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“Patología causada por defecto en la transmisión
neuromuscular debida a un ataque mediado
por anticuerpos en los receptores de
Acetilcolina en la unión neuro-
muscular; la cual se caracteriza
por Debilidad Fluctuante que
mejora tras el reposo y/o
fármacos inhibidores de
colinesterasa”
Lewis P. Rowland. Myasthenia Gravis. Merritt's Neurology . 10th Edition (June 2000). Chapter 120. 545-549
Epidemiología
Prevalencia en EEUU 14-20 por cada 100.000 habitantes.
36.000 – 60.000 casos
Mujeres 2ª - 3ª década
Hombres 7ª - 8ª década
James F. Howard. Clinical Overview. Of MG. Myasthenia Gravis Foundation Of America 2010, http://www.myasthenia.org/
Willis 1672 – Primera descripción
Jolly 1895 – Miastenia Gravis
Laquer y Weigert 1901 – Timoma/MG
Reman 1932 y Walker 1934 – Fisostigmina
Castleman y Norris 1949 – Cambios en Timo
Patrick, Lindstrom y otros 1973 - Autoinmune
Historia
Ropper, A. Samuels, M. Myasthenia Gravis and related disorders of the neuromuscular juntion. Adams & Victor’s Principles of Neurology, 9th Ed. Chapter 53
Etiología y Patogenia
Etiología y Patogenia
Anticuerpos unidos al AChR(Ac Anti-AChR)
Ig G incrementa degradación de AChR
Destrucción de membrana postsináptica, mediada por complemento (aplanamiento)
Etiología y Patogenia
Ropper, A. Samuels, M. Myasthenia Gravis and related disorders of the neuromuscular juntion. Adams & Victor’s Principles of Neurology, 9th Ed. Chapter 53
Naturaleza fluctuante
Distribución de la Debilidad
Respuesta a drogas colinérgicas
Manifestaciones Clínicas
RemisiónExacerbación -- Crisis
Músc. OcularesMúsc. Orofaríngeos y/o FacialesMúsc. CuelloExtremidades
Lewis P. Rowland. Myasthenia Gravis. Merritt's Neurology . 10th Edition (June 2000). Chapter 120. 545-549
Emergencia Neurológica…!!!
Insuficiencia Respiratoria potencialmente Mortal
Se presenta en un 15-20%
Recidiva en 1/3 pacientes (75% primer año)
Mortalidad 4% (patologías concomitantes)
Exacerbación de sintomatología previa con posterior Disnea, Diaforesis, Cianosis, Taquipnea, Temblor, etc.
Tratamiento:
* Generales (UCI-VM?)
* Específico
Crisis Miasténica
•Fluctuación rápida de síntomas miasténicos
•Disminución progresiva de la actividad diaria
•Disminución progresiva de peso
•Aumento de la dosis de IACasa*
•Caída en flexión de la cabeza
•Disartria y disfagia progresiva
•Infección respiratoria
Signos Predictores de CM
Toyka K., Müllges W. Myastenia Gravis and LEMS. In Hacke E.(ed). Neuro Critical Care. Heidelberg. 1994
Mellado, P. Crisis Miasténicas. Dpto Neurología. Universidad Católica de Chile. http://escuela.med.puc.cl/paginas/publicaciones/neurologia/cuadernos/1997/pub_12_97.html
Bloqueo Postsináptico
Exceso de Inhibidores de la Acetilcolinesterasa (IACasa)
Signos y Síntomas Colinérgicos:
* Taquicardia
* Calambres
* Fasciculaciones
* Aumento de Secreciones
* Náuseas o vómitos
Dx Diferencial administración de IACasa (en UCI)
Crisis Colinérgica
Mellado, P. Crisis Miasténicas. Dpto Neurología. Universidad Católica de Chile. http://escuela.med.puc.cl/paginas/publicaciones/neurologia/cuadernos/1997/pub_12_97.html
Clasificación
GRUPO I (Ocular):
* 15-20%.
* afectación músculos oculomotores.
* si no se generaliza a los 2 años es pocoprobable que lo haga.
GRUPO II (Generalizada):
* leve o IIA 30%
* grave o IIB 20%
* afectación músculos craneales, tronco, extremidades pero no la respiración.
* asociada a hiperplasia tímica o timoma.
* responde a los anticolinesterásicos.
GRUPO III (Aguda Fulminante):
* 11%
* debilidad general aguda o subaguda y en menos de 6 meses afectación de la musculatura bulbar o respiratoria.
* asociada a alta incidencia de timoma.
* pronóstico grave.
GRUPO IV (Tardía Grave):
* 9%
* debilidad permanente con posible afectación respiratoria.
