcting this even where presentation is late. PATIENT CONCERNS: A 49-year-old male admitted into the emergency department with a complaint of lethargy and severe hyponatremia, with subsequent ODS supervening on initial attempts at correction. DIAGNOSIS: Rapid rise in serum sodium concentration (121âmmol/L in 8âhours from a nadir of 101âmmol/L), concomitant deterioration in patient's conscious level support the diagnosis of ODS. INTERVENTION: Concomitant administration of 5% dextrose water with desmopressin with a therapeutic objective of gradual relowering of serum sodium concentration. OUTCOMES: Significant improvement in patients' conscious level and motor function with the commencement of sodium relowering therapy. The patient was eventually discharged home. LESSONS: Regardless of the temporal profile of neurologic sequelae following ODS due to hyponatremia, its worthwhile attempting initial sodium relowering with dextrose 5% and desmopressin and then monitoring of biochemical and neurologic markers.
Assuntos
Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/terapia , Hiponatremia/complicações , Antidiuréticos/administração & dosagem , Antidiuréticos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/uso terapêutico , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico , Quimioterapia Combinada/métodos , Glucose/administração & dosagem , Glucose/uso terapêutico , Humanos , Hiponatremia/terapia , Doença Iatrogênica , Letargia/etiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Solução Salina Hipertônica/efeitos adversos , Sódio/sangue , Edulcorantes/administração & dosagem , Edulcorantes/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated. MATERIALS AND METHODS: Between October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics. RESULTS: Clinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl. CONCLUSIONS: Simplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Imunoglobulina G/sangue , Glicoproteína Mielina-Oligodendrócito/sangue , Adulto , Idoso , Autoanticorpos/líquido cefalorraquidiano , Estudos de Coortes , Doenças Desmielinizantes/líquido cefalorraquidiano , Feminino , Seguimentos , Células HEK293 , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Glicoproteína Mielina-Oligodendrócito/líquido cefalorraquidiano , Adulto JovemRESUMO
Irradiation of food at 50-55 kGy results in a profound, chronic demyelinating-remyelinating disease of the entire central nervous system (CNS) in cats, named Feline Irradiated Diet-Induced Demyelination (FIDID). This study examines the early stages of demyelination and long-term consequences of demyelination and remyelination on axon survival or loss. Myelin vacuolation is the primary defect leading to myelin breakdown, demyelination then prompt remyelination in the spinal cord and brain. There is no evidence of oligodendrocyte death. The spinal cord dorsal column is initially spared yet eventually becomes severely demyelinated with subsequent loss of axons in the core and then surface of the fasciculus gracilis. However remyelination of the sub-pial axons in the dorsal column results in their protection. While there was a lack of biochemical evidence of Vitamin B12 deficiency, the pathological similarities of FIDID with sub-acute combined degeneration (SCD) led us to explore treatment with Vitamin B12. Treatment led to recovery or improvement in some cats and neurologic relapse on cessation of B12 therapy. While the reason that irradiated food is myelinotoxic in the cat remains unresolved, nonetheless the neuropathological changes match exactly what is seen in SCD and its models and provide an ideal model to study the cellular and molecular basis of remyelination.
Assuntos
Doenças Desmielinizantes/patologia , Dieta , Degeneração Neural/patologia , Radiação , Doença Aguda , Animais , Axônios/patologia , Gatos , Doença Crônica , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Macrófagos/patologia , Masculino , Metaboloma , Microglia/patologia , Bainha de Mielina/metabolismo , Degeneração Neural/sangue , Degeneração Neural/fisiopatologia , Neuropatologia , Remielinização , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Fatores de Tempo , Vitamina B 12/sangueRESUMO
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system that commonly manifests as a complex neuropsychiatric syndrome. Antibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with a range of clinical presentations including acute disseminated encephalomyelitis (ADEM), optic neuritis, and transverse myelitis. The concurrence of NMDAR encephalitis and demyelinating syndromes is rare. We describe the case of a 29-year-old male with NMDAR encephalitis and overlapping MOG antibody disease. The aim of this report is to add to the growing knowledge of phenotypic characteristics of overlap syndromes as their clinical and prognostic features may differ from those of single antibody disease.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/sangue , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico por imagem , Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/sangue , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Doenças Desmielinizantes/complicações , Humanos , MasculinoRESUMO
Importance: Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices. Objective: To characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination. Design, Setting, and Participants: In this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018. Main Outcomes and Measures: Presence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, magnetic resonance imaging, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain magnetic resonance imaging lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure. Results: Of the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2-13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody-positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody-positive participants (67%), but magnetic resonance imaging characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody-positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status. Conclusions and Relevance: Myelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximatively half of cases. Even when persistently positive, most anti-MOG antibody-positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy.
