Diagnosis and Management of Myasthenia Gravis

Myasthenia Gravis
Myasthenia Gravis
Diagnosis and management
Diagnosis and management
Dr.
Dr. Thanin
Thanin Asawavichienjinda
Asawavichienjinda, M.D.
, M.D.

Myasthenia Gravis
Myasthenia Gravis
• A neuromuscular disorder characterized by
weakness and fatigability of skeletal muscles
• The underlying defect: A decrease in the
number of available acetylcholine receptors
(AChRs) at neuromuscular junctions due to an
antibody-mediated autoimmune attack.
•
• Preferable name: Autoimmune myasthenia
Preferable name: Autoimmune myasthenia
• Treatment now available for MG is highly
effective, although a specific cure has
remained elusive
Harrison 2001

Myasthenia Gravis: Epidemiology
•
• In the USA, the prevalence is 14.2 cases/1
In the USA, the prevalence is 14.2 cases/1
million people
million people
•
• Appear at any age
Appear at any age
•
• In women, the onset between 20 and 40 years
In women, the onset between 20 and 40 years
of age
of age
•
• Among men, at 40
Among men, at 40-
-60
60
• Overall, women are affected more frequently
than men, in a ratio of approximately 3:2.
•
• Familial occurrence is rare
Familial occurrence is rare
JOAO 2004

•
• Annual incidence: 0.25
Annual incidence: 0.25-
-2/100,000
2/100,000
•
• Spontaneous remission: 20%
Spontaneous remission: 20%
•
• Without treatment, 20
Without treatment, 20-
-30% die in 10
30% die in 10
years
years
•
• MG is a heterogeneous disorder
MG is a heterogeneous disorder
–
– 90% no specific cause
90% no specific cause
•
• Genetic predisposing factor: HLA association;
Genetic predisposing factor: HLA association;
HLA
HLA-
-BW46 in
BW46 in chinese
chinese ocular MG
ocular MG
–
– Thymic
Thymic tumor: 10%
tumor: 10%
Lancet 2001

Myasthenia Gravis:
Myasthenia Gravis: Pathophysiology
Pathophysiology
NEJM 1994; Neurologic clinics 1994; BJA 2002; JOAO 2004
• Autoimmune response mediated by
specific anti-AChR antibodies
• Pathogenic antibodies are IgG and are T
cell dependent, Sensitized T
Sensitized T-
-helper cells
helper cells
• Autoimmune response, the thymus
appears to play a role
• 75%: thymus abnormal
– 65%: hyperplasia
– 10%: thymoma, rarely in children; often
rarely in children; often
(20%) in patients aged 30
(20%) in patients aged 30-
-40 years
40 years

Myasthenia Gravis:
Pathophysiology
–
– Postsynaptic nicotinic
Postsynaptic nicotinic
acetylcholine receptor:
acetylcholine receptor:
reduce the number of
reduce the number of
functional receptors
functional receptors
•
• loss of structural
loss of structural
integrity of receptors:
integrity of receptors:
by
by Ab
Ab and complement
and complement
–
– Morphologic changes
Morphologic changes
of simplification of
of simplification of
the pattern of
the pattern of
postsynaptic
postsynaptic
membrane folding;
membrane folding;
–
– An increased gap
An increased gap
between the nerve
between the nerve
terminal and the
terminal and the
post synaptic muscle
post synaptic muscle
membrane
membrane
•
• Blockade
Blockade
•
• ⇑
⇑ Turnover of
Turnover of AchRs
AchRs:
:
Accelerated
Accelerated
degradation of
degradation of
acetylcholine
acetylcholine
receptors
receptors
NEJM 1994, 1997; Neurologic clinics 1997; BJA 2002; JOAO 2004

Myasthenia Gravis:
Pathophysiology
NEJM 1994; BJA 2002
•
• Reduced
Reduced AchR
AchR density
density
–
– results in end
results in end-
-plate potentials of
plate potentials of
diminished amplitude which fail to
diminished amplitude which fail to
trigger action potentials in some fibers
trigger action potentials in some fibers
causing a failure in initiation of muscle
causing a failure in initiation of muscle
fibre
fibre contraction
contraction –
– power of the whole
power of the whole
muscle is reduced
muscle is reduced
•
• The amount of
The amount of ACh
ACh released per
released per
impulse normally declines on
impulse normally declines on
repeated activity (termed
repeated activity (termed
presynaptic
presynaptic rundown)
rundown)