* mala respuesta a anticolinesterásicos y corticoides
Ossermann KE. Myasthenia gravis. New York: Grune and Stratton; 1958
Class I Any ocular muscle weaknessMay have weakness of eye closureAll other muscle strength is normal
Class II Mild weakness affecting other than ocular musclesMay also have ocular muscle weakness of any severity
IIa Predominantly affecting limb, axial muscles, or bothMay also have lesser involvement of oropharyngeal muscles
IIb Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both
Class III Moderate weakness affecting other than ocular musclesMay also have ocular muscle weakness of any severity
IIIa Predominantly affecting limb, axial muscles, or bothMay also have lesser involvement of oropharyngeal muscles
IIIb Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both
Class IV Severe weakness affecting other than ocular musclesMay also have ocular muscle weakness of any severity
IVa Predominantly affecting limb and/or axial musclesMay also have lesser involvement of oropharyngeal muscles
IVb Predominantly affecting oropharyngeal, respiratory muscles, or both
May also have lesser or equal involvement of limb, axial muscles, or both
Class VDefined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.
Jaretzki, A. et al. Myasthenia Gravis Recomendations for Clinical Reserch Standards. Neurology, 2000; 55:16-23
Historia Clínica y Exploración Física
Ac. Anti-AChR – Especificidad 99.9% Sensibilidad 88%
Prueba del Edrofonio (Tensilon®)
1-2mgs-15seg – 3mgs-15seg – 5mgs-15seg (máx 10mgs) IV
Prueba de la Neostigmina
1.5 – 2mgs IM + Atropina 0.4mgs IM. 20min – 2hrs.
EMG - Respuesta decreciente del potencial evocado debido a estimulación repetitiva del nervio
TAC de Tórax (Timo)
Ice Pack Test (MG Ocular ) – Especificidad 98.3% Sensibilidad 76.9%
Diagnóstico
Lewis P. Rowland. Myasthenia Gravis. Merritt's Neurology . 10th Edition (June 2000). Chapter 120. 545-549
J R Soc Med Sh Rep 2010;1:14. DOI 10.1258/shorts.2009.090037
Myasthenic Synromes Causal Agent or Gene Defect Onset Decade Treatment Clinical Features
Acquired Myasthenic Syndromes
Presynaptic
Botulism Peptide toxin from C. botulinum Any Supportive; ventilation Blurred vision, dysphagia, limb weakness
Lambert-Eaton
myasthenic syndrome
Autoimmune reduction in calcium-
mediated quantal release
Midlife 3,4-DAP Truncal weakness, dysautonomic features
Possibly IVIgTwo-thirds have cancer
Synaptic
Insecticides Organophosphates (inh AChE) Any Remove toxins Miosis, diarrhea, cramps, weakness
AtropineDelayed sensorimotor neuropathy
Postsynaptic
Myasthenia gravis Autoimmune attack on postsynaptic
membrane
Adult AChE inhibitors, IVIg Diplopia, ptosis
Other immunosuppressants Limb weakness with exertion
Antibodies to AChR or MuSK protein
Snake venom toxins Multiple peptide toxins that lyse muscle,
bind Na and K channels
Any Supportive Acute weakness
Possibly AChE inhibitors
Hereditary and Congenital Myasthenic Syndromes
Presynaptic
Episodic apnea Choline acetyltransferase 1st AChE inhibitors Mild episodes of weakness; recurrent apnea.
Ptosis commonApnea monitor
Paucity of synaptic vesicles Unknown 1st AChE inhibitors Recurrent, sometimes pronounced weakness
Synaptic
AChE deficiency AChE 1st None Diffuse weakness, ptosis
Collagen tail for AChE Avoid AChE inhibitors
DOK-7 "synopathy" DOK-7 mutation 1st None Limb-girdle, ptosis
Postsynaptic
Slow channel syndrome AChR subunits 1st–6th Quinidine, AChE inhibitors Ptosis, diffuse weakness, delayed motor milestones
Avoid 3,4-DAP Often show atrophy of dorsal forearms
Fast channel syndrome AChR subunits 1st 3,4-DAP Ptosis, recurrent weakness, motor development
delays
Primary AChR deficiency AChR subunits 1st AChE inhibitors, 3,4-DAP Ptosis, recurrent weakness, motor development
delays
Rapsyn deficiency Rapsyn 1st AChE inhibitors, 3,4-DAP Ptosis, recurrent weakness
Plectin deficiency Plectin 1st 3,4-DAP Myasthenic features, epidermolysis bullosaRopper, A. Samuels, M. Myasthenia Gravis and related disorders of the neuromuscular juntion. Adams & Victor’s Principles of Neurology, 9th Ed. Chapter 53
Anticolinesterásicos• Piridostigmina 30-90mg c/6hrs
• Neostigmina 7.5-45mg c/2-6hrs
Corticoesteroides• Prednisona 15 - 60mg/día
Inmunosupresores• Azatioprina 50-250mg/día
• Ciclofosfamida 50mg/kg/día 4 días
Tratamiento
Ropper, A. Samuels, M. Myasthenia Gravis and related disorders of the neuromuscular juntion. Adams & Victor’s Principles of Neurology, 9th Ed. Chapter 53
Tratamiento
Inmunoglobulina EV• 2mg/kg fraccionado en 3-5 días
• “Flulike syndrome”
Plasmaféresis• 125cc/kg (durante 1 semana)
• 80% Anticuerpos circulantes
Timectomía• 18-55 años
• Remisión 35% (1-2 años)
• 50% Mejoría
Ropper, A. Samuels, M. Myasthenia Gravis and related disorders of the neuromuscular juntion. Adams & Victor’s Principles of Neurology, 9th Ed. Chapter 53
Rituximab for Myasthenia Gravis
In generalized myasthenia gravis (MG), a wide array of immunosuppressive and immunomodulating treatments is being used in clinical practice, but most drugs lack evidence from randomized controlled trials supporting their use. Furthermore, many patients develop serious side effects or do not respond sufficiently to these drugs.