Assuntos
Autoanticorpos/imunologia , Doenças Desmielinizantes/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Autoanticorpos/sangue , Autoantígenos/imunologia , Criança , Doenças Desmielinizantes/sangue , Feminino , Humanos , Masculino , SíndromeRESUMO
OBJECTIVE: To compare response to rituximab (RTX) between adult patients positive for myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies. METHODS: We prospectively studied adult patients with MOG or AQP4 antibodies who received RTX under an individualized dosing schedule adapted to the biological effect of RTX monitored by memory B-cell measurement. Memory B cells were counted monthly and when relapse occurred. The biological effect of RTX was considered significant with <0.05% memory B cells in peripheral blood lymphocytes. RESULTS: In 16 patients with MOG antibodies and 29 with AQP4 antibodies, mean follow-up was 19 (range = 9-38) and 38 (13-79) months. Under RTX, 10 relapses occurred in 6 of 16 (37.5%) patients with MOG antibodies, and 13 occurred in 7 of 29 (24%) with AQP4 antibodies. The median time of relapse after the most recent infusion was 2.6 (0.6-5.8) and 7 (0.8-13) months, respectively (p < 0.001). Memory B cells had reemerged in 2 of 10 (20%) relapses in patients with MOG antibodies and 12 of 13 (92.5%) with AQP4 antibodies (p < 0.001). INTERPRETATION: In AQP4 antibody-associated disorder, relapse mostly occurs when the biological effect of RTX decreases, which argues for treatment efficacy. In MOG antibody-associated disorder, the efficacy of RTX is not constant, because one-third of patients showed relapse despite an effective biological effect of RTX. In this subpopulation, memory B-cell depletion was unable to prevent relapse, which was probably caused by different immunological mechanisms. These findings should be used to improve treatment strategies for MOG antibody-associated disorder. ANN NEUROL 2020;87:256-266.
Assuntos
Aquaporina 4/imunologia , Doenças Desmielinizantes/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/imunologia , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Subpopulações de Linfócitos B/efeitos dos fármacos , Contagem de Células , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species. METHODS: The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared. RESULTS: Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG-. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG- children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration. CONCLUSIONS: Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.
Assuntos
Autoanticorpos/sangue , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/diagnóstico por imagem , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/sangue , Adolescente , Animais , Autoanticorpos/líquido cefalorraquidiano , Criança , Pré-Escolar , Doenças Desmielinizantes/líquido cefalorraquidiano , Encefalomielite Autoimune Experimental/líquido cefalorraquidiano , Feminino , Humanos , Macaca , Masculino , Glicoproteína Mielina-Oligodendrócito/líquido cefalorraquidianoRESUMO
PURPOSE OF REVIEW: Pediatric central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM). As diagnostic criteria become more inclusive, the risk of misdiagnosis of atypical demyelinating diseases of rheumatologic, infectious, and autoimmune etiology increases. RECENT FINDINGS: We review mimics of multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis, including rheumatologic diseases: systemic lupus erythematosus and neuro-Behçet disease; infectious diseases: human immunodeficiency virus, progressive multifocal leukoencephalopathy, and subacute sclerosis panencephalitis; and autoimmune diseases including X-linked Charcot-Marie-Tooth disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and autoimmune glial fibrillary acidic protein (GFAP) encephalopathy. Atypical demyelinating disease may mimic classic neuroinflammatory diseases of the central nervous system. Imaging may meet criteria for a diagnosis of multiple sclerosis, or patients may present with optic neuritis and transverse myelitis consistent with neuromyelitis optica spectrum or myelin oligodendrocyte glycoprotein (MOG) antibody disorders. Through careful history-taking and review of atypical MRI findings, we may avoid misdiagnosis and mistreatment.