Transcript myasthenia gravis

MYASTHENIA GRAVIS
Dr. M. SOFI MD; FRCP (London);
FRCPEdin; FRCSEdin
History of MG
Sir Thomas Willis
a woman who spoke
freely and readily
enough for a while,
but after a long
period of speech was
not able to speak a
word for one or two
hours”
This has been
interpreted as being
the first written
description of
myasthenia gravis.
Thomas Willis (1621–1675)
History of MG
"The excessive fatigues he
encountered wrecked his
constitution.………………his
eyelids were too heavy that
he could not see unless they
were lifted up by his
attendants.“
While in Jamestown, Chief
Opechancanough was able to
rest and he then could raise
himself up to a standing
position.
Chief Opechancanough
Opchanacanough was a tribal chief of the Powhatan Confederacy of what is now
Virginia in the United States, and its leader from sometime after 1618 until his
Epidemiology: Myasthenia Gravis




Most common disorder
of NMJ transmission
Annual incidence of 1020 new cases per million
Prevalence: 14.2:100000
(US) but on rise due to ↓
mortality, longer survival
The M:F ratio of MG in
children and adults is 2:3.


Onset of MG at a young age is
slightly more common in
Asians than in other races
Age of onset has a bimodal
distribution
 Second and third
decades (female
predominance)
 Sixth to eighth decade
(male predominance)
Generalized Myasthenia (Grob et al. ‘81)
women
men
140
120
100
n=868
80
60
40
20
0
1st
2nd
3rd
4th
5th
6th
7th
8th
Ocular Myasthenia (Grob et al. ‘81)
women
men
35
30
25
n=168
20
15
10
5
0
1st
2nd
3rd
4th
5th
6th
7th
8th
T-synaptic terminal Axon
M-Muscle cell.
Pathophysiology




To understand MG, familiarity with
normal anatomy and functioning of
NMJ is necessary.
The nerve terminal of the motor
nerve enlarges at its end, which is
called the bouton terminale
(terminal bulb).
The presynaptic membrane (nerve
membrane), postsynaptic
membrane (muscle membrane),
and synaptic cleft (space between
the 2 membranes) constitute the
NMJ.
Synaptic cleft and postsynaptic
membrane with multiple folds and
embedded with several acetylcholine
receptors.
NMJ Transmission
Chemical synapses



Illustration of the major
elements in chemical
synaptic transmission.
An electrochemical wave
called an action potential
travels along the axon of a
neuron.
When the wave reaches a
synapse, it provokes release
of neurotransmitter
molecules, which bind to
chemical receptor
molecules located in the
membrane of another
neuron, on the opposite
side of the synapse.
Pathophysiology



MG is an autoimmune
channelopathy: antibodies
directed against the body's
own proteins.
Autoantibodies [IgG]
develop against ACh
nicotinic postsynaptic
receptors.
The antibodies are produced
by plasma cells, derived from
B-cells converted into
plasma cells by T-helper cell
stimulation.




Cholinergic nerve conduction to
striated muscle is impaired and
postsynaptic receptor are
destroyed.
The cholinergic receptors of
smooth and cardiac muscle
are not affected by the disease.
Patients become symptomatic
once the number of ACh
receptors is reduced to about
30% of normal.
Serum IgG from MG patients
increases degradation of AChR.
NORMAL
NMJ
ABNORMAL
NMJ
Presenting symptoms
Other disorders to consider
Ocular (50 percent)
Brainstem and cranial nerve lesions (including Horner's
syndrome), thyroid ophthalmopathy, oculopharyngeal
muscular dystrophy, chronic external ophthalmoplegia
(mitochondrial disease)
Bulbar (15 percent)
Brainstem and multiple cranial nerve lesions, motor
neuron disease, obstructive or malignant lesion of the
nasal and oropharynx
Limb weakness (<5
percent)
Motor neuron disease, chronic inflammatory
demyelinating polyneuropathy (CIDP) and other motor
neuropathies, multiple radiculopathies, Lambert-Eaton
myasthenic syndrome, myopathies
Isolated neck
(uncommon)
Motor neuron disease, inflammatory myopathy,
paraspinous myopathy
Isolated respiratory
(rare)
Motor neuron disease, acid maltase deficiency,
polymyositis
Distal limb (rare)
Motor neuron disease, CIDP and other motor
neuropathies, distal myopathies
Signs and Symptoms
• The usual initial complaint
is a specific muscle
weakness rather than
generalized weakness
• Extraocular muscle
weakness or ptosis is
present initially in 50% of
patients
• The disease remains
exclusively ocular in only
16% of patients
• Rarely, patients have
generalized weakness
without ocular muscle
weakness
• Bulbar muscle
weakness is also
common, along with
weakness of head
extension and flexion
• Limb weakness may be
more severe proximally
than distally
• Isolated limb muscle
weakness is the present
in fewer than 10% of
patients
Signs and Symptoms
• Weakness is least severe
in the morning and
worsens as the day
progresses
• Weakness is increased
by exertion and
alleviated by rest
• Weakness progresses
from mild to more severe
over weeks or months,
with exacerbations and
remissions
• Weakness tends to
spread from the ocular
to facial to bulbar
muscles and then to
truncal and limb muscles
• About 87% of patients
have generalized disease
within 13 months after
onset
• Less often, symptoms
may remain limited to
the extraocular and
eyelid muscles for years
PYSICAL EXAMINATION FOR MG
Muscle fatigability can be
tested for many muscles.
A thorough investigation
includes:
 looking upward and
sideward for 30 seconds:
ptosis and diplopia
 looking at the feet while
lying on the back for 60
seconds
 keeping the arms
stretched forward for 60
seconds