We report three patients with generalized MG who were treated with rituximab, a monoclonal antibody against CD20+ cells that causes prolonged B cell depletion. In all three patients, treatment with rituximab led to a sustained clinical improvement and discontinuation or reduction of prednisolone and other drugs. Rituximab was well tolerated. Therapy with rituximab was guided by the total count of peripheral B lymphocytes. Reviewing the anecdotal literature on rituximab for MG, we conclude that preliminary data on the efficacy and safety of rituximab are encouraging and that further studies in MG seem warranted
Stieglbauer, K. and Cols. Rituximab for myasthenia gravis . Journal of the Neurological Sciences. Volume 280 Issue 1, Pages 120-122, 15 May 2009
Successful treatment of refractory generalized Myasthenia Gravis with Rituximab
OBJECTIVE: Myasthenia gravis (MG) is an autoimmune neuromuscular disorder for which currenttherapies carry a high risk of side-effects and may be insufficient in stabilizing the clinical status. Manytherapeutic options can be ruled, such as thymectomy, corticosteroids, azathioprine, cyclophosphamide,mycophenolate mofetil, methotrexate, intravenous immunoglobulin (IVIg) or less frequentlyplasmapheresis must be ruled.METHODS: We followed prospectively six patients with MG who presented with a poor response to twoor three lines of immunosuppressive conventional drugs associated with oral corticosteroids. All but onewere acetylcholine receptor negative and three were anti-MuSK positive. IVIg did not improved theneurological status and all patient required high doses of cholinesterase inhibitors.RESULTS: Rituximab was introduced with a mean follow-up of 1.5 years (375 mg/m(2), days 1, 8, 15, 28during the first month and then one dose every 2 months). After 2 years of follow-up, all patients stoppedcorticosteroids and tapered off cholinesterase inhibitors from 60 to 180 mg/day without severe infectiousevents.CONCLUSION: Rituximab, a chimeric IgG k monoclonal antibody that target CD20 is used for thetreatment of relapsing/refractory CD20 positive low-grade non-Hodgkin's lymphoma and otherautoimmune neuromuscular diseases. Four previous short reports have described a good response of MGassociated with lymphoma with rituximab. It appears to be a promising and effective drug for thetreatment of MG without lymphoma, with a substantial benefit to the clinical status and good tolerability.
Lebrun, C. Successful treatment of refractory generalized myasthenia gravis with Rituximab. Eur J Neurol. 2009 Feb;16(2):246-50.
Rituximab in the management of refractory Myasthenia Gravis
Myasthenia gravis (MG) is an immune-mediated disorder with a variableresponse to treatment. In this study, patients with refractory MG who weretreated with Rituximab were identified. A review of patients referred to theYale Neuromuscular Clinic was performed. Patients with refractory MG whowere treated with Rituximab were reviewed for response to treatment.Patients who had muscle-specific kinase (MuSK) or acetylcholine receptor(AChR) antibodies were included. Six patients were identified who met thecriteria described. All patients tolerated Rituximab without side effects andhad a reduced need for immunosuppressants and/or improvement in clinicalfunction. Patients with refractory MG appeared to respond to Rituximab inthis small, retrospective study. This result suggests that a larger, prospectivetrial is indicated.
Zebardast , N. Rituximab in the management of refractory Myasthenia Gravis. Muscle Nerve. 2010 Mar;41(3):375-8
I. Relajantes musculares:
Mayores: Menores:Curarizantes: Bloqueo competitivo. Benzodiacepinas.
(d- tubocurarina, pancuronium). Meprobamato.Despolarizantes: Succinilcolina. Blaclofen.
Dantrolene.Otros.
