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Evolución Clínica Y Recurrencia De Crisis UNIVERSIDAD DE COSTA RICA SISTEMA DE ESTUDIOS DE POSTGRADO “Evolución clínica y recurrencia de crisis en pacientes con miastenia gravis no timomatosa de inicio temprano sometidos a timectomía en el servicio de neurología del Hospital Rafael Ángel Calderón Guardia, C.S.S.S, de enero de 1991 a julio 2014”. Tesis sometida a la consideración de la Comisión del Programa de Postgrado en Especialidades Médicas para optar por el grado de Médico asistente especialista en Neurología CANDIDATO FEDERICO ÁLVAREZ MATA Ciudad Universitaria Rodrigo Facio, Costa Rica 2016 DEDICATORIA A mi padre René Álvarez y a mi abuelo Memo que a través de sus dolencias generaron el interés en esta disciplina. A mi hermano René que siempre me ha servido de inspiración por su vocación a la profesión médica y su amor al conocimiento. A mi familia por su apoyo constante e incondicional, por brindarme consuelo y darme aliento siempre que lo necesito y ser mi más grande dicha. A Dios que todo debo y que ha sido mi fortaleza siempre, le pido: “mientras me concedas vida y el ejercicio de mi profesión, dame suficientes energías para perseverar en continuo estudio y lograr acrecentar y renovar mis conocimientos en beneficio de mis enfermos”. ii AGRADECIMIENTOS Deseo expresar mi más sincero y profundo agradecimiento a las siguientes personas: Al Dr. Miguel Barboza Elizondo por su guía incondicional y apoyo constante en la realización de este trabajo. Al Dr. José Mainieri Hidalgo y a la Dra. Andrea Mata Blanco, del departamento de Cirugía de Tórax del H.R.A.C.G por todo el apoyo brindado en la realización de este trabajo y por tan certeras recomendaciones. Al Dr. Juan Ignacio Padilla Cuadra de la Unidad de Neurocríticos H.R.A.C.G, por su guía y sabios consejos. A los doctores Kenneth Carazo y Freddy Henríquez Varela, por los consejos y la ayuda en la realización y el proceso de revisión del presente documento. Al Dr. Huberth Fernández Morales, por su apoyo docente en el campo de la neurología y la formulación de interrogantes que generaron la búsqueda de nuevos conocimientos. A las autoridades del CLOBI y de la Dirección del Hospital Rafael A. Calderón Guardia por la colaboración para la realización de la investigación Al Lic. Israel Montero Vargas, jefe del Archivo del H.R.A.C.G por toda la ayuda brindada en el proceso de revisión de expedientes. iii "Esta tesis fue aceptada por la Comisión del Programa de Estudios de Posgrado en Medicina de la Universidad de Costa Rica, con10 requisito parcial para optar al grado de Especialista en Neurología" Dr. Huberth Fernández Morales Director de Posgrado en Neurología Carazo Céspedes · uez Varela Dr. Rob, rto Vargas Howell Asesor / / / Br. Fedenco Álvarez Mata Candidato iv TABLA DE CONTENIDOS DEDICATORIA......................................................................................... ii AGRADECIMIENTOS…............................................................................ iii TRIBUNAL EXAMINADOR…...................................................................................... iv ÍNDICE GENERAL................................................................................................ v LISTA TABLAS..................................................................................................xiv LISTA FIGURAS.................................................................................................xv ABREVIATURAS................................................................................... xvii RESUMEN.............................................................................................. xx INTRODUCCIÓN...................................................................................... 1 CAPITULO I: MARCO TEÓRICO.......................................................... 5 1. UNIÓN NEUROMUSCULAR………………………….……………………….6 1.1. Fisiología de la trasmisión neuromuscular…………………………….....6 1.2. Desarrollo del Sistema Neuromuscular……………………………….….10 1.3. Moléculas importantes para el desarrollo y función de la UNM……………………………………………………………………………………...11 1.4. Moléculas involucradas en la trasmisión neuromuscular de los potenciales de acción………………………………..……………………………….13 v 1.4.1. Receptor de acetilcolina………………………………………...………...…13 1.4.2. Esterasa de acetilcolina…………………………………………………...…15 1.4.3. Canales de Sodio dependientes de voltaje………………………….……16 1.5. Lista central de las proteínas necesarias para la formación de la UNM……………………………………………………………………………………...17 1.5.1. Las moléculas expresadas por la neurona motora…………………….17 1.5.1.1. Agrina…………………………………………………………………………18 1.6. Moléculas expresadas en el músculo……………………………………..20 1.6.1. Kinasa músculo específica……………………………………………….….20 1.6.2. Proteína 4 relacionada al receptor de lipoproteína de baja densidad………………………………………………………………………………...22 1.6.3. Regulación “aguas abajo” de tirosina quinasas 7…………………..