Miastenia gravis: Registro de 190 casos en un centro único / Myasthenia gravis. Register of 190 cases in a single center

La miastenia gravis (MG) es una enfermedad autoinmune mediada por anticuerpos dirigidos contra proteínas post sinápticas de la unión neuromuscular. El objetivo de este estudio fue describir los aspectos clínicos, epidemiológicos y serológicos de pacientes con MG en un Hospital Público de la Ciudad de Buenos Aires. Se realizó un análisis retrospectivo sobre 190 enfermos con diagnóstico de MG. La edad media de inicio de la enfermedad fue de 38 años; 57 (30%) fueron MG de inicio tardío (inicio de síntomas > 50 años). La relación mujer/hombre fue 1.7/1. La enfermedad se inició más tempranamente en las mujeres que en los hombres, media 32 vs. 48 años (p < 0.0001). La MG familiar autoinmune representó el 3.2 % (6 casos). La forma más común de presentación fue con manifestaciones oculares puras (52%). El 12.1% (23/190) fue considerada MG ocular en el seguimiento. La MG asociada a timoma se presentó en 22 casos (11.6%). El 27.1% presentó otra enfermedad autoinmune asociada, siendo las tiroideas las más frecuentes. El 81.4% tuvo anticuerpos anti-receptores de acetilcolina (ACRA) positivos y 22.7% de los ACRA negativos fueron positivos para anticuerpos anti-tirosina quinasa musculo especifica (anti-MusK). La evolución clínica fue favorable, hallándose más de la mitad de los casos en remisión o manifestaciones mínimas en la última visita. La mayoría requirió inmunosupresión para control de la sintomatología, el 78% recibió corticoides y el 48% un inmunosupresor no esteroideo.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. The aim of this study was to evaluate clinical, epidemiological and serological features of patients with MG in a Public Hospital of Buenos Aires City. A retrospective analysis of 190 patients diagnosed with MG was performed. The mean age of MG onset was 38 years, 30% had late-onset MG (onset age > 50 years). The female/male ratio was 1.7 / 1. Disease started earlier in women than in men, mean 32 vs. 48 years (p < 0.0001). Familial autoimmune MG represented 3.2% of the cases. Most of the patients initiated their disease with a pure ocular form (52%). 12.1% (23/190) were considered ocular MG at follow-up. Thymoma-associated MG represented 11.6% of cases. 27.1% had other associated autoimmune disease, thyroid disorders were the most frequent. 81.4% were anti-acetylcholine receptor antibody (AChR-ab) positive MG; 22.7% of AChR-ab negatives were positive for anti-muscle specific kinase (MusK) antibodies. Clinical outcome was relatively good; more than half of cases were in remission or minimal manifestations at the last visit. The majority of patients required immunosuppression to control the symptoms, 78% received corticosteroids and 48%, a non-steroidal immunosuppressant.

Blepharospasm with elevated anti-acetylcholine receptor antibody titer / Blefaroespasmo com título elevado de anticorpos antirreceptores de acetilcolina

ABSTRACT Objective: To determine whether serum levels of anti-acetylcholine receptor antibody (anti-AChR-Abs) are related to clinical parameters of blepharospasm (BSP). Methods: Eighty-three adults with BSP, 60 outpatients with hemifacial spasm (HFS) and 58 controls were recruited. Personal history, demographic factors, response to botulinum toxin type A (BoNT-A) and other neurological conditions were recorded. Anti-AChR-Abs levels were quantified using an enzyme-linked immunosorbent assay. Results: The anti-AChR Abs levels were 0.237 ± 0.022 optical density units in the BSP group, which was significantly different from the HFS group (0.160 ± 0.064) and control group (0.126 ± 0.038). The anti-AChR Abs level was correlated with age and the duration of response to the BoNT-A injection. Conclusion: Patients with BSP had an elevated anti-AChR Abs titer, which suggests that dysimmunity plays a role in the onset of BSP. An increased anti-AChR Abs titer may be a predictor for poor response to BoNT-A in BSP.

