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INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.
Assuntos
Biomarcadores/análise , Genômica/métodos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Adolescente , Adulto , Idoso , Argentina , Criança , Pré-Escolar , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Leucodistrofia Metacromática/classificação , Leucoencefalopatias/classificação , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy was described for the first time in 2016. The most common clinical manifestation is meningoencephalomyelitis associated with a characteristic imaging pattern that allows diagnostic suspicion and its confirmation through determination of antibodies in serum and cerebrospinal fluid (CSF). We present a case of a 35-year-old patient with involvement of the central and peripheral nervous system and a recent diagnosis of thyroid cancer, which compared to the compatible clinical picture of meningoencephalomyelitis, characteristic findings on MRI and after the exclusion of alternative pathologies, we finally arrived at the diagnosis by the positive determination of anti-GFAP in CSF. The patient underwent surgical treatment and radioactive iodine for the diagnosed thyroid tumor and she subsequently received treatment with corticosteroids with partial improvement of the neurological symptomatology. We emphasize that in this pathology the MRI images usually depict a characteristic pattern, although not pathognomonic, it is necessary to consider other causes. Before a high suspicion of this entity due to the clinical and imaging picture, it is convenient to measure the antibody in CSF, given the greater sensitivity and specificity compared to its serum screening, in order to arrive to the definitive etiological diagnosis as it was done in the clinical case that is presented.
La astrocitopatía autoinmune asociada a proteína ácida fibrilar glial (GFAP) fue descripta por primera vez en el año 2016. La manifestación clínica más frecuente es la meningoencefalomielitis asociado a un patrón imagenológico característico que permite la sospecha diagnóstica y su confirmación mediante la determinación de los anticuerpos en suero y en líquido cefalorraquídeo (LCR). Presentamos el caso de una paciente de 35 años con compromiso del sistema nervioso a nivel central y periférico y un reciente diagnóstico de cáncer de tiroides, que frente al cuadro clínico compatible de meningoencefalomielitis, los hallazgos característicos en resonancia magnética y luego de la exclusión de enfermedades alternativas, finalmente se arribó al diagnóstico por la determinación positiva de anti GFAP en LCR. Realizó tratamiento quirúrgico y con iodo radioactivo por su tumor hallado y posteriormente recibió tratamiento con corticoides con mejoría parcial de la signo-sintomatología neurológica. Destacamos que en esta enfermedad las imágenes por resonancia magnética presentan un patrón característico, aunque no patognomónico, siendo necesario considerar otras causas. Ante una alta sospecha de esta entidad por el cuadro clínico e imagenológico, es conveniente realizar dosaje del anticuerpo en LCR, dada la mayor sensibilidad y especificidad en comparación con su pesquisa en suero, con el fin de arribar al diagnóstico etiológico definitivo como en el caso clínico presentado.
Assuntos
Proteína Glial Fibrilar Ácida , Imageamento por Ressonância Magnética , Adulto , Feminino , Humanos , Astrócitos/patologia , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/imunologia , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/imunologiaRESUMO
INTRODUCTION: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. METHODS: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clinical, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. RESULTS: Fifteen patients were included. All had diminished results in at least one test. Memory was the most affected domain. Patients who were under immunosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). CONCLUSION: Our results show that, despite the monophasic course of this disease, all patients had persistent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.
Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actualmente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, transversal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tratamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encontraban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) versus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doenças Autoimunes do Sistema Nervoso , Encefalite , Humanos , Argentina/epidemiologia , Cognição , Estudos Transversais , Progressão da Doença , Estudos ProspectivosRESUMO
BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) is an antibody-mediated disorder of the Central Nervous System where a leading role of the complement system has been demonstrated. OBJECTIVE: To measure the levels of complement factors C3, C4 and C5a in serum and plasma of clinical remission patients with AQP4-IgG + NMOSD. METHODS: Twelve patients with NMOSD AQP4 + according to 2015 criteria from a General Hospital in Buenos Aires, Argentina, were included in the study, and 19 age- and sex-matched healthy volunteers as a control group (HC). AQP4 antibodies were measured in serum by CBA analysis. Fresh blood samples were centrifuged to obtain serum and plasma. C3, C4, and AQP4 antibodies were measured in the serum, whereas C5a was measured in the plasma, which was obtained using Futhan (BD FUT-175®, BD Biosciences, San Jose, CA, USA). RESULTS: The complement factors, C3, C4, and C5a were measured in all samples. The mean concentration of C3 was 130.7 mg/dl (SD 16.1 mg/dl), and the mean concentration of C4 was 21.6 mg/dl (SD 4.8 mg/dl); both values were within the normal reference range (C3: 84-193 mg/dl; C4: 20-40 mg/dl) and were not significantly different (p > 0.05) from the mean levels in healthy controls (C3: 116.9 mg/dl; C4: 21.9 mg/dl). When analyzing the mean plasma level of C5a, we found a statistically significant difference (p = 0.0444) between the mean concentration of C5a in NMOSD patients (43.1 ng/ml; SD 48.7 ng/ml) and the HC group (17.7 ng/ml; SD 16.7 ng/ ml). CONCLUSIONS: In conclusion, the present study demonstrates that plasma C5a may be interesting to investigate as a potential biomarker of disease activity in NMOSD, in a larger and prospective cohort.