….23 1.6.4. Proteína de la sinapsis asociada al receptor de 43 kda……………....24 1.6.5. Receptor de acetilcolina……………………………………………………...25 1.7. Proteínas auxiliares que contribuyen a la formación UNM………….26 1.7.1. El complejo distrofina-glicoproteína……………………………………....26 1.7.2. Neuregulinas…………………………………………………………………...28 1.7.3. Receptores ErbB…………………………………………………………….…29 1.7.4. Wnt…………………………………………………………………………….…30 2. PATOGÉNESIS DE LA MIASTENIA GRAVIS………………………………32 2.1. Introducción…………………………………………………………………..….32 2.2. Mecanismos de anticuerpos AChR…………………………………………..34 vi 2.3. Fracaso de tolerancia del AChR en la miastenia gravis………….……..36 2.4. Mecanismos de anticuerpos MuSK………………………………………….38 2.5. El IgG4 MuSK bloquea la señalización de MuSK………………………...39 2.6. El concepto de casos “seronegativos”…………………………………….…43 2.7. El papel de la glándula del timo……………..……………………………..44 2.7.1. Timo funcionalidad normal………………………………………………….44 2.7.2. Timo en la patogénesis de la miastenia gravis………………………….47 3. MIASTENIA GRAVIS………………………………………………………..…...52 3.1. Epidemiología…………………………………………………………………….52 3.2. Genética…………………………………………………………………………...54 3.2.1. Primera GWAS en EOMG……………………………………………………56 3.2.2. Loci de HLA susceptibles a la aparición MG…………………………...57 3.2.3. Miastenia gravis MuSK………………………………………………….…..57 3.3. Clínica de la miastenia gravis…………………………………………….…..58 3.3.1. Cuadro clínico general……………………………………………………....58 3.3.2. Crisis miasténicas……………………………………………………………..64 3.3.2.1. Epidemiología………………………………………………………………..64 3.3.2.2. Evaluación de la disfunción respiratoria……………………………...65 3.3.2.3. Manejo respiratorio de la crisis miasténica………………………..…67 3.3.2.3.1. Intubación y ventilación mecánica………………………………..…67 3.3.2.3.2. Ventilación no invasiva………………………………………………...69 vii 3.3.2.4. Complicaciones en el manejo de las crisis miasténicas…………...70 3.3.2.5. Crisis colinérgica…………………………………………………………...71 3.3.2.6. Conclusión……………………………………………………………………71 3.3.3. Subgrupos de miastenia gravis…………………………………………....72 3.3.3.1. Miastenia gravis familiar………………………………………………….72 3.3.3.2. Miastenia gravis juvenil………………………………………………..…73 3.3.3.3. Miastenia gravis de inicio temprano con anticuerpos contra AChR……………………………………………………………………………………..73 3.3.3.4. Miastenia gravis de inicio tardío con anticuerpos AChR……………………………………………………………………………………..74 3.3.3.5. Miastenia gravis asociada a MuSK………………………………….….74 3.3.3.6. Miastenia gravis asociada a Lrp4…………………………………….…75 3.3.3.7. Miastenia gravis generalizada con anticuerpos negativos………...75 3.3.3.8. Miastenia gravis ocular…………..……………………………………….76 3.3.3.9. Miastenia gravis refractaria…………..………………………………….76 3.3.4. Métodos diagnósticos…………………………………………………………77 3.3.4.1. Pruebas electrofisiológicas……………………………………………..…77 3.3.4.1.1. Estimulación repetitiva del nervio…………………………………...78 3.3.4.1.2. Electromiografía de fibra única……………………………………….79 3.3.4.2. Pruebas inmunológicas……………………………………………….…..81 3.3.4.2.1. Anticuerpos AChR…………………………………………………….…81 3.3.4.2.2. Anticuerpos anti-músculo estriado……………………………….…82 viii 3.3.4.2.3. Anticuerpos contra MuSK……………………………………………..83 3.3.4.2.4. Otros anticuerpos…………………………………………………….….83 3.3.4.3. Estudios de imágenes…………………………………………………..…83 3.3.4.4. Pruebas de glándula tiroides y autoinmunes…………………….….85 3.3.4.5. Otras pruebas……………………………………………………………....85 3.3.4.5.1. Test del hielo…………………………………………………………...…86 3.3.4.6. Pruebas farmacológicas………………………………………………......86 3.3.4.6.1. Prueba de edrofonio……………………………………………….….…86 3.4. Manejo de la miastenia gravis…………………………………………….….88 3.4.1. Terapia farmacológica…………………………………………………….....88 3.4.1.1. Inhibidores de acetilcolinesterasa………………………………………89 3.4.1.2. Inmunomodulación a corto plazo……………………………………….90 3.4.1.2.1. Plasmaféresis……………………………………………………………..91 3.4.1.2.2. Inmunoglobulina intravenosa………………………………………...92 3.4.1.3. Terapias inmunes a largo plazo…………………………………………94 3.4.1.3.1. Corticoesteroides……………………………………………………..….94 3.4.1.3.2. Agentes inmunosupresores no esteroideos……………………...…96 3.4.1.3.2.1. Azatioprina…………………………………………………………..….96 3.4.1.3.2.2. Micofenolato de mofetilo……………………………………………..97 3.4.1.3.2.3. Ciclofosfamida………………………………………………………....98 3.4.1.3.2.4. Ciclosporina…………………………………………………………....99 ix 3.4.1.3.2.5. Tacrólimus…………………………………………………………....100 3.4.1.3.2.6. Rituximab…………………………………………………………..…101 3.4.1.3.2.7. Belimumab…………………………………………………………….101 3.4.1.3.2.8. Eculizumab………………………………………………………..….102 3.4.1.3.2.9. Bortezomib…………………………………………………………….103 3.4.1.3.2.10. Etanercept…………………………….………………………….….103 3.4.1.3.2.11. Factor estimulante de colonias de granulocitos y macrófagos…………………………………………………………………………….104 3.4.2. Terapia quirúrgica……………………………………………………….…..104 3.4.2.1.
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