II. Antibióticos y similaresAGRAVAN DUDOSOS SIN RIESGO
-Aminoglucósidos: Ampicilina 1. Penicilina.-Estreptomicina. Eritomicina 1. Cloranfenicol.-Dihidroestreptomicina. Sulfamidas 2. Vancomicina.Kanamicina. Cefalosporina-Neomicina. Gentamicina.-Tobamicina. Amikacina.-Paramomicina. Sisomicina.-Viomicina. Spectinomicina.
-Macrólidos:-Telitromicina (muy peligroso y ya ha causado algunas muertes).- Azitromicina.
-Quinolonas:- Ciprofloxacino. Norfloxacino.
-Betalactámicos:- Imipenem.
-Fosfonatos:- Fosfomicina.
-Polipéptidos:-Colisitina. Polimixinas (A, B, E).-Bacitracina.
-Tetraciclinas.-Aminoácidos monobásicos:-Lincomicina. Clindamicina.
1. Eritromicina y Amplicilina producen bloqueo de placa neuromuscular en el EMG pero no existe evidencia en la clínica.2. Se ha encontrado actividad de bloqueo pero no se ha observado dificultad en su uso en pacientes con miastenia.
III. Otros:-Amantadina. Emetina.-Apronitina (Trasylol).-Antiácidos que contengan sales de magnesio.-Inhibidores de la acetilcolinesterasa. (Usados solo por indicación del neurólogo).-Contrastes iodados: Ácido lodotalámico (Conray 60% i.v.).
IV. Inmunizaciones:-Vacuna antitetánica. -Antitoxina tetánica.
V. Antipalúdicos:-Quinina. -Cloroquina.
VI. Fármacos cardiovasculares:AGRAVAN PELIGROSOS-Quinidina Antagonistas del calcio (sin evidencia clínica)-Procainamida. Lidocaína.-Ajmalina. Hidantoínas.-Guanetidina. Gangliopléjicos (trimetafan y otros).-Betabloqueantes (propanolol, oxoprenolol, timolol, pindolol, sotalol, practolol).-Sulfato magnésico.-Reserpina.
NOTA: En situaciones de necesidad cardiológica y con indicación no sustituible pueden usarse estos fármacos con las debidas precauciones.
VII. Anticomiciales:-Hidantoínas (Fenitoína, Mefenitoína).-Barbitúricos. Trimetadiona.-Benzodiacepínicos. Etosuximida.
VIII. Psicótropos:Benzodiacepinas y derivados. Meprobamato. Carbonato de litio.Antidepresivos: -Tricíclicos: -Amitriptilina (Triptizol). -Imipramina (Tofranil).
-Inhibidores de la MAO: Fenelcina (Nardelzine).Neurolépticos: -Fenotiacina: -Clorpromacina. -Promacina.
-Butirofenonas: -Haloperidol. -Droperido.Paraldehído, Tricloroetanol, Anfetaminas.
FÁRMACOS EN MIASTENIA GRAVIS
Asociación Miastenia de España (AMES) www.miasteniagravis.es
FÁRMACOS EN MIASTENIA GRAVIS
IX. Antihistamínicos:-Difenhidramina.
X. Hipnóticos:-Barbitúricos. -Benzodiacepínicos.
XI. Analgésicos:-Morfina; precaución con otros opiáceos.-Dipirona magnésica (Nolotil).-Butilescopolamina o hioscina (Buscapina).-Butilescopolomina Dipirona (Buscapina Compositum). NOTA: Aconsejamos usar tanto analgésicos como antitérmicos: Ácido acetilsalicílico y paracetamol.
XII. Antirreumáticos:-D -Penicilamina. -Cloroquina. - Colchicina.
XIII. Agentes hormonales:-ACTH y corticoides (usar sólo bajo indicación del neurólogo).-Hormona tiroidea. -Occitocina. -Anticonceptivos.
XIV. Anestésicos:
ANESTÉSICOS GENERALES ANESTÉSICOS LOCALES-Eter y cloroformo. -Lidocaína.-Ketamina (Ketolar).-Propanidida (Epontol).-Metoxifluorane.
XV. Anticolinérgicos:Por su efecto antimuscarínico podrían enmascarar una crisis colinérgica en un paciente que estuviese tratado con anticolinesterásicos, por tanto no es aconsejable usarlos por vía general, salvo que así lo indique el neurólogo.
XVI. Diuréticos:Evitar aquellos que depletan potasio. Pueden usarse los que lo retienen.
XVII. Laxantes y enemas:Debe tenerse precaución porque pueden depleccionar potasio. Evitar preparados de magnesio. Los laxantes disminuirán la absorción de anticolinesterásicos orales.
Asociación Miastenia de España (AMES) www.miasteniagravis.es
El experimentador que no sabe lo que busca
no comprenderá lo que encuentra
Claude Bernard
Fisiólogo francés