Ten deep knee bends
Walking 30 steps on both
the toes and the heels
Five sit-ups, lying down
and sitting up completely
"Peek sign": after complete
initial apposition of the lid
margins, they quickly
(within 30 seconds) start
to separate and the sclera
starts to show
Additional Tests for MG Diagnosis
Ice pack test
 MG who has ptosis, placing
ice over an eyelid will lead to
cooling of the lid, which leads
to improvement of the ptosis.
 Lightly placing ice that is in a
surgical glove or that is
wrapped in a towel over the
eyelid will cool it within 2
minutes.
 Positive test is clear resolution
of the ptosis.
 This test has a pooled
sensitivity and specificity of
82% and 96%, respectively.



Patients with respiratory
distress should have an
evaluation of pulmonary
function.
This evaluation includes pulse
oximetry, a measure of
pulmonary function ( PEFR,
[FEV1]), and ABG sampling to
determine PCO2 level.
Evidence of hypoxemia, poor
respiratory effort, or CO2
retention is an indication for
intubation and mechanical
ventilation.
Tensilon Test






Edrophonium is an AChE inhibitor.
Rapid onset (30s) and short duration of action
(about 5 minutes).
Focus on a weak muscle group and evaluate
for change.
Initial dose of 2mg given IV. If no change give
additional 8mg IV.
Beware cholinergic effects (nausea, diarrhea,
salivation, fasciculations, bradycardia).
Have atropine at bedside.
Additional Tests for MG Diagnosis
Anti–acetylcholine receptor
antibody
 (AChR) antibody (Ab) test is
reliable for (MG).
 Highly specific (100%).
 Positive in 90% generalized
MG.
 50-70% ocular MG
False-positive anti-AChR Ab
test results occur in:
 Thymoma without MG
 L-Eaton myasthenic
syndrome
 R A treated with
penicillamine
Anti-MuSK– antibodies
 About 1/2 Seronegative MG may
have positive (Anti-MuSK
antib)
 Anti-MuSK (Muscle specific
tyrosine kinase) positive
individuals may have more
pronounced
 Bulbar weakness
 Tongue and facial atrophy.
 Neck, shoulder and
respiratory involvement
without ocular weakness.
Approximate sensitivity of the confirmatory
tests for myasthenia gravis
Generalized
Ocular myasthenia
myasthenia percent
percent positive
positive
AChR antibodies
80 to 90
40 to 55
MuSK antibodies
(in AChR Ab
negative patients)
40 to 50
<10
Repetitive nerve
stimulation
75
<50
Single fiber
electromyography
92 to 99
80 to 95
MG: myasthenia gravis; AChR: acetylcholine receptor; MuSK:
muscle-specific kinase.
Other studies (Imaging)
•
Plain chest radiographs
may identify a thymoma as an
anterior mediastinal mass
• Chest computed tomography
is important to identify or
rule out thymoma or thymic
enlargement in all cases of
MG
• In strictly ocular MG,
magnetic resonance imaging
of the brain and orbit is
helpful to evaluate for mass
lesions compressing the
cranial nerves or a brainstem
lesion that may masquerade
as ocular MG
Thymoma
MG: DIFFFERENTIAL DIAGNOSIS











