重症肌无力英文版书-myasthenia gravis-lwx

Myasthenia gravis

Obiectives

1. To grasp the clinical features, diagnosis and treatment of myasthenia gravis(MG)

2.

To

understand

the

pathogenesis,

clinical

subtypes

of

MG

and

subtype

of

myasthenic crisis and treatment.

3.

To

know

the

pathological

change

of

MG

and

other

neuromuscular

junction

diseases.

Key concepts

MG is a disorder of the neuromuscular transmission owing to antibody

-

mediated

attack

on

acetylcholine

receptors(ACHR)

or

against

the

muscle

-

specific

receptor

tyrosine

kinase

(MuSK)

at

neuromuscular

junctions.

Muscle

weakness

occurs

In

association with continuous effort and improvement with rest is an important feature

of

the

disease.

Pharmacologic

testing,

electrophysiological

testing

and

the

concentrations of serum autoantibodies can help to confirm the diagnosis. Treatment

used

in

patients

with

MG

is

individualized

Myasthenic

crisis

is

an

exacerbation

of

myasthenia

leading

to

paralysis

of

respiratory

muscles

that

requires

an

urgent

respiratory support.

10. 1. 1 Introduction

Myasthenia

Gravis

(MG)

is

an

acquired

autoimmune

disorder

of

the

neuromuscular junction (NM)) at the postsynaptic level. The cause of the disorder is

antibodies

directed

at

the

acetylcholine

receptor

(ACHR)

or

against

the

muscle

-

specific

receptor

tyrosine

kinase

(MuSK).

The

abnormalities

(neoplasia

and

hyperplasia

of

the

thymus

gland)

play

a

part

role

in

patients

with

anti

-

AChR

antibodies. The main clinical manifestations are characterized by fluctuating, fatigable

weakness

of

muscles,

worsening

by

physical

exertion

and

improving

by

rest

and

cholinesterase inhibitors(CHEI) treatment. The prevalence rate for MG is about 5 to

15/100,000.

10. 1. 2 Pathogenesis

Transmitting electrical impulse from the nerve terminal to the underlying muscle

cells

is

the

function

of

the

neuromuscular

junction.

In

the

neuromuscular

junction,

acetylcholine(Ach)is

synthesized

in

the

motor

nerve

terminal

and

stored

in

vesicles(quanta). When an action potential travels down a motor nerve and reaches the

nerve terminal. Ach is released from 150 to 200 vesicles, then binds to ACHR of the

postsynaptic membrane, whereupon the calcium channels in the receptors transiently

open,

generating

an

endplate

potential.

If

the

depolarization

is

sufficiently

large

enough, it initiates an action potential that is propagated.

The

condition

of

MG

is

caused

by

sensitized

T

-

helper

cells

and

an

immunoglobulin

antibody

G(IGG)

-

directed

attack

on

the

nicotinic

acetylcholine

receptor

of

the

NMI.

A

variety

of

experimental

studies

support

this

hypothesis:

1.

Acetylcholine

receptor

antibodies

are

present

in

most

patients

with

MG.

choline receptor antibodies can be transferred passively to animals producing

experimental autoimmune MG. l of acetylcholine receptor antibodies leads

to

recovery.

s

immunized

with

an

acetylcholine

receptor

begin

producing

acetylcholine

receptor

antibodies,

which

can

provoke

an

autoimmune

disease(i,

e.

experimental autoimmune MG) closely resembling the naturally occurring disease.

In

MG,

binding

of

antibody

to

the

ACHR

initiates

autoimmune

attack

on

the

endplate region. The number of acetylcholine receptors is substantially reduced. The

reduced

number

of

acetylcholine

receptors

leads

to

diminution

of

the

end

plate

potential, so that no action potentials can be generated in the affected fibers. If many

fibers

are

affected,

the

muscle

is

weak.

With

repeated

contraction

of

a

muscle,

neuromuscular

transmission

fails

at

an

ever

larger

number

of

synapses,

and

the

weakness becomes progressively more severe.

Though

MG

patients

with

antibodies

to

Musk

exhibit

clinical

weakness

and

electrophysiologic

findings

that

are

quite

similar

to

MG

patients

with

ACHR

antibodies,

MUSK

initiates

aggregation

of

AChRs

at

the

muscle

endplate

during

development

but

the

function

of

MUSK

in

mature

skeletal

muscle

and

the

pathophysiology of MG related to Musk antibodies are currently unknown.

How

the

antibodies

act

at

the

receptor

surface

of

the

end

plate

is

not

entirely

clear. Neuromuscular transmission can be impaired in several ways: antibodies

may block the binding of ACh to the ACh receptors. IgG from myasthenic

patients has been shown to induce a two to three fold increase in the degradation rate

of Ach receptors. This may be the result of the capacity of antibodies to cross

-

link the

receptors, which are gathered into clusters in the muscle membrane, internalized by a

process

of

endocytosis,

and

degraded.

