RESUMEN
Aquaporin-4 (AQP4) is the target of the specific immunoglobulin G autoantibody (AQP4-IgG) produced in patients with neuromyelitis optica spectrum disorders (NMOSD). Previous studies demonstrated that AQP4-IgG binding to astrocytic AQP4 leads to cell-destructive lesions. However, the early physiopathological events in Müller cells in the retina are poorly understood. Here, we investigated the consequences of AQP4-IgG binding to AQP4 of Müller cells, previous to the inflammatory response, on two of AQP4's key functions, cell volume regulation response (RVD) and cell proliferation, a process closely associated with changes in cell volume. Experiments were performed in a human retinal Müller cell line (MIO-M1) exposed to complement-inactivated sera from healthy volunteers or AQP4-IgG positive NMOSD patients. We evaluated AQP4 expression (immunofluorescence and western blot), water permeability coefficient, RVD, intracellular calcium levels and membrane potential changes during hypotonic shock (fluorescence videomicroscopy) and cell proliferation (cell count and BrdU incorporation). Our results showed that AQP4-IgG binding to AQP4 induces its partial internalization, leading to the decrease of the plasma membrane water permeability, a reduction of swelling-induced increase of intracellular calcium levels and the impairment of RVD in Müller cells. The loss of AQP4 from the plasma membrane induced by AQP4-IgG positive sera delayed Müller cells' proliferation rate. We propose that Müller cell dysfunction after AQP4 removal from the plasma membrane by AQP4-IgG binding could be a non-inflammatory mechanism of retinal injury in vivo, altering cell volume homeostasis and cell proliferation and consequently, contributing to the physiopathology of NMOSD.
Asunto(s)
Acuaporina 4/sangre , Membrana Celular/metabolismo , Células Ependimogliales/metabolismo , Inmunoglobulina G/metabolismo , Neuromielitis Óptica/sangre , Retina/metabolismo , Acuaporina 4/administración & dosificación , Biomarcadores/sangre , Línea Celular Transformada , Membrana Celular/patología , Proliferación Celular/fisiología , Tamaño de la Célula , Células Ependimogliales/patología , Homeostasis/fisiología , Humanos , Inmunoglobulina G/administración & dosificación , Neuromielitis Óptica/patología , Retina/lesiones , Retina/patologíaRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Encefalitis/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Inmunoterapia/métodos , Adolescente , Adulto , Anciano , Argentina , Azatioprina/uso terapéutico , Niño , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Intercambio Plasmático/métodos , Rituximab/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Autoimmune encephalitis refers to a group of pathologies described in the last two decades, characterized by neuropsychiatric symptoms of subacute presentation, mediated by antibodies directed against neuronal membrane proteins. Within this group, encephalitis mediated by antibodies against the NMDA receptor of glutamate is a particular clinical entity, given that its expression is dominated by psychiatric symptoms that usually occur at the onset of the disease. In this paper we describe five cases of NMDA encephalitis in adult patients followed up in the last four years in a public hospital in the City of Buenos Aires, Argentina. We also include a review of the current literature. We emphasize the clinical description of the psychiatric symptoms of presentation, since these lead to the patient's first contact with the health system. Given the difficulty in our environment to implement the determination of autoantibodies, the ability to clinically recognize this pathology becomes paramount to establish an early preliminary diagnosis and not to delay immunosuppressive therapy, thus allowing for a better prognosis.
Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato , Adulto , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Argentina , Autoanticuerpos , Humanos , Receptores de N-Metil-D-AspartatoRESUMEN
UNLABELLED: The aim of the present research was to investigate cognitive pattern of patients with neuromyelitis optica (NMO) and to compare it with multiple sclerosis (MS) patients' performance. METHODS: Fourteen NMO, 14 relapsing remitting multiple sclerosis (RRMS), and 14 healthy control patients participated in the investigation. Neuropsychological functions were evaluated with the Brief Repeatable Neuropsychological Battery for MS; Symbol Digit Modalities Test; Digit Span; and Semantic Fluency. RESULTS: Fifty-seven percent of NMO patients and 42.85% of the MS ones had abnormal performance in at least two cognitive tests. The NMO Group showed abnormal performance in verbal fluency, verbal and visual memories, with greater attention deficits. NMO patients outperformed healthy control in the paced auditory serial addition test (PASAT). However, no difference was found between NMO and RRMS patients. CONCLUSIONS: The NMO Group showed more dysfunction in attention and verbal fluencies than in verbal and visual memories. When compared with the MS patients, a similar dysfunction pattern was found. O objetivo da presente pesquisa foi investigar o padrão cognitivo de pacientes com neuromielite óptica (NMO) e compará-lo com o desempenho de pacientes com esclerose múltipla (EM). Métodos: Quatorze pacientes com NMO, 14 com esclerose múltipla recorrente remitente (EMRR) e 14 participantes do Controle saudáveis participaram da presente investigação. As funções neuropsicológicas foram avaliadas com a Bateria Breve de Testes Neuropsicológicos de Rao, Teste Símbolo Digit e a Fluência Semântica. Resultados: Cinquenta e sete por cento dos pacientes com NMO e 42,85% daqueles com EM apresentaram desempenho anormal em pelo menos dois testes cognitivos. O Grupo NMO apresentarou desempenho anormal na fluência verbal e nas memórias visual e verbal, com maiores déficits de atenção. Pacientes com NMO superaram os controles saudáveis em PASAT. No entanto, não foi encontrada diferença entre os pacientes com NMO e aqueles com EMRR. Conclusões: O Grupo NMO mostrou mais disfunção nas fluências de atenção e verbais do que nas memórias verbal e visual. Quando comparados com os pacientes com EM, um padrão de disfunção semelhante foi encontrado.