ALS
Basilar artery thrombosis
Brain stem gliomas
Cavernous sinus thrombosis
Dermatositis/Polymyositis
LEMS
Multiple sclerosis
Sarcoidosis & neuropathy
Thyroid disease
Tolosa-Hunt Syndrome
Myasthenic syndromes







Mitochondrial myopathies ±
external ophthalmoplegia
Neurasthenia
Oculopharyngeal muscular
dystrophy
Botulism
Brainstem syndromes
Compressive lesions of cranial
nerves
Congenital myasthenic
syndromes
Repititve nerve
stimulation
Anti-AChE inhibitors stopped 6-24 hrs prior to
testing.
 2-3 electric shocks/second delivered, action
potentials recorded.
 In normal individual, amplitude of evoked
muscle action potential dose not change.
 In MG, rapid reduction in the amplitude of the
evoked response of more than 10-15%

Single Fiber EMG
The most sensitive test for MG
 Electrode measures action
potentials of two muscle fibers innervated by the
same motor axon.
 Variability in time of the 2nd action potential relative
to the 1st is called “jitter”.
 MG causes increased “jitter”.
Anti-cholinesterase Inhibitor



Anti-cholinesterase Inhibitor (AChEI) inhibits
the cholinesterase enzyme from breaking down
acetylcholine, increasing both the level and
duration of action of the neurotransmitter
acetylcholine.
Acetylcholinesterase inhibitors:
 Occur naturally as venoms and poisons.
 Are used as weapons in the form of nerve
agents.
Are used medically:
 In myasthenia gravis, to prevent enzymatic
breakdown of ACh to increase neuromuscular
transmission.
 In the treatment of Glaucoma.
 To treat Alzheimer's disease.
 To treat Lewy Body Dementia.
 As an antidote to anticholinergic poisoning.
Acetylcholine
Acetylcholinesterase
Cholinesterase Inhibitors




MG is one of the most
treatable neurologic disorders.
These agents increase the
amount of available ACh at the
NMJ by inhibiting the
degradation of ACh.
Most patients are able to
titrate the dosage of their
medication to control the
symptoms of the disease, but
severe exacerbations can occur
in patients with previously
well-controlled disease




Pyridostigmine is the most
used AChE inhibitor.
Peak serum concentrations
reach in 90 to 120 minutes and
has a similar half-life.
60 to 120 mg every 3 to 4 hours
are most effective.
Patients may modify their
dose to their level of activity
It is rare for pyridostigmine
alone to improve transmission
to a satisfactory level, and
therefore most patients
require more definitive
therapy.
Immune modulation:
Most patients with generalized MG require additional immunomodulating
therapy. Immunomodulation can be achieved by various medications, such as
commonly used corticosteroids
• The corticosteroid regimen • Other medications that are
should be tailored
used to treat more difficult
according to the patient’s
cases include
overall improvement.
– azathioprine,
– mycophenolate mofetil,
• The lowest effective dose
– cyclosporine,
should be used on a long– cyclophosphamide
term basis.
• However, the effectiveness of
• Because of the delayed
many of these medications is
onset of effects, steroids are
far from proved, and caution
not recommended for
should be advised against
routine use in the
using any of them lightly
emergency department
(ED).
Plasmapheresis and IVIG
Plasmapheresis
IVIG
 The response occurs over  The recommended total
hours to days and is
monthly dose is 2 g/kg in
useful to treat or abort
five daily doses slowly
myasthenic crisis
enough to avert rate
preoperatively.
related side effects.
 Pathogenic antibodies
 Half-life of IVIg is about
removed at NMJ.
4weeks, and monthly
doses are reasonable, with
 Usually a course of 5
the goal of slowly tapering
exchanges over a 2 week
the frequency of
period is useful for relief
treatments based on the
of symptoms.
clinical status.
 Clinical responses occur
over 2 to 4 weeks.
THYMECTOMY



Thymus has a central role in
pathogenesis - thymectomy
is an important part of Rx.
Radiographic/CT evidence of
an anterior mediastinal mass
warrants thymectomy at any
age because 10% of patients
with MG will have thymoma.
In the absence of mediastinal
mass, it seems appropriate to
counsel the patient to
undergo thymectomy to
increase the probability of
sustained remission.
“Ernst Ferdinand Sauerbruch”,
German surgeon (1875-1951)
performed thymectomy for the
relief of myasthenia gravis.