Miastenia Gravis

actualizacin
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
Epidemiologa
Incidencia: 10 x milln x ao

Prevalencia: 14 x 100,000 habitantes

Se estima que en los Estados Unidos hay
70,000 personas con Miastenia Gravis.
Miastenia 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.
Unin neuromuscular
Edad de inicio
2a. y 3a. dcada en la mujer.
7a. y 8a. dcada en el hombre
Los hombres son mas afectados
que las mujeres.

Miastenia Gravis
Datos Clnicos

A) Debilidad.


B) Fatigabilidad.
Miastenia Gravis
La debilidad es
el sntoma
cardinal de la
Miastenia
Gravis
MIASTENIA GRAVIS
MIASTENIA GRAVIS
Manifestaciones Cl
Manifestaciones Cl

nicas
nicas

Diplop
Diplop

a
a
/
/
Ptosis
Ptosis

Disnea
Disnea
/
/
Ortopnea
Ortopnea

Disartria
Disartria

Disfagia
Disfagia

Debilidad a la masticaci
Debilidad a la masticaci

n
n

Fatiga
Fatiga
Sntomas Iniciales
Ptosis o diplopa en 2/3 de los
pacientes
Dificultad para la masticacin,
deglucin 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 Miastnica
La crisis ocurre
cuando un paciente
experimenta debilidad
muscular que
compromete la
funcin respiratoria
Puede ser miastnica o
colinrgica
Es una urgencia
neurolgica
MIASTENIA GRAVIS
MIASTENIA GRAVIS
Crisis
Crisis
Miast
Miast

nica
nica

Suspensi
Suspensi

n de la medicaci
n de la medicaci

n
n

Infecci
Infecci

n Respiratoria
n Respiratoria

Alteraci
Alteraci

n Emocional
n Emocional

Intervenci
Intervenci

n Quir
n Quir

rgica
rgica

Acci
Acci

n de drogas
n de drogas

Trastornos de absorci
Trastornos de absorci

n
n
Lindtrom Lindtrom, ,Fujii Fujii MG MG Adv Adv. In . In
inmunology inmunology, 42:233/284,89 , 42:233/284,89
Procedimientos Diagnsticos
Prueba del Tensiln
Es positiva en mas del 90% de los pacientes

Puede ser positiva en otras enfermedades

Precaucin. Paciente hospitalizado.

Prueba de Neostigmina
MIASTENIA GRAVIS
MIASTENIA GRAVIS
Pruebas diagn
Pruebas diagn

sticas
sticas

Pruebas
Pruebas
Farmacol
Farmacol

gicas
gicas

Pruebas
Pruebas
Inmunitarias
Inmunitarias

Pruebas
Pruebas
Electrofisiol
Electrofisiol

gicas
gicas
Prueba de Tensiln
Paciente
hospitalizado
Canalizado.exam
en completo. Sv.
Atropina
Equipo de paro
Despues de tensiln
Prueba de tensiln
Antes de tensiln
Anticuerpos Antireceptores de
acetilcolina
Presentes
85% MG Generalizada.
55% MG ocular.
No predicen la severidad
Su presencia ante datos clnicos
confirma el diagnstico.
Su ausencia no excluye el Dx.

Procedimientos Diagnsticos
Electromiografa.

Estimulacin repetitiva

EMG de fibra nica
Clasificacin Clnica
Generalizada
Neonatal
Congnita
Juvenil
Adulto leve, mod. y severa
Ocular - Juvenil y del Adulto
MIASTENIA GRAVIS
MIASTENIA GRAVIS
Diagn
Diagn

stico Diferencial
stico Diferencial

Esclerosis lateral
Esclerosis lateral
Amiotr
Amiotr

fica
fica

Neuropat
Neuropat

a
a
Perif
Perif

rica
rica

Miopat
Miopat

as
as

Lambert
Lambert
-
-
Eaton
Eaton

Oftalmoplegia
Oftalmoplegia
externa progresiva
externa progresiva

Otros
Otros
Drachman Drachman. MG. . MG.
Current Current, , Decker Decker- -85 85
LAMBERT
LAMBERT
-
-
EATON
EATON
Datos Cl
Datos Cl

nicos
nicos

Asociaci
Asociaci

n con
n con
cancer
cancer

Debilidad de miembros inferiores
Debilidad de miembros inferiores

REM disminuidos o ausentes
REM disminuidos o ausentes

Mejor
Mejor

a con esfuerzos
a con esfuerzos

Boca seca
Boca seca

Los s
Los s

ntomas oculares son m

ntomas oculares son m

nimos
nimos
NCNA, NCNA, vol vol 2/1994 2/1994
Steinert
Kearn-sayre
tratamiento
1.- anticolinestersicos.
2.- esteroides.
3.- inmuno supresores.
4.- plasmaferesis
5.- inmunoglobulina.
6.- timectomia
Dosis equivalentes de anticolinesterasicos
Dosis (mg) y va
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
Anticolinestersicos
toxicidad y efectos secundarios
Muscarnicos
Msculo liso
Clicos-diarrea
Nausea,vmito
Miosis pupilar
Broncoespasmo
Glandulas
Sialorrea,diaforesis
Nicotnicos
Musculoesqueleticos
Fasciculaciones
Espasmos musculares
debilidad
Glucocorticoides
Efectos secundarios a largo plazo
Gastrointestinales
Nausea,vmitos,
Gastritis, ulceras
Dermatologicos
acn, hirsutismo
Cushing
Endocrinos:
Hiperglucemia
Hipokalemia.
Inmunolgicos:
Inmunodepresin.
Hematolgicos:
petequias
Cardiovascular
HAS
edema
Oftalmolgicos:
Cataratas
Glaucoma
Psicolgicos:
Depresin
Insomnio.
Otros:
Aumento de
peso
Azatioprina
Efectos secundarios
Gastrointestinales Nausea,vmitos,diarrea
Ulceras,malestar
Hematolgicos Leucopenia, anemia
Trombocitopenia.
Heptico Enzimas Hepticas
elevadas
Inmunolgico
Mayor susceptibilidad a
infecciones
Neoplsico
Incrementa el riesgo para
linfoma
Timectomia

No se practica en la
MG ocular.
No se realiza
despus de los 60
aos (a menos que
haya timoma).
Requiere
preparacin.
Mejores resultados
en mujeres jvenes.
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 vidas
Es un placer indescriptible!

Rubn Daro
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
Ca
2+
(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 Ca
2+
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 dont.

Drug Interactions:
Cholinesterase Inhibitors decrease the effectiveness of
nondepolarizing agents
Aminoglycoside antibiotics (e.g. streptomycin)
decrease ACh release by competing with Ca
2+

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 is
characterized 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
GABA
A
in the CNS)
Baclofen (GABA
B

agonist note error
in your handouts)
Primarily used in the
treatment of
spastiticy
associated with
spinal cord injury
Spasmolytic Drugs