3.

Antibodies

may

cause

a

complemen t

-

mediated

destruction

of

the

postsynaptic

folds.

The

latter

two

mechanisms would be expected to reduce the number of Ach receptors at the synapse.

Most

patients

with

MG

have

thymic

abnormalities

and

a

positive

response

to

thymectomy, so it is logical to implicate this gland in the pathogenesis of the disease.

Both T and B cells from the myasthenic thymus are particularly responsive to the Ach

receptor. Moreover, the

thymus

contains

(resembling striated muscle)

that bear surface Ach receptors. However, the thymic myoid cells are unlikely the foci

of immunologic stimulation in MG. The most important reason is that such cells are

even more abundant in the normal than in the myasthenic thymus.

1. 3 Pathology

The

thymus

gland:

About

80%

of

patients

with

MG

have

thymic

hyperplasia,

lymphoid

follicular

hyperplasia

and

increased

germinal

center.

Approximately

10%

-

20% of MG patients have a thymoma.

Nerve

-

muscle junction: In MG, the folds of the Junction are reduced or absent.

Complements(C3, C9 and the membrane attack complex)and immune complex can be

demonstrated on the post

-

synaptic membrane.

Muscle fibers: Few abnormalities are seen In muscle biopsies, including atrophy

of type 2 fibers, and sometimes atrophy of type 1 fibers, which may be accompanied

by the presence of small dark angulated fibres. Lymphorrhages have been reported in

myasthenia gravis, they are not a consistent feature.

10.1.4 Clinical Features

Although MG may appear at any age, it has a bimodal peak of age at onset. In

women,

the

onset

usually

occurs

between

20

and

40

years

of

age;

among

men,

the

onset is usually at 40 to 60 years of age. The incidence of MG is slightly greater in

women than in men. The disorder is characterized by fluctuating fatigable weakness

of

specific

muscle

groups

rather

than

with

generalized

fatigue.

The

weakness

is

generally worse later in the day and improves with rest.

The

distribution

of

muscle

weakness

often

has

a

characteristic

pattern.

Accordingly, the earliest manifestations of the disease are often ptosis, diplopia nasal

speech,

dysphagia,

and

weakness

of

neck

extension.

There

are

also

purely

ocular

forms

of

the

disease.

The

muscles

of

the

trunk

and

limbs

generally

do

not

become

weak until later. Ptosis is the most common initial presentation and may be unilateral

or bilateral, which becomes worse after repeated forceful closing and opening of the

eyes.

Unlike

third

cranial

nerve

palsies,

MG

never

affects

pupillary

function.

Difficulty of chewing, speaking, or swallowing may also be the initial presentation.

Some

patients

may

have

severe

fatigability

and

weakness

during

mastication

Myasthenic weakness of laryngeal muscles is associated with a hoarse, breathy voice.

Examination may reveal reduced or absent palate elevation. Tongue weakness may be

demonstrated

when

the

patient

attempts

to

protrude

either

cheek

with

the

tongue

against

the

resistance

of

the

examiner’s

finger

applied

to

the

cheek.

Jaw

closure

muscles are frequently affected in MG, but strength is usually normal in jaw opening

muscles. Patients may complain of difficulty in chewing hard food. Weakness of the

larynx

and

pharynx

causes

dysphonia

and

dysphagia,

occurring

in

as

many

as

one

third of patients. Neck flexor and extensor muscles are often weak in MG.

Myasthenic crisis: Myasthenic crisis is defined as an exacerbation of weakness

sufficient

to

endanger

life;

it

usually

consists

of

respiratory

failure

caused

by

diaphragmatic and intercostal muscle weakness. The most common cause of crisis is

infection

Crisis

rarely

occurs

in

properly

managed

patients.

The

possibility

that

the

deterioration

could

be

due

to

excessive

anticholinesterase

medicatio n(

crisis

be

treated

immediately,

because

the

mechanical

and

immunologic

defenses

of

the

patient

can

be

assumed

to

be

compromised.

If

the

limb

muscles

are

involved,

the

proximal

muscles

are

usually

more

severely

affected

than

the

distal

ones.

Cholinesterase inhibitors of the treatment is effective. this is another characteristic of

MG.

The course of the illness. The signs and symptoms can fluctuate in severity from

day to day, from week to week, and over longer times. In typical untreated cases, the

manifestations

of

disease

gradually

spread

from

the

eyes

to

the

facial

and

bulbar

muscles and then to the trunk and limbs. The first manifestation of the disease is in

the eyes in half of all cases and the eyes are eventually involved in more than 90%.

Generalization of manifestations practically always occurs within 3 years of onset. In

16%

of

untreated

cases,

however,

the

disease

manifestations

remain

permanently

confined to the extraocular muscles.