Asunto(s)
Cognición , Esclerosis Múltiple Recurrente-Remitente/psicología , Neuromielitis Óptica/psicología , Adulto , Análisis de Varianza , Atención/fisiología , Estudios de Casos y Controles , Depresión/fisiopatología , Femenino , Humanos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Habla/fisiología , Trastornos del Habla/fisiopatología , Adulto JovenRESUMEN
The aim of the present research was to investigate cognitive pattern of patients with neuromyelitis optica (NMO) and to compare it with multiple sclerosis (MS) patients' performance. Methods: Fourteen NMO, 14 relapsing remitting multiple sclerosis (RRMS), and 14 healthy control patients participated in the investigation. Neuropsychological functions were evaluated with the Brief Repeatable Neuropsychological Battery for MS; Symbol Digit Modalities Test; Digit Span; and Semantic Fluency. Results: Fifty-seven percent of NMO patients and 42.85% of the MS ones had abnormal performance in at least two cognitive tests. The NMO Group showed abnormal performance in verbal fluency, verbal and visual memories, with greater attention deficits. NMO patients outperformed healthy control in the paced auditory serial addition test (PASAT). However, no difference was found between NMO and RRMS patients. Conclusions: The NMO Group showed more dysfunction in attention and verbal fluencies than in verbal and visual memories. When compared with the MS patients, a similar dysfunction pattern was found.
O objetivo da presente pesquisa foi investigar o padrão cognitivo de pacientes com neuromielite óptica (NMO) e compará-lo com o desempenho de pacientes com esclerose múltipla (EM). Métodos: Quatorze pacientes com NMO, 14 com esclerose múltipla recorrente remitente (EMRR) e 14 participantes do Controle saudáveis participaram da presente investigação. As funções neuropsicológicas foram avaliadas com a Bateria Breve de Testes Neuropsicológicos de Rao, Teste Símbolo Digit e a Fluência Semântica. Resultados: Cinquenta e sete por cento dos pacientes com NMO e 42,85% daqueles com EM apresentaram desempenho anormal em pelo menos dois testes cognitivos. O Grupo NMO apresentarou desempenho anormal na fluência verbal e nas memórias visual e verbal, ...
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Cognición , Esclerosis Múltiple Recurrente-Remitente/psicología , Neuromielitis Óptica/psicología , Análisis de Varianza , Atención/fisiología , Estudios de Casos y Controles , Depresión/fisiopatología , Memoria/fisiología , Pruebas Neuropsicológicas , Trastornos del Habla/fisiopatología , Habla/fisiologíaRESUMEN
Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. Methods: We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. Results: All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. Conclusions: Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica. .
Espasmos tônicos têm sido mais frequentemente associados com esclerose múltipla. Foram publicados até agora poucos relatos de série de pacientes com neuromielite óptica e espasmos tônicos. Métodos: Foram analisadas as características e a frequência de espasmos tônicos em 19 indivíduos com neuromielite óptica. Os dados foram coletados por meio de um questionário semiestruturado para espasmos tônicos, mediante a avaliação retrospectiva dos prontuários e a análise dos dados clínicos Resultados: Todos os pacientes com neuromielite óptica exceto um apresentaram espasmos tônicos. Os principais fatores desencadeantes foram movimentos bruscos e fatores emocionais. Espasmos foram frequentemente associados a perturbações sensoriais e se agravaram durante a fase aguda da doença. A carbamazepina foi utilizada frequentemente para tratar os sintomas, com boa resposta. Conclusões: Os espasmos tônicos são manifestações clínicas frequentes em pacientes com neuromielite óptica. .
Asunto(s)
Adolescente , Niño , Preescolar , Femenino , Humanos , Neuromielitis Óptica/complicaciones , Espasmo/etiología , Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/fisiopatología , Factores de Riesgo , Encuestas y Cuestionarios , Espasmo/tratamiento farmacológico , Espasmo/fisiopatologíaRESUMEN
UNLABELLED: Tonic spasms have been most commonly associated with multiple sclerosis. To date, few reports of series of patients with neuromyelitis optica and tonic spasms have been published. METHODS: We analyzed the characteristics and frequency of tonic spasms in 19 subjects with neuromyelitis optica. Data was collected using a semi-structured questionnaire for tonic spasms, by both retrospectively reviewing medical records and performing clinical assessment. RESULTS: All patients except one developed this symptom. The main triggering factors were sudden movements and emotional factors. Spasms were commonly associated to sensory disturbances and worsened during the acute phases of the disease. Carbamazepine was most commonly used to treat the symptom and patients showed good response to the drug. CONCLUSIONS: Tonic spasms are a common clinical manifestation in patients with neuromyelitis optica.
Asunto(s)
Neuromielitis Óptica/complicaciones , Espasmo/etiología , Adolescente , Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/fisiopatología , Factores de Riesgo , Espasmo/tratamiento farmacológico , Espasmo/fisiopatología , Encuestas y CuestionariosRESUMEN
Müller cells are mainly involved in controlling extracellular homeostasis in the retina, where intense neural activity alters ion concentrations and osmotic gradients, thus favoring cell swelling. This increase in cell volume is followed by a regulatory volume decrease response (RVD), which is known to be partially mediated by the activation of K(+) and anion channels. However, the precise mechanisms underlying osmotic swelling and subsequent cell volume regulation in Müller cells have been evaluated by only a few studies. Although the activation of ion channels during the RVD response may alter transmembrane potential (Vm), no studies have actually addressed this issue in Müller cells. The aim of the present work is to evaluate RVD using a retinal Müller cell line (MIO-M1) under different extracellular ionic conditions, and to study a possible association between RVD and changes in Vm. Cell volume and Vm changes were evaluated using fluorescent probe techniques and a mathematical model. Results show that cell swelling and subsequent RVD were accompanied by Vm depolarization followed by repolarization. This response depended on the composition of extracellular media. Cells exposed to a hypoosmotic solution with reduced ionic strength underwent maximum RVD and had a larger repolarization. Both of these responses were reduced by K(+) or Cl(-) channel blockers. In contrast, cells facing a hypoosmotic solution with the same ionic strength as the isoosmotic solution showed a lower RVD and a smaller repolarization and were not affected by blockers. Together, experimental and simulated data led us to propose that the efficiency of the RVD process in Müller glia depends not only on the activation of ion channels, but is also strongly modulated by concurrent changes in the membrane potential. The relationship between ionic fluxes, changes in ion permeabilities and ion concentrations -all leading to changes in Vm- define the success of RVD.
Asunto(s)
Tamaño de la Célula , Potenciales de la Membrana , Retina/citología , Línea Celular , Humanos , ÓsmosisRESUMEN
We have previously demonstrated that in renal cortical collecting duct cells (RCCD(1)) the expression of the water channel Aquaporin 2 (AQP2) raises the rate of cell proliferation. In this study, we investigated the mechanisms involved in this process, focusing on the putative link between AQP2 expression, cell volume changes, and regulatory volume decrease activity (RVD). Two renal cell lines were used: WT-RCCD(1) (not expressing aquaporins) and AQP2-RCCD(1) (transfected with AQP2). Our results showed that when most RCCD(1) cells are in the G(1)-phase (unsynchronized), the blockage of barium-sensitive K(+) channels implicated in rapid RVD inhibits cell proliferation only in AQP2-RCCD(1) cells. Though cells in the S-phase (synchronized) had a remarkable increase in size, this enhancement was higher and was accompanied by a significant down-regulation in the rapid RVD response only in AQP2-RCCD(1) cells. This decrease in the RVD activity did not correlate with changes in AQP2 function or expression, demonstrating that AQP2-besides increasing water permeability-would play some other role. These observations together with evidence implying a cell-sizing mechanism that shortens the cell cycle of large cells, let us to propose that during nutrient uptake, in early G(1), volume tends to increase but it may be efficiently regulated by an AQP2-dependent mechanism, inducing the rapid activation of RVD channels. This mechanism would be down-regulated when volume needs to be increased in order to proceed into the S-phase. Therefore, during cell cycle, a coordinated modulation of the RVD activity may contribute to accelerate proliferation of cells expressing AQP2.
