Miastenia Gravis 2011

“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

Anticuerpos unidos al AChR(Ac Anti-AChR)

Ig G incrementa degradación de AChR

Destrucción de membrana postsináptica, mediada por complemento (aplanamiento)

Etiología y Patogenia


Naturaleza fluctuante

Distribución de la Debilidad

Respuesta a drogas colinérgicas

Manifestaciones Clínicas

RemisiónExacerbación -- Crisis

Músc. OcularesMúsc. Orofaríngeos y/o FacialesMúsc. CuelloExtremidades


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


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


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


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


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


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

http://www.proverbia.net/enviar_frase.asp?id=10632

http://www.proverbia.net/enviar_frase.asp?id=10632

Miastenia Gravis 2011

Health & Medicine

Transcript of Miastenia Gravis 2011