Miastenia Gravis

actualización

Dr. Juan Lozano

Thomas Willis (1621-1675), English physician, published a book, De anima brutorum(1) in

1672 in which he wrote about "a woman who temporarily lost her power of speech and became 'mute as a fish. '"(1) This has been interpreted as being the first written

description of myasthenia gravis. Thomas Willis was born in Great Bedwin, a

Wiltshire village in England. He graduated from Oxford University

Legion with a Bachelor of Medicine in 1646. In 1660 he was appointed Sedleian Professor of Natural Philosophy at Oxford and given

the M.D.(2)

Her first patient, 'Mrs. M.', had had intermittent weakness for 14 years and had been admitted to St. Alfege's Hospital about 2 months prior to the treatment given by Dr. Walker because of an exacerbation. Mrs. M's muscle power was restored about 30 mins after the hypodermic injection of physostigmine sulphate (gr. 1/60) --- the effect lasted up to 4 hours. The case was written up in the Lancet 2nd June 1934, pp. 1200-1 and was also reported in the local newspaper The Kentish Mercury on 15th March 1935.

Dra. Mary Walker

'Mrs. M.' before (left image) and after (right image) injection of physostigmine. Before - patient cannot raise left eyelid. After - eye is fully open.These photos were reproduced from a cine film and appeared in reverse (right for left) in The Lancet 1934 (i) 1200-1. They are reproduced here with correct orientation.

Paciente de la Dra Walker

GENTE FAMOSA CON MG

• David Niven

• Aristotle Onassis

• Sir Lawrence Olivier

• Phil Silvers (actor - Sgt. Bilko)

• "Sleepy" (© Disney) of Snow White and the Seven Dwarfs was supposedly based on a friend of Walt Disney who had MG

Julie Long

artista

Jerry lewis

Epidemiología

•Incidencia: 10 x millón x año

•Prevalencia: 14 x 100,000 habitantes

•Se estima que en los Estados Unidos hay 70,000 personas con Miastenia Gravis.

Miastenia GravisMiastenia Gravis

• En la persona joven predomina en la mujer

• En la persona anciana predomina en el hombre.

Miastenia Gravis

• Es universal.• No es Hereditaria.• No es contagiosa.• No tiene

preferencias estacionales.

• Afecta todas las edades.

Unión neuromuscular

Edad de inicio

2a. y 3a. década en la mujer.

7a. y 8a. década en el hombre

Los hombres son mas afectados que las mujeres.

Miastenia GravisDatos Clínicos

A) Debilidad.

B) Fatigabilidad.

Miastenia Gravis

La debilidad es el síntoma cardinal de la Miastenia Gravis

MIASTENIA GRAVISMIASTENIA GRAVISManifestaciones ClManifestaciones Clíínicasnicas

DiplopDiplopííaa//PtosisPtosis

DisneaDisnea//OrtopneaOrtopnea

DisartriaDisartria

DisfagiaDisfagia

Debilidad a la masticaciDebilidad a la masticacióónn

FatigaFatiga

Síntomas Iniciales

• Ptosis o diplopía en 2/3 de los pacientes

• Dificultad para la masticación, deglución o para hablar en 1/6 de los pacientes.

• En un 10% hay debilidad localizada

Miastenia Gravis

La Pupila nunca se afecta en la Miastenia Gravis.

DEBILIDAD FATIGABLE

Crisis Miasténica

• La crisis ocurre cuando un paciente experimenta debilidad muscular que compromete la función respiratoria

• Puede ser miasténica o colinérgica

• Es una urgencia neurológica

MIASTENIA GRAVISMIASTENIA GRAVISCrisis Crisis MiastMiastéénicanica

SuspensiSuspensióón de la medicacin de la medicacióónn

InfecciInfeccióón Respiratorian Respiratoria

AlteraciAlteracióón Emocionaln Emocional

IntervenciIntervencióón Quirn Quirúúrgicargica

AcciAccióón de drogasn de drogas

Trastornos de absorciTrastornos de absorcióónnLindtromLindtrom,,Fujii Fujii MG MG AdvAdv. In. In

inmunologyinmunology, 42:233/284,89, 42:233/284,89

Procedimientos DiagnósticosPrueba del Tensilón

• Es positiva en mas del 90% de los pacientes

• Puede ser positiva en otras enfermedades

• Precaución. Paciente hospitalizado.