Myasthenia Gravis: Clinical Features
–
– Fluctuating weakness of voluntary
Fluctuating weakness of voluntary
muscles (fatigability)
muscles (fatigability)
•
• Worsen after exertion and improve with
Worsen after exertion and improve with
rest
rest
–
– No abnormality of cognition, sensory
No abnormality of cognition, sensory
function, or autonomic function
function, or autonomic function
JOAO 2004

•
• Initial symptoms involve the ocular
Initial symptoms involve the ocular
muscles in 60%
muscles in 60%
•
• All patients will have ocular involvement
All patients will have ocular involvement
within 2 years of disease onset
within 2 years of disease onset
JOAO 2004

•
• Ocular manifestations
Ocular manifestations
–
– Ptosis
Ptosis,
, uni
uni-
- or bilateral is very common and
or bilateral is very common and
may occur while patients reading, or during
may occur while patients reading, or during
long period of driving
long period of driving
JOAO 2004

Ptosis and impaired orbicularis oculi

•
• Ocular manifestations
Ocular manifestations
–
– Diplopia
Diplopia:
: Extraocular
Extraocular muscle weakness may
muscle weakness may
also present asymmetrically
also present asymmetrically
JOAO 2004

•
• Bulbar involvements
Bulbar involvements
–
– Difficulty chewing, speaking, or swallowing:
Difficulty chewing, speaking, or swallowing:
initial symptoms in 17% of patients
initial symptoms in 17% of patients
•
• Fatigability and weakness during mastication
Fatigability and weakness during mastication
•
• Unable to keep jaw closed after chewing
Unable to keep jaw closed after chewing
•
• Slurred and nasal speech
Slurred and nasal speech
Neurologic clinics 1997; JOAO 2004

•
• Limb muscles weakness:
Limb muscles weakness:
–
– Initial symptoms in fewer than 10%
Initial symptoms in fewer than 10%
–
– Upper extremities weakness is more
Upper extremities weakness is more
common than lower extremities,
common than lower extremities,
asymmetrical
asymmetrical
–
– Involve proximal muscles than distal
Involve proximal muscles than distal
–
– Involve neck muscles: neck flexion weaker
Involve neck muscles: neck flexion weaker
than neck extension
than neck extension

•
• Respiratory insufficiency
Respiratory insufficiency
–
– The initial presentation is rare
The initial presentation is rare
–
– Occurring precipitously in a patient with
Occurring precipitously in a patient with
recent worsening of symptoms
recent worsening of symptoms
Neurologic clinics 1997

Myasthenia Gravis:
Myasthenia Gravis:
•
• Precipitating events
Precipitating events
–
– Systemic illness
Systemic illness
–
– Viral upper respiratory tract infection
Viral upper respiratory tract infection
–
– Receiving general anesthesia
Receiving general anesthesia
–
– Receiving neuromuscular blocking agents
Receiving neuromuscular blocking agents
–
– Pregnancy, menstrual cycle
Pregnancy, menstrual cycle
–
– Extreme heat
Extreme heat
–
– Stress
Stress

Medications induce or exacerbate
MG
MG
•
• Definite association
Definite association
–
– Penicillamine
Penicillamine, corticosteroids
, corticosteroids
•
• Probable association
Probable association
–
– Anticonvulsants
Anticonvulsants (
(phenytoin
phenytoin)
);
;
–
– Anti
Anti-
-infectives
infectives (
(aminiglycosides
aminiglycosides,
,
ciprofloxacin)
ciprofloxacin);
;
–
– Beta
Beta-
-adrenergic receptor
adrenergic receptor-
-blocking drugs;
blocking drugs;
–
– Lithium carbonate;
Lithium carbonate;
–
– Procainamide
Procainamide HCl
HCl
Archives of Internal Med 1997