Assuntos
Aquaporina 4 , Neuromielite Óptica , Humanos , Complemento C5a , Estudos Prospectivos , Autoanticorpos , Imunoglobulina GRESUMO
BACKGROUND: Neuromyelitis Optica spectrum disorder (NMOSD) is an antibody-mediated autoimmune disease of the CNS, which especially affects the optic nerves and spinal cord. There is little known in Latin America (LATAM) about NMOSD, and few reports have been published in the literature so far. We aimed to describe an NMOSD study in a single center from Argentina. METHODS: A retrospective cross sectional study was carried out in a single reference center in the city of Buenos Aires, Argentina. Data were collected from January 2000 through December 2021 using medical records from patients attending Ramos Mejia Hospital in Buenos Aires, Argentina. Here we describe the clinical, laboratory, MRI, disability course, and treatment of 92 NMOSD patients. RESULTS: Mean age at the onset of symptoms was 31 years (range 2-68) with a female/male ratio of 4.8:1. 71.7 % had an early onset before the age of 50 years old, 8.7 % had a late onset of the disease and 19.6 % had an onset at pediatric age. The first symptom of NMOSD was optic neuritis in 47.8 % of the patients, followed by transverse myelitis, 33.7 % and area postrema syndrome, 5.4 %. 96.7 % of patients relapsed at least once during the follow-up period. The mean of the expanded disability status scale (EDSS) was 4.0 (range 2-8). 34,8 % had one or more associated autoimmune diseases. 78,6 % had a positive result for AQP4-IgG. The ratio of male to female was 1:8.4 vs.1:1.2 in the seropositive group vs. the seronegative. CSF results showed OCB type 2 in 6.3 %. The brain MRI did not show brain lesions in 71,7 % of the patients. 17 % presented spinal cord lesions with less than 3 vertebral segments. All patients received treatment with immunosuppressive drugs. Rituximab and azathioprine were the most used. CONCLUSIONS: This is the largest hospital-based study in an Argentina cross-sectional study of patients with NMOSD. Recurrent disease, early age at onset, female prevalence in AQP4-IgG+ patients, and the difficulty to assess new treatments, are the highlight features in our study of patients. Further Argentinian and LATAM studies will provide more information.
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Neuromielite Óptica , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/complicações , Estudos Transversais , Estudos Retrospectivos , Aquaporina 4 , Argentina/epidemiologia , Imunoglobulina G , AutoanticorposRESUMO
Autoimmune encephalitis (AE) is a common cause of noninfectious acute encephalitis. We aimed to provide the first review of immune therapy regimens used for patients with AE in Latin America, as well as the safety and efficacy associated with them, by reviewing the medical records of Argentine patients with AE treated between 2013 and 2018. Data included clinical symptoms, laboratory tests, electroencephalography, magnetic resonance imaging, cerebral spinal fluid, and neoplasm screenings. We examined ten AE patients who received first-line immunotherapy at a median of 2.5 months following symptom onset. Among these patients, five required second-line treatment: three received therapy at a median of 4 months (2-112) after symptom onset and were treated with rituximab, while two received therapy at a median of 4.5 (4-5) months after onset and received methylprednisolone for 6 months and initiated chronic treatment with azathioprine. By the last follow-up, their respective outcomes improved significantly. On the modified Rankin Scale, the median score decreased from 5 to 1 (p ≤ 0.05). Only two of the ten patients in our series experienced relapses; both had been treated with a combination of methylprednisolone and IVIG. The regimen after recurrence included rituximab and corticoids plus azathioprine. Neither patient had experienced another relapse by their last follow-up. Our findings demonstrate the importance of early and aggressive immunosuppressive therapy to achieve a good clinical outcome and a fast recovery without relapses.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Encefalite/tratamento farmacológico , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Adolescente , Adulto , Idoso , Argentina , Azatioprina/uso terapêutico , Criança , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Troca Plasmática/métodos , Rituximab/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Although the pathogenesis of myasthenia gravis (MG) is well known, prognostic markers are not yet available. We assessed the utility of anti-acetylcholine receptor (AChR) antibody (AChR-ab) titer and concentration of C3, C4, and C5a as potential severity biomarkers in MG. METHODS: Levels of C3, C4, C5a, and AChR-ab were measured in 60 AChR-ab-positive patients with MG. Their relationship with clinical severity was analyzed using the activities of daily living (ADL) and MG composite (MGC) scales. RESULTS: AChR-ab titer correlated with severity of MG according to ADL (p = 0.002) and MGC scales (p = 0.001). When patients were classified according to disease duration, a statistically significant correlation between AChR-ab titer and clinical severity was only found in the subgroup of patients with fewer than 5 years from symptoms onset. C5a levels showed a positive correlation with MG severity according to the ADL scale (p = 0.041; τb = 0.18), although C5a levels were not different from the control group. DISCUSSION: AChR-ab titers and C5a levels could potentially be considered markers of severity in patients with MG.
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Resumen Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actual mente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, trans versal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tra tamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encon traban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) ver sus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.
Abstract Introduction: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. Methods: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clini cal, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. Results: Fifteen patients were included. All had di minished results in at least one test. Memory was the most affected domain. Patients who were under im munosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). Conclusion: Our results show that, despite the mo nophasic course of this disease, all patients had persis tent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.