• Prueba de Neostigmina

MIASTENIA GRAVISMIASTENIA GRAVISPruebas diagnPruebas diagnóósticassticas

Pruebas Pruebas FarmacolFarmacolóógicasgicas

Pruebas Pruebas InmunitariasInmunitarias

Pruebas Pruebas ElectrofisiolElectrofisiolóógicasgicas

Prueba de Tensilón

• Paciente hospitalizado

• Canalizado.examen completo. Sv.

• Atropina

• Equipo de paro

Despues de tensilón

Prueba de tensilón

Antes de tensilón

Anticuerpos Antireceptores de acetilcolina

• Presentes • 85% MG Generalizada. 55% MG ocular.• No predicen la severidad• Su presencia ante datos clínicos

confirma el diagnóstico.• Su ausencia no excluye el Dx.

Procedimientos DiagnósticosElectromiografía.

• Estimulación repetitiva

• EMG de fibra Única

Clasificación Clínica

Generalizada Neonatal

Congénita

Juvenil

Adulto leve, mod. y severa

Ocular - Juvenil y del Adulto

MIASTENIA GRAVISMIASTENIA GRAVISDiagnDiagnóóstico Diferencialstico Diferencial

Esclerosis lateral Esclerosis lateral AmiotrAmiotróóficafica

NeuropatNeuropatíía a PerifPerifééricarica

MiopatMiopatííasas

LambertLambert--EatonEaton

Oftalmoplegia Oftalmoplegia externa progresivaexterna progresiva

OtrosOtrosDrachmanDrachman. MG.. MG.

CurrentCurrent, , DeckerDecker--8585

LAMBERTLAMBERT--EATONEATONDatos ClDatos Clíínicosnicos

AsociaciAsociacióón con n con cancercancer

Debilidad de miembros inferioresDebilidad de miembros inferiores

REM disminuidos o ausentesREM disminuidos o ausentes

MejorMejoríía con esfuerzosa con esfuerzos

Boca secaBoca seca

Los sLos sííntomas oculares son mntomas oculares son míínimosnimos

NCNA, NCNA, vol vol 2/19942/1994

SteinertKearn-sayre

tratamiento

• 1.- anticolinesterásicos.

• 2.- esteroides.

• 3.- inmuno supresores.

• 4.- plasmaferesis

• 5.- inmunoglobulina.

• 6.- timectomia

Dosis equivalentes de anticolinesterasicos Dosis (mg) y vía

Oral IM IV Jarabe

Neostigmina 15

Neostigmina 1.5 0.5

Mestinon 60 2 0.7 60 mg

5 ml

Mestinon

Timespan

90 - 180

Ambenomio 7.5

Anticolinesterásicostoxicidad y efectos secundarios• Muscarínicos• Músculo liso• Cólicos-diarrea• Nausea,vómito• Miosis pupilar• Broncoespasmo

• Glandulas• Sialorrea,diaforesis

• Nicotínicos• Musculoesqueleticos• Fasciculaciones• Espasmos musculares• debilidad

GlucocorticoidesEfectos secundarios a largo plazo

GastrointestinalesNausea,vómitos,

Gastritis, ulceras

Dermatologicosacné, hirsutismo

Cushing

Endocrinos:Hiperglucemia

Hipokalemia.

Inmunológicos:Inmunodepresión.

Hematológicos:petequias

CardiovascularHAS

edema

Oftalmológicos:Cataratas

Glaucoma

Psicológicos:Depresión

Insomnio.

Otros:Aumento de

peso

AzatioprinaEfectos secundarios

Gastrointestinales Nausea,vómitos,diarrea

Ulceras,malestar

Hematológicos Leucopenia, anemia

Trombocitopenia.

Hepático Enzimas Hepáticas

elevadas

Inmunológico Mayor susceptibilidad a

infecciones

Neoplásico Incrementa el riesgo para

linfoma

Timectomia •No se practica en la MG ocular.

•No se realiza después de los 60 años (a menos que haya timoma).

•Requiere preparación.

•Mejores resultados en mujeres jóvenes.

•Se prefiere abordaje transesternal.

TIMOMA

Terapias emergentes

• Micofenolato de mofedetilo

• tacrolimus

El que alguien toque mi vida es un privilegio,

Tocar la vida de alguien es un honor,Pero el ayudar a que otros toquen sus

propias vidasEs un placer indescriptible!