MG
MG
•
• Possible association
Possible association
–
– Anticholinergic
Anticholinergic drugs
drugs (
(artane
artane)
);
;
–
– Anti
Anti-
-infectives
infectives (
(ampicillin
ampicillin,
, imipenem
imipenem, erythromycin,
, erythromycin,
pyrantel
pyrantel)
);
;
–
– Cardiovascular drugs
Cardiovascular drugs (
(propafenone
propafenone HCl
HCl,
, verapamil
verapamil)
);
;
–
– Cholroquine
Cholroquine phosphate;
phosphate;
–
– Neuromuscular
Neuromuscular-
-blocking drugs
blocking drugs (
(vecuronium
vecuronium,
,
succinylcholine
succinylcholine)
);
;
–
– Ocular drugs
Ocular drugs (
(proparacaine
proparacaine HCl
HCl,
, tropicamide
tropicamide)
);
;
–
– Miscellaneous drugs
Miscellaneous drugs (
(acetazolamide
acetazolamide,
, carnitine
carnitine,
,
interferon
interferon alfa
alfa,
, trandermal
trandermal nicotine)
nicotine)
Archives of Internal Med 1997

MG: Classification
MG: Classification
•
• Osserman
Osserman Classification
Classification
Grade I: involve focal disease (restricted to
Grade I: involve focal disease (restricted to
ocular muscle)
ocular muscle)
Grade II: generalized disease
Grade II: generalized disease
IIa
IIa: mild
: mild
IIb
IIb: moderate
: moderate
Grade III: severe generalized disease
Grade III: severe generalized disease
Grade IV: a crisis with life
Grade IV: a crisis with life-
-threatening
threatening
impairment of respiration
impairment of respiration
NEJM 1994

MG: Classification
MG: Classification
•
• MG Foundation of America Clinical
MG Foundation of America Clinical
Classification
Classification
Grade I: Any ocular muscle weakness
Grade I: Any ocular muscle weakness
Grade II: Mild weakness affecting other than ocular
Grade II: Mild weakness affecting other than ocular
muscles
muscles
IIa
IIa: limb and/or axial weakness; less
: limb and/or axial weakness; less oropharyngeal
oropharyngeal
involvement
involvement
IIb
IIb:
: oropharyngeal
oropharyngeal and/or respiratory weakness
and/or respiratory weakness
Grade III: Moderate weakness affecting other than
Grade III: Moderate weakness affecting other than
ocular muscles (
ocular muscles (a,b
a,b)
)
Grade IV: Severe weakness affecting other than
Grade IV: Severe weakness affecting other than
ocular muscles (
ocular muscles (a,b
a,b)
)
Grade V: Defined by tracheal
Grade V: Defined by tracheal intubation
intubation
BMC musculoskeletal disorders 2004

•
• Clinical course
Clinical course
–
– Most progress if no treatment
Most progress if no treatment
–
– 66%: maximum weakness during the first
66%: maximum weakness during the first
year
year
–
– Spontaneous improvement occurs early in
Spontaneous improvement occurs early in
the course
the course
–
– Ocular type
Ocular type
•
• 66% develop generalized disease in one year
66% develop generalized disease in one year
•
• 14% not progress after 2 years
14% not progress after 2 years

•
• Clinical course
Clinical course
–
– Active stage (5
Active stage (5-
-7 y)
7 y): fluctuation and
: fluctuation and
progression for several years:
progression for several years: thymectomy
thymectomy
benefit
benefit
–
– Inactive stage (10 y)
Inactive stage (10 y) : fluctuation while
: fluctuation while
intercurrent
intercurrent illness or other identifiable
illness or other identifiable
factors (drugs, pregnancy):
factors (drugs, pregnancy): thymectomy
thymectomy no
no
benefit
benefit
–
– Burnt
Burnt-
-out stage
out stage: after 15
: after 15-
-20 years; fixed
20 years; fixed
weakness with atrophic muscles
weakness with atrophic muscles

Myasthenia Gravis: Diagnosis
•
• Clinical manifestations: chronic
Clinical manifestations: chronic
intermittent muscle weakness;
intermittent muscle weakness;
fatigability
fatigability
•
• Provocative test:
Provocative test:
–
– Physiologic:
Physiologic:
•
• Look up for several minutes; counting aloud to
Look up for several minutes; counting aloud to
100; repetitively testing the proximal muscles
100; repetitively testing the proximal muscles
–
– Pharmacologic:
Pharmacologic:
•
• Curare test: to demonstrate generalized MG
Curare test: to demonstrate generalized MG
(
(Neurologic clinics 1994)
JOAO 2004