Asunto(s)
Acuaporina 2/metabolismo , Proliferación Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Riñón/citología , Animales , Acuaporina 2/genética , Compuestos de Bario/farmacología , Señalización del Calcio , Línea Celular , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Cloruros/farmacología , Citometría de Flujo , Puntos de Control de la Fase G1 del Ciclo Celular , Microscopía por Video , Presión Osmótica , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Transporte de Proteínas , Ratas , Rojo de Rutenio/farmacología , Fase S , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , TransfecciónRESUMEN
NMO-IgG autoantibody selectively binds to aquaporin-4 (AQP4), the most abundant water channel in the central nervous system and is now considered a useful serum biomarker of neuromyelitis optica (NMO). A series of clinical and pathological observations suggests that NMO-IgG may play a central role in NMO physiopathology. The current study evaluated, in well-differentiated astrocytes cultures, the consequences of NMO-IgG binding on the expression pattern of AQP4 and on plasma membrane water permeability. To avoid or to facilitate AQP4 down-regulation, cells were exposed to inactivated sera in two different situations (1 hr at 4°C or 12 hr at 37°C). AQP4 expression was detected by immunofluorescence studies using a polyclonal anti-AQP4 or a human anti-IgG antibody, and the water permeability coefficient was evaluated by a videomicroscopy technique. Our results showed that, at low temperatures, cell exposure to either control or NMO-IgG sera does not affect either AQP4 expression or plasma membrane water permeability, indicating that the simple binding of NMO-IgG does not affect the water channel's activity. However, at 37°C, long-term exposure to NMO-IgG induced a loss of human IgG signal from the plasma membrane along with M1-AQP4 isoform removal and a significant reduction of water permeability. These results suggest that binding of NMO-IgG to cell membranes expressing AQP4 is a specific mechanism that may account for at least part of the pathogenic process.
Asunto(s)
Acuaporina 4/metabolismo , Astrocitos/efectos de los fármacos , Inmunoglobulina G/farmacología , Neuromielitis Óptica/inmunología , Agua/metabolismo , Adulto , Animales , Animales Recién Nacidos , Antígenos de Neoplasias/metabolismo , Astrocitos/fisiología , Biotinilación , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunoglobulina G/sangre , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Neuromielitis Óptica/patología , Permeabilidad/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Ratas , Adulto JovenRESUMEN
Collecting ducts (CD) not only constitute the final site for regulating urine concentration by increasing apical membrane Aquaporin-2 (AQP2) expression, but are also essential for the control of acid-base status. The aim of this work was to examine, in renal cells, the effects of chronic alkalosis on cell growth/death as well as to define whether AQP2 expression plays any role during this adaptation. Two CD cell lines were used: WT- (not expressing AQPs) and AQP2-RCCD(1) (expressing apical AQP2). Our results showed that AQP2 expression per se accelerates cell proliferation by an increase in cell cycle progression. Chronic alkalosis induced, in both cells lines, a time-dependent reduction in cell growth. Even more, cell cycle movement, assessed by 5-bromodeoxyuridine pulse-chase and propidium iodide analyses, revealed a G2/M phase cell accumulation associated with longer S- and G2/M-transit times. This G2/M arrest is paralleled with changes consistent with apoptosis. All these effects appeared 24 h before and were always more pronounced in cells expressing AQP2. Moreover, in AQP2-expressing cells, part of the observed alkalosis cell growth decrease is explained by AQP2 protein down-regulation. We conclude that in CD cells alkalosis causes a reduction in cell growth by cell cycle delay that triggers apoptosis as an adaptive reaction to this environment stress. Since cell volume changes are prerequisite for the initiation of cell proliferation or apoptosis, we propose that AQP2 expression facilitates cell swelling or shrinkage leading to the activation of channels necessary to the control of these processes.
Asunto(s)
Adaptación Fisiológica , Alcalosis/patología , Alcalosis/fisiopatología , Apoptosis , Acuaporina 2/metabolismo , Ciclo Celular , Túbulos Renales Colectores/patología , Animales , Proliferación Celular , Corteza Renal/patología , Ratas , Factores de TiempoRESUMEN
Escala dirigida a facilitar el reconocimiento de este evento, y que explora aspectos como la conciencia, signos focales, lenguaje, mímica, y fuerza en miembros inferiores y superiores
Asunto(s)
Identificación de la Emergencia , Examen Neurológico/métodos , Examen Neurológico , Accidente CerebrovascularRESUMEN
Escala dirigida a facilitar el reconocimiento de este evento, y que explora aspectos como la conciencia, signos focales, lenguaje, mímica, y fuerza en miembros inferiores y superiores(AU)