RESUMO Objetivo: Determinar se os níveis séricos do anticorpo antirreceptor de acetilcolina (anti-AChR-Abs) estão relacionados aos parâmetros clínicos do blefaroespasmo (BSP). Métodos: Fora recrutados 83 adultos com BSP, 60 pacientes ambulatoriais com espasmo hemifacial (HFS) e 58 controles. Foi aplicado um questionário para registrar história pessoal, fatores demográficos, resposta à toxina botulínica tipo A (BoNT-A) e outras condições neurológicas. Os níveis de anti-AChR-Abs foram quantificados usando um ensaio imunoenzimático. Resultados: O nível de anti-AChR-Abs foi de 0,237 ± 0,022 unidades de densidade óptica (OD) no grupo BSP, significativamente diferente em comparação com o grupo HFS (0,160 ± 0,064) e o grupo controle (0,126 ± 0,038). O nível de anti-AChR-Abs se correlacionou com a idade e a duração da resposta à injeção de BoNT-A. Conclusão: Pacientes com BSP apresentaram títulos elevados de anti-AChR-Abs, o que sugere que a desimunidade desempenha um papel no surgimento de BSP. O aumento do título de anti-AChR-Abs pode ser um preditor de resposta insuficiente à BoNT-A em BSP.

Envolvimento de auto-anticorpos na fisiopatologia da Doença de Chagas / Role of autoantibodies in the physiopathology of chagas' disease

A doença de Chagas é um sério problema de saúde na América Latina. Entre 25 por cento e 30 por cento dos pacientes infectados evoluem para a forma crônica (CCC), observando-se danos miocárdicos progressivos e, freqüentemente, morte súbita. Anticorpos com atividade para receptores de membrana acoplados a proteína G, adrenérgicos ou colinérgicos podem estar presentes no soro desses pacientes. No presente artigo serão discutidas a etiologia e a contribuição dos anticorpos na fisiopatologia da doença de Chagas.

Chagas' disease is a serious health problem in Latin America. Between 25 to 30% of the infected patients develop the chronic form of the disease, with progressive myocardial damage and often, sudden death. Adrenergic or cholinergic antibodies with G-protein coupled membrane receptor activity may be present in the sera of these patients. The present study discusses the etiology and the contribution of antibodies to the physiopathology of Chagas' disease.

Neuromuscular junctional disorders.

Neuromuscular junctional disorders (NMJ) in children are distinct entity. They may be acquired or hereditary. They pose problem in diagnosis because of the higher occurrence of sero negative Myasthenia Gravis (MG) cases in children. The identity of MusK antibody positivity in a good percentage of sero negative cases further adds to problems in diagnosis. The Congenital Myasthenic Syndrome (CMS) which are rare disorders of hereditary neuromuscular transmission (NMT) has to be differentiated because immunotherapy has no benefit in this group. Molecular genetic studies of these diseases helps to identify specific type of CMS which is important as other drugs like Fluoxetine, Quinidine are found to be effective in some. In infancy, all can manifest as floppy infant syndrome. The important key to diagnosis is by detailed electrophysiological studies including repetitive nerve stimulation at slow and high rates and its response to anticholinesterases and estimation of Acetyl choline receptor antibodies. Other causes of neuromuscular transmission defects viz. snake venom poisoning and that due to drugs are discussed.

Acetylcholine receptor antibody in Thai generalized myasthenia gravis patients.

The authors studied acetylcholine receptor antibody (AChR Ab) in twenty-six Thai patients diagnosed as having generalized myasthenia gravis and fifteen control cases. AChR Ab assay was done by radio-immunoassay technique and reported by titer in nmole/L. The positive result was defined by titer more than 0.5 nmole/L. In the myasthenia gravis group, age ranged from 18 to 64 years old with mean of 34 years old. The female: male ratio was 4.2:1. Duration of disease before taking blood sample ranged from 1 month to 14 years with a mean of 3.9 year The AChR Ab could be detected in 21 out of 26 patients (80.7%). In the control group, tests were all negative. The results of the test made the sensitivity of 80.7% and specificity of 100%. The positive predictive value was 100%, the negative predictive value was 75%, and the prevalence was 60.3%. There was no correlation between AChR Ab titer and clinical features. This test is a very valuable test in case of uncertainly in the diagnosis of myasthenia gravis.

Miastenia gravis en pediatría / Myastenia gravis in paediatrics

La miastenia gravis corresponde a una patología auto inmune que se presenta en todas las edades. Tiene una frecuencia general de 10 a 20 por 100 000 individuos y aproximadamente un 15 por ciento corresponde a niños. Se caracteriza por la presencia de debilidad muscular y fatiga fácil secundaria a una alteración de la transmisión sináptica neuromuscular. Su patogenia se basa en la presencia de anticuerpos antireceptor de acetilcolina que generan el bloqueo y destrucción de los receptores de acetilcolina de la unión neuromuscular. Estos anticuerpos al ser pesquisados en un paciente con clínica sugerente confirman el diagnóstico. A pesar del conocimiento actual de la enfermedad su tratamiento aún es controversial existiendo distintas alternativas. En la última década han existido avances en la descripción de mecanismos fisiopatológicos involucrados en la miastenia gravis y asimismo nuevas opciones terapéuticas. El objetivo de esta revisión fue actualizar el conocimiento de la miastenis gravis en pediatría principalmente en las áreas de diagnóstico y tratamiento. Se realizó una revisión en las bases de datos Cochrane, Medline y Doyma de los últimos 10 años. Los resultados muestran descripciones moleculares de la patología, experiencias de la timectomía como tratamiento en niños e investigaciones en el manejo inmunológico de la enfermedad.