Enhanced
Enhanced ptosis
ptosis

•
• Pharmacological tests
Pharmacological tests

•
• Tensilon
Tensilon test:
test:
–
– Using
Using edrophonium
edrophonium chloride: short acting
chloride: short acting
acetylcholinesterase
acetylcholinesterase inhibitor
inhibitor
–
– 10 mg of
10 mg of edrophonium
edrophonium (0.15
(0.15-
-0.2 mg/kg)
0.2 mg/kg)
used
used
–
– A small test dose (2 mg) iv; after 1 min. no
A small test dose (2 mg) iv; after 1 min. no
improvement and side effect, the
improvement and side effect, the
remainder given slowly
remainder given slowly
–
– The effect of
The effect of edrophonium
edrophonium: in 30 sec. and
: in 30 sec. and
last fewer than 10 min.
last fewer than 10 min.
JOAO 2004

•
• Tensilon
Tensilon test:
test:
–
– Having false positive (LEMS, MND, MS,
Having false positive (LEMS, MND, MS,
tumor, DM cranial neuropathy,
tumor, DM cranial neuropathy,
mitochondrial
mitochondrial myopathy
myopathy) and false negative
) and false negative
–
– Side effects: N/V, tearing, salivation,
Side effects: N/V, tearing, salivation,
muscle fasciculation, abdominal cramp,
muscle fasciculation, abdominal cramp,
bronchospasm
bronchospasm,
, bradycardia
bradycardia, cardiac arrest
, cardiac arrest
–
– Cardiac monitoring
Cardiac monitoring
–
– Atropine available: 0.6 mg IV
Atropine available: 0.6 mg IV
JOAO 2004

•
• Neostigmine
Neostigmine test
test
–
– Longer acting
Longer acting
–
– 1.5 mg IM or 0.5 mg IV
1.5 mg IM or 0.5 mg IV
–
– Action begins in 15
Action begins in 15-
-30
30 mins
mins and lasts up to
and lasts up to
3 hours
3 hours

•
• Electrophysiological tests
Electrophysiological tests

•
• Repetitive nerve stimulation
Repetitive nerve stimulation
–
– 3 Hz is used for 60 sec.
3 Hz is used for 60 sec.
–
– A greater than 15% decrement of the
A greater than 15% decrement of the
amplitude of CMAP is considered positive
amplitude of CMAP is considered positive
–
– The yield of the test increases if proximal
The yield of the test increases if proximal
nerves are stimulated
nerves are stimulated
–
– May be abnormal in ALS, peripheral
May be abnormal in ALS, peripheral
neuropathy,
neuropathy, radiculopathy
radiculopathy, MS
, MS
Neurologic clinic 1997; JOAO 2004

•
• SFEMG
SFEMG
–
– Signals are recorded only from muscle
Signals are recorded only from muscle
fibers close to the recording surface of
fibers close to the recording surface of
the needle electrode
the needle electrode
–
– Measure the relative firing (action
Measure the relative firing (action
potentials) of adjacent muscle fibers from
potentials) of adjacent muscle fibers from
the same motor unit during voluntary
the same motor unit during voluntary
activity
activity
–
– The variation (time) in firing between these
The variation (time) in firing between these
firing is called jitter (
firing is called jitter (µ
µsec)
sec)

•
• SFEMG
SFEMG
–
– Normal jitter ranges from 10
Normal jitter ranges from 10-
-50
50 µ
µsec
sec
–
– Increased jitter is seen in MG (100
Increased jitter is seen in MG (100 µ
µsec or
sec or
greater)
greater)
–
– Neuromuscular block occurs as end
Neuromuscular block occurs as end-
-plate
plate
potentials fail to reach adequate threshold
potentials fail to reach adequate threshold
to generate action potential
to generate action potential
–
– Time for end
Time for end-
-plate potential to reach the
plate potential to reach the
threshold for action potential generation is
threshold for action potential generation is
longer
longer

•
• SFEMG
SFEMG
–
– Most sensitive
Most sensitive
–
– Difficult to perform
Difficult to perform
–
– Need experience of the
Need experience of the EMGer
EMGer
INDAPS 2004

•
• SFEMG
SFEMG
–
– May be abnormal (F+) in neuropathies,
May be abnormal (F+) in neuropathies,
mitochondrial
mitochondrial myopathies
myopathies, nerve injury,
, nerve injury,
anterior horn cell disorders
anterior horn cell disorders
–
– May have false negatives in mild affected,
May have false negatives in mild affected,
or on immunosuppressive treatment
or on immunosuppressive treatment