 Rubén Darío

Major Events in Neuromuscular Transmission• Motor neuron depolarization causes action potential to

travel down the nerve fiber to the neuromuscular junction (1).

• Depolarization of the axon terminal causes an influx of Ca2+ (2) which triggers fusion of the synaptic vesicles (3) and release of neurotransmitter (Acetylcholine; ACh) (4).

• ACh diffuses across the synaptic cleft and binds to post-synaptic ACh receptor (AChR) located on the muscle fiber at the motor end-plate (5).

• Binding of ACh to AChRs opens the channels causing an influx of Na (5), depolarization of the sarcolemma that travels down the t-tubules (6) and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum - CONTRACTION.

• Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) (7).

Two main Types of Neuromuscular Blocking Drugs

• Nondepolarizing (competitive)

• Depolarizing

Mechanism of Action of Nondepolarizing Neuromuscular Blocking Drugs

Non-depolarizing (competitive).

• Prototype of Non-depolarizing is tubocurarine (new generation: pancuronium and gallamine).

• Mechanism of Action: In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh.

• At higher does they can block prejunctional Na channels thereby decreasing ACh release.

• Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors).

Nondepolarizing Agents

• Therapeutic Use: Adjuvant drugs in surgical anesthesia

• Pharmacology: Must be given by injection because they are poorly absorbed orally. Do not cross the BBB. Generally excreted unchanged (i.e. not metabolized).

• Adverse Effects: Tubocurarine causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. Newer generation don’t.

Drug Interactions: • Cholinesterase Inhibitors decrease the effectiveness of

nondepolarizing agents • Aminoglycoside antibiotics (e.g. streptomycin) decrease

ACh release by competing with Ca2+ – increase action of nondepolarizing drugs

• Calcium channel blockers increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs)

• Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by 1) decreasing excitability of motoneurons, 2) increasing muscle blood flow, and 3) decreased kinetics of AChRs (increase action of nondepolarizing drugs)

Depolarizing

Agents

Depolarizing Agents• Prototype of depolarizing agent is succinylcholine (only

depolarizing drug in clinical use).• Mechanism of Action: Similar action to ACh, but longer

acting. • Phase 1: Membrane is depolarized by opening AChR

channels causing brief period of muscle fasciculation.• Phase II: End-plate eventually repolarizes, but because

succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate.

• Because of the mechanism of action of depolazing drugs is similar to ACh, their blocking effects are augmented by AChE inhibitors.

Depolarizing Agents

• Therapeutic Use: Adjuvant drugs in surgical anesthesia

• Pharmacology: Duration of action is short (several minutes) because it is rapidly broken down by plasma cholinesterases (must be administered by continuous infusion)

• Adverse Effects: When administered with halothane some genetically susceptible people (inherited autosomal dominant condition) experience malignant hyperthermia. Treatment: rapid cooling of the body and dantrolene

Cholinesterase Inhibitors

Cholinesterase Inhibitors

• Examples: Neostigmine, edrophonium.• Mechanism of Action: Inhibit acetylcholinesterase

• Therapeutic Use: • Antidote for nondepolarizing blockers• Treatment of myasthenia gravis (neostigmine)• Diagnosis of myasthenia gravis (edrophonium)

                                              

Myasthenia Gravis

Myasthenia Gravis is an autoimmune Disease that ischaracterized by a decrease in number of AChR

Because there are fewer AChR to bind to the end plate potentials (EPPs) are smaller.

With smaller EPPs the“safety factor” is reduced there is less chance that the post-synaptic muscle fibres will be activated

Note: The amplitude of the end plate-potential is directly related to the amount of ACh that binds to the post-synaptic AChRs.

Myasthenia Gravis

Adverse Effects

• Actions of generalized cholinergic activation (muscarinic and nicotinic).

• Abdominal cramping• Diarrhea• Flushing (transient redness of the face and neck)• Increased salivation• Miosis (contraction of the pupils)• Incontinence• Bronchospasms (can exacerbate bronchial asthma)

Malignant Hyperthermia

Dantrolene (interferes with EC coupling by decreasing Ca exflux from the SR

Diazepam (A Benzodiazepine that probably facilitates the actions of GABAA in the CNS)

Baclofen (GABAB agonist – note error in your handouts)

Primarily used in the treatment of spastiticy associated with spinal cord injury

Spasmolytic Drugs