Myasthenia gravis.

Myasthenia gravis is the prototype neuromuscular disease with immunological pathogenesis. The recognition and interpretation of the symptoms should be stressed as the diagnosis is initially achieved on clinical ground. Tests in the areas of immunology, electrophysiology and imaging further help the diagnosis, management and prognosis of the condition. The recent knowledge of immunology seems to point to variations in the immune abnormalities, but it remains to be seen whether the differences have clinical relevance. With the availability of intensive care units, the management of acute events in the myasthenic patients has improved considerably and the morbidity is reduced. Long term remissions are achievable in majority of patients, with supervised use of immunosuppression. In the modern times, the grave connotations of the name myasthenia gravis may be only rarely justified.

Autoimmune myasthenia gravis in two brothers.

Two brothers with immune-mediated myasthenia gravis are presented for the rarity. The clinical presentation was dissimilar. Both had acetylcholine receptor antibody positivity and one had thymoma. Both responded to immunomodulation and thymectomy. Relevant literature is reviewed.

Los anticuerpos antirreceptores ß-adrenérgicos en el síndrome de taquicardia sinusal inapropiada, ¿un nuevo factor en su fisiopatogénesis? / Anti ß-adrenergic receptor antibodies in inappropiate sinus tachycardia syndrome, a novel physiopatogenic factor?

INTRODUCCION: El síndrome de taquicardia inapropiada (STSI) se ha atribuído a un aumento de la frecuencia intrínseca del nódulo sinusal, asociado con hipersensibilidad -adrenérgica y atenuación de la respuesta a la estimulación vagal. No se ha explorado la posibilidad de que en su patogenia intervenga una alteración inmunorregulatoria que involucre a los receptores -adrenérgicos. OBJETIVO: Evaluar la presencia de anticuerpos antirreceptores -adrenérgicos (Ac anti-) y antirreceptores M2-colinérgicos (Ac anti-M2) en pacientes con STSI. MATERIAL Y METODOS: Se incluyeron 10 mujeres de 21 a 64 años portadoras del síndrome y 10 voluntarias sanas. La presencia de Ac anti- y Ac anti-M2 se determinó por el efecto cronotrópico de la IgG sobre cultivos de miocardiocitos de ratas neonatas en condiciones basales y luego de adicionar los bloqueantes atropina (10-7 mol/L) y propanolol (10-7 mol/L). RESULTADOS: La IgG de las voluntarias sanas no presentó anticuerpos antirreceptores autonómicos. En cambio, 8 de las 10 pacientes con STSI presentaron Ac anti- (80 por ciento, p= 0,0004), pero en ninguna de ellas se detectaron Ac anti-M2. CONCLUSION: Un porcentaje elevado de las pacientes con STSI presentan anticuerpos que reconocen y estimulan los receptores ß-adrenérgicos. Esta observación inédita sugiere la posibilidad de que en la patogenia de este síndrome participe una anormalidad inmunorregulatoria que involucra a esos receptores.

Myasthenia gravis in children: analysis of 18 patients

Myasthenia gravis (MG) in childhood is rare comprising 10 to 20 percent of all myasthenic patients. We studied 18 patients with MG whose first symptoms started from 1 to 12 years of age, followed at the Department of Neurology of the UNIFESP-EPM, from January 1983 to August 1997. There were 10 girls and 8 boys (1.2:1). Eleven patients (61 percent) presented moderate or severe generalized disease and 4 (22 percent) had at least one myasthenic crisis. EMG with supramaximal repetitive nerve stimulation was diagnostic in 8 (47 percent) out of 17 patients, and chest CT was normal in 14 patients. Seropositivity to acetylcholine receptor antibodies was found in 81.6 percent (9 out of 11 tested) and the levels had no relation to clinical severity. Nine out of 16 patients (56 percent) worsened with pyridostigmine alone and were treated with prednisone. Four out of those nine continued worsening despite steroids and were subjected to thymectomy (all showed thymic lymphoid follicular hyperplasia). Three patients (75 percent) improved markedly after thymectomy and one (25 percent) worsened, eventually getting better with intravenous immunoglobulin and oral azathioprine. MG treatment, using all resources available, has to be individualized for each child