•
• Immunological tests
Immunological tests

•
• Antibody to acetylcholine receptor
Antibody to acetylcholine receptor
–
– Present in almost all patients with
Present in almost all patients with thymoma
thymoma
–
– Absent in ocular type
Absent in ocular type
–
– Absent in 20% of generalized MG
Absent in 20% of generalized MG
JOAO 2004

•
• Sleep test and rest test
Sleep test and rest test
–
– Rest test for ocular (
Rest test for ocular (ptosis
ptosis) type
) type (AAO 2002)
(AAO 2002)

•
• Ice test
Ice test
–
– Muscles in MG function better in a lower
Muscles in MG function better in a lower
temperature
temperature
•
• Decreased
Decreased acetylcholinesterase
acetylcholinesterase activity
activity
•
• Increased depolarizing effect of acetylcholine
Increased depolarizing effect of acetylcholine
at motor endplates
at motor endplates
–
– Applying ice pack on the eyelid during
Applying ice pack on the eyelid during
closing for 2
closing for 2 mins
mins.
.
–
– Positive: lid fissure increases by 2 mm or
Positive: lid fissure increases by 2 mm or
more from baseline
more from baseline (
(Curr
Curr Opin
Opin Neurol
Neurol 2001)
2001)
JOAO 2004

Before ice test After ice test
ice test rest test

Ocular MG
Ocular MG Sensitive
Sensitive
•
• Tensilon
Tensilon test
test 86%
86% (F +) (side effect)
(F +) (side effect)
•
• RNS (EOM)
RNS (EOM) 48%
48% (F+) (invasive)
(F+) (invasive)
•
• AchR
AchR-
-Ab
Ab:
: 45
45-
-65%
65% (rare F +) (expensive)
(rare F +) (expensive)
•
• SFEMG (gold standard)
SFEMG (gold standard) 95%
95% (F +) (pain)
(F +) (pain)
(
(orbicularis
orbicularis oculi
oculi and
and frontalis
frontalis)
)
•
• Sleep test
Sleep test simple and safe but takes time (30
simple and safe but takes time (30 mins
mins.) and place
.) and place
•
• Rest test
Rest test 50% no F+
50% no F+ (AAO 2000)
(AAO 2000)
•
• Ice test for
Ice test for ptosis
ptosis:
: 95% no
95% no F+
F+(Curr
(Curr Opin
Opin Neurol
Neurol 2001)
2001)
Neurologic clinics 1997; J med Assoc Thai 2001; JOAO 2004

Generalized MG
Generalized MG Sensitive
Sensitive
•
• Tensilon
Tensilon test
test 95
95
•
• RNS
RNS higher than in ocular MG (F+)
higher than in ocular MG (F+)
•
• AchR
AchR-
-Ab
Ab:
: 90%
90% (rare F +)
(rare F +)
•
• SFEMG
SFEMG 100%
100% (F +)
(F +)
JOAO 2004

Myasthenia Gravis: Differential
Diagnosis
Diagnosis
•
• From generalized MG
From generalized MG
–
– ALS: Asymmetric muscle weakness and atrophy
ALS: Asymmetric muscle weakness and atrophy
–
– Other NMJ disorders
Other NMJ disorders
•
• Lambert Eaton
Lambert Eaton myasthenic
myasthenic syndrome
syndrome
•
• Congenital
Congenital myasthenic
myasthenic syndrome
syndrome
•
• Neurotoxins
Neurotoxins
–
– Botulism: Generalized limb weakness
Botulism: Generalized limb weakness
–
– Venoms: snakes, scorpions, spiders
Venoms: snakes, scorpions, spiders
–
– Inflammatory
Inflammatory demyelinating
demyelinating diseases
diseases
•
• GBS: ascending limb weakness
GBS: ascending limb weakness
•
• Miller Fisher syndrome
Miller Fisher syndrome
•
• Chronic
Chronic
–
– Inflammatory muscle disorders: Painful proximal
Inflammatory muscle disorders: Painful proximal
symmetric limb weakness; no ocular involvement
symmetric limb weakness; no ocular involvement
–
– Periodic paralysis: Intermittent generalized muscle
Periodic paralysis: Intermittent generalized muscle
weakness; no ocular involvement
weakness; no ocular involvement JOAO 2004