Clinical Subtype

(1)

Adult

patients

with

MG

can

be

classified

according

to

the

Osserman's

classification.

This scale divides cases of myasthenia into five varieties, one of which has two

subtypes:

I: Ocular myasthenia (15%

-

20%)< /p>

-

myasthenia confined to the eyes.

II a: Mild generalized myasthenia with slow progression(30%). No crisis. Drug

responsive.

II b: Moderately severe form of generalized myasthenia(20%

-

25%). The muscles

of respiration are not affected. Skeletal and bulbar muscles are involved but no crisis,

drug response less than satisfactory.

Ill

：

Acute

and

rapidly

progressive

myasthenia

(15%6).

Abrupt

onset

and

progression, with involvement of the muscles of respiration within 6 months of onset.

Respiratory crisis and poor drug response.

IV:

Chronic,

severe

myasthenia(10%).

Progression

from

groups

I

or

II

after

a

relatively stable course lasting 2 years. Patients in groups Ill and IV more often have a

thymoma than those in groups or II, and suffer a higher mortality.

V:

Muscle

atrophy

(not

due

to

disuse

)in

late

generalized

disease,

restricted

to

skeletal muscles and usually related to the duration of the disease an clinical severity

( myasthenic myopathy).

(2)

Neonatal myasthenia gravis

Neonatal myasthenia gravis results from passive transfer of maternal anti

-

AChR

antibodies and is self

-

limiting. 15 of babies born to myasthenic mother show signs of

myasthenia

(hypotonia,

weak

cry

and

suck).

This

is

a

transitory

phenomenon

with

short duration and recover is usually complete within 2 months of birth, without later

relapse.

(3)

Congenital myasthenic syndrome

the onset maybe congenital or in early adulthood. The affected infants had been

born to non

-

myasthenic mothers.

10. 1. 5 Ancillary Tests

(1) Repetitive nerve stimulation(RNS)

RNS

perform

1,

3

or

5

-

HZ

repetitive

stimulation

with

the

patient

at

rest.

Normally,

there

should

be

less

than

a

10%

decrement

from

the

baseline

value

Acetylcholinesterase

inhibitors

should

not

be

taken

for

at

least

12

hours

prior

to

testing.

In

general

proximal

muscles

including

facial

muscles,

deltoid,

and

biceps

brachii are more likely to exhibit

abnormal

findings. RNS

studies may demonstrate

impaired neuromuscular transmission, but they are relatively insensitive in ocular and

in mild generalized MG.

(2) Single fiber electromyography(SFEMG)

SFEMG

is

an

even

more

sensitive

test.

In

myasthenia

gravis,

this

test

reveals

increased jitter and more frequent blockades. If a normal jitter is found in a clinically

weak muscle, the reason of weakness in that muscle is not from MG.

(3) The testing of AchR

-

Ab titers

It's the most sensitive and specific test for MG. Positive antibody studies confirm

MG

in

a

patient

with

appropriate

symptoms

and

clinical

findings.

ACHR

binding

antibodies

are

present

in

approximately

80%

-

90%

of

patients

with

generalized

MG

but

in

only

55%

of

patients

with

ocular

MG.

The

degree

of

for

the

test

results

does

not

correlate

with

the

severity

of

disease.

MUSK

antibodies

to

MUSK

have

been

demonstrated

in

about

one

third

of

patients

with

generalized

Achr

-

ab

negtive MG. Ryanodine antibodies are associated with late

-

onset MG. Patients with

ryanodine

antibodies

may

exhibit

severe,

t reatment

-

resistant

MG

associated

with

malignant thymomas.

(4) Other testings

Chest

CT

should

be

performed

to

demonstrate

or

rule

out

a

thymoma/thymic

hyperplasia. Since MG often coexists with other autoimmune disorders, particularly

autoimmune thyroid disease, patients should undergo thyroid function testing along

with testing for other autoimmune disorders when clinically appropriate.

10. 1.6 Diagnosis and Differential Diagnosis

There

are

no

widely

accepted

formal

diagnostic

criteria

for

MG

patients.

The

most important elements of diagnosis are clinical history and examination findings of

fluctuating

and

fatigable

weakness,

particularly

involving

extraocular

and

bulbar

muscles.

The

laboratory

tests

that

are

available

to

confirm

the

clinical

diagnosis

of

MG include pharmacologic testing, electrophysiological testing and tests to measure

the

concentrations

of

serum

autoantibodies.

Neostigmine

can

elicits

unequivocal

Improvement

in

strength.

RNS

studies

and/or

SFEMG

demonstrate

a

primary

postsynaptic neuromuscular junctional disorder. AchR

-

Ab titers are the most sensitive

and specific test for MG, approximately 90% of patients with generalized MG have

positive antibodies.