Inmunogénesis de la miastenia gravis / The immunogenesis of myasthenia gravis

La principal inspiración de esta actualización proviene de las publicaciones periódicas que hace la New York Academy of Sciences, la cual destina un número, cada 3-4 años, a tratar los nuevos aspectos tanto clínicos como de ciencias básicas sobre el comportamiento anormal de la transmisión neuromuscular en la Miastenia Gravis. Una parte breve del trabajo se destina a la historia fascinante del descubrimiento de la Miastenia autoinmune experimental. Enseguida se revisa parcialmemte la composición molecular del receptor nicotímico de la Acetilcolina (RAc) en el músculo. Posteriormente se suceden las referencias a la producción de anticuerpos de la clase IgG contra las subunidades alfa del receptor de Ac, la interacción de los linfocitos B como células presentadoras en el contexto del complejo mayor de histocompatibilidad de la clase II y su participación de la tríada, que se completa con el antígeno y los receptores de los linfocitos T. Se alude al empleo de los polipéptidos sintéticos que reproducen secuencias aminoácidas de las subunidades de los receptores del músculo humano y que permitirían, eventualmente, utilizarlos como una suerte de inactivadores de las células T autoinmunes. Una sección importante se refiere a la presencia en la Miastenia Gravis de clonos patológicos de las células T en el suero de los pacientes, contra las cadenas alfa del RAc, pero también se enfatiza la presencia de clonos de células T autoinmunes en el sistema inmunitario normal. Se señala que no se sabe con certeza por qué se rompe la tolerancia autoinmunitaria. Termina la revisión analizando extensamente la participación del Timo en la formación de anticuerpos contra la placa motora sin eludir la complejidad y el misterio que reside en la intimidad histológica y molecular de dicho proceso. Se plantea la duda que sea el Timo el factor causal de la MG y se postula que su patología hiperplásica o tumoral sería un epifenómeno de un proceso más general de alteración autoinmunitaria

Miastenia grave familiar: relato de caso em gêmeas idênticas / Familial myasthenia gravis: a case report in identical twins

Trata-se do sétimo relato da literatura mundial de casos de miastenia gravis em gêmeos homozigóticos em que ambos säo acometidos. O homozigotismo foi provado com certeza por estudo de HLA e a forma adquirida da doença foi provada por determinaçäo de níveis elevados de anticorpos anti-receptor de acetilcolina, havendo também níveis elevados de anticorpos antimúsculo estriado, sem outras evidências de timoma

Acetylcholine receptor antibody in patients with myasthenia gravis.

The determination of acetylcholine receptor antibody (AChR Ab) titer by an enzyme-linked immunosorbent assay (ELISA) in patients with myasthenia gravis was introduced. The optimal conditions were determined by chequerboard determination. The specificity was confirmed by inhibition tests. The sensitivity is 9 p mole. The comparison of AChR Ab titers among 49 myasthenic patients, 19 non-myasthenic neurological patients and 20 healthy blood donors has shown that it is a highly sensitive, specific, reproducible, rapid, simple and inexpensive method for determining AChR Ab and that it is highly valuable for the diagnosis of myasthenia gravis.

Induction of experimental myasthenia gravis in Rhesus monkeys: a model for the study of the human disease

Experimental autoimmune myasthenia gravis (EAMG) was induced in thesus monkeys using purified acetylcholine recptor (AChR) from Torpedo california. A single dose of 80 µg induced antibody formation two weeks after injection. Two subsequent doses at two-week intervals caused clinical signs (anorexia, fatigability, weight loss, ptosis and dysphagia) which initially responded to treatment with neostigmine. Histologic examination of post-mortem tissues revealed lesions characteristic of myasthenia gravis in man: musuclar atrophy, fibrous degeneration and lymphocytic infiltration. Antibodies were quantitated in the sera of three other monkeys which received only 60 µg of purified AChR. Abnormally high titers persisted for two years (60-200µg/ml versus 0-10µg/ml for controls). A monkey injected with 60µgAChR as part of reconstituted membrane vesicles had lower titers (30-50µg/ml) than those which received purified receptor. Only those monkeys with antibody titers exceeding 800 µg/ml developed overt disease. These titers were 4-100 times higher than those reported for myasthenic humans. The antibody-antigen molar ratios were higher for monkeys with disease than for asymptomatic animals. These data suggest that the diversity of antibody molecules synthesized by the sensitized monkeys determined the appearance of clinical signs, and that the cross reaction of tanti-torpedo antivodies with monkey receptor was primarily responsible for the development of EAMG