Diagnosis
Diagnosis
•
• From Bulbar Myasthenia
From Bulbar Myasthenia
–
– Brainstem stroke
Brainstem stroke
–
– Pseudobulbar
Pseudobulbar palsy
palsy
•
• From Ocular Myasthenia
From Ocular Myasthenia
–
– MS: UMN; bilateral
MS: UMN; bilateral internuclear
internuclear ophthalmoplegia
ophthalmoplegia
–
– Mitochondrial
Mitochondrial cytopathy
cytopathy (chronic progressive
(chronic progressive
external
external ophthalmoplegia
ophthalmoplegia)
)
–
– Oculopharyngeal
Oculopharyngeal muscular dystrophy
muscular dystrophy
–
– Thyroid
Thyroid ophthalmopathy
ophthalmopathy
JOAO 2004

Myasthenia Gravis
Myasthenia Gravis
•
• Management
Management
–
– Diagnosis
Diagnosis
–
– Searching for associated diseases
Searching for associated diseases
–
– Treatments
Treatments
–
– Avoiding and treating precipitating
Avoiding and treating precipitating
factors
factors

Myasthenia Gravis:
Myasthenia Gravis:
•
• Associated diseases
Associated diseases
–
– Thymoma
Thymoma
–
– Nonthymus
Nonthymus neoplasm in 3%
neoplasm in 3%
–
– DM in 7%
DM in 7%
–
– Thyroid disease in 6%
Thyroid disease in 6%
–
– Rheumatoid arthritis in fewer than 2%
Rheumatoid arthritis in fewer than 2%
–
– Pernicious anemia,
Pernicious anemia, pancytopenia
pancytopenia,
,
thrombocytopenia and SLE in fewer than
thrombocytopenia and SLE in fewer than
1%
1%
–
– Polymyositis
Polymyositis,
, dermatomyositis
dermatomyositis, psoriasis,
, psoriasis,
scleroderma
scleroderma (BJA 2002)
(BJA 2002)

Myasthenia Gravis: Treatment
•
• The goal is to achieve remission
The goal is to achieve remission
–
– Symptoms free and taking no medication
Symptoms free and taking no medication
•
• By increased neuromuscular transmission
By increased neuromuscular transmission
•
• Reduce autoimmunity
Reduce autoimmunity
•
• Others: having a normal quality of life
Others: having a normal quality of life
even if some signs remaining and
even if some signs remaining and
cholinesterase inhibitors taking
cholinesterase inhibitors taking
JOAO 2004

•
• No single treatment is ideal for all
No single treatment is ideal for all
patients
patients
–
– Each patient needs an individual plan
Each patient needs an individual plan
–
– Treatment may have to be changed time
Treatment may have to be changed time
to time
to time
•
• Obtain the best response while keeping
Obtain the best response while keeping
the risk and side effects as low as
the risk and side effects as low as
possible
possible

Ocular MG
15% never spread out (Neurologic clinics 1994)
Spontaneous remission (JOAO 2004)
Good response to pyridostigmine
If spread out, in 2 y - thymectomy
If not response to pyridostigmine
Add prednisolone: 10-30 mg/d for 2-3
months or incrementing dose; after
maximum benefit slow tapering
If not effective, getting along with
dysfunction; maneuvers and simple
mechanical devices used
Or high-dose daily prednisolone +
azathioprine or even thymectomy
If ptosis is fixed; surgical shortening of
the eyelid to be considered (JOAO 2004;
Neurologic clinics 1994)
Harrison 2001

Generalized MG
No bulbar involvement: remission
No bulbar involvement: remission
Thymectomy
Thymectomy: Indications
: Indications
-
- Thymoma
Thymoma
-
- Those are medically stable and aged
Those are medically stable and aged
60 years or younger (puberty)
60 years or younger (puberty)
(
(Neurologic clinics 1994; NEJM 1994)
35% have clinical remission; 50%:
35% have clinical remission; 50%:
improvement
improvement (
(Neurologic clinics 1994; NEJM 1994)
Clinical improvement in 6
Clinical improvement in 6-
-12 m. after
12 m. after
(
(JOAO 2004)
1
1-
-2 years after surgery,
2 years after surgery,
immunosuppressive therapy to be
immunosuppressive therapy to be
considered if functional limitations
considered if functional limitations
(
(Neurologic clinics 1994)
)
Harrison 2001

•
• Generalized MG with onset in
Generalized MG with onset in
childhood
childhood
–
– More benign than in adult; less associated
More benign than in adult; less associated
with
with thymoma
thymoma, and remit spontaneously
, and remit spontaneously
–
– ChE
ChE inhibitors only apply otherwise
inhibitors only apply otherwise
disabling signs exist, steroid will be
disabling signs exist, steroid will be
recommended
recommended
–
– Thymectomy
Thymectomy if not respond to
if not respond to
prednisolone
prednisolone

•
• Generalized MG with late
Generalized MG with late-
-life onset
life onset
–
– Less likely to improve after
Less likely to improve after thymectomy
thymectomy
–
– Surgery carries greater risk
Surgery carries greater risk
–
– Treatment with
Treatment with ChE
ChE inhibitors
inhibitors
–
– Severe cases worth to use
Severe cases worth to use prednisolone
prednisolone
and
and azathioprine
azathioprine

Myasthenic crisis
Sudden worsening of respiratory function
Sudden worsening of respiratory function
+
+ profound muscle weakness
profound muscle weakness
-
- Negative
Negative inspiratory
inspiratory force of less than
force of less than -
-20
20
cmH
cmH2
2O
O
-
- Tidal volume of less than 4mL/kg
Tidal volume of less than 4mL/kg
-
- Force vital capacity < 15
Force vital capacity < 15 mL
mL/kg (normal 50
/kg (normal 50-
-
60 in female, 70 in male)
60 in female, 70 in male)
Neurologic
Neurologic emergency
emergency
Causes: concurrent infection,
medications, drug withdrawal
medications, drug withdrawal (
(JOAO 2004)
)
DDx
DDx from cholinergic crisis: clinical and
from cholinergic crisis: clinical and
tensilon
tensilon test
test
Management
Management
-
-Stop every medications
Stop every medications
-
-Assisted ventilation
Assisted ventilation
-
-Treating
Treating ppf
ppf.
.
-
-If not improve
If not improve
-
-IVIg
IVIg or
or plasmapheresis
plasmapheresis (
(JOAO 2004)
) Harrison 2001

•
• Acetylcholinesterase
Acetylcholinesterase inhibitors
inhibitors
–
– Symptomatic improvement for a period of
Symptomatic improvement for a period of
time
time
–
– Initial therapy
Initial therapy
–
– Onset in 30
Onset in 30 mins
mins.
.
–
– Peak effect at 2 hrs.
Peak effect at 2 hrs.
–
– Half life approximately 4 hrs.
Half life approximately 4 hrs.
–
– Lower risks and side effects than others:
Lower risks and side effects than others:
abdominal cramping,
abdominal cramping, n/v
n/v increased
increased
salivation, and diarrhea
salivation, and diarrhea
NEJM 1994; Neurologic clinics 1997

•
inhibitors
–
– Benefit most patients but incomplete
Benefit most patients but incomplete
after weeks or months treatment; require
after weeks or months treatment; require
further therapeutic measures
further therapeutic measures
–
– No fixed dosage schedule suits all
No fixed dosage schedule suits all
patients
patients
–
– The need for
The need for ChE
ChE inhibitors varies from
inhibitors varies from
day
day-
-to
to-
-day and during the same day
day and during the same day
–
– A sustained
A sustained-
-release preparation used only
release preparation used only
at bedtime
at bedtime
NEJM 1994; Neurologic clinics 1997

•
inhibitors
–
– Pyridostigmine
Pyridostigmine bromide is used
bromide is used
•
• Starting with 30 mg every 4 to 6 hours;
Starting with 30 mg every 4 to 6 hours;
titrated depending on clinical symptoms and
titrated depending on clinical symptoms and
patient tolerability
patient tolerability
•
• Cholinergic crisis if too much of this
Cholinergic crisis if too much of this
medication (max. Dose = 450 mg/d)
medication (max. Dose = 450 mg/d)
•
• Lowest amount with maximum benefit
Lowest amount with maximum benefit
•
• 30 minutes before eating for patients with
30 minutes before eating for patients with
oropharyngeal
oropharyngeal weakness
weakness
60 mg pyridostigmine = 15 mg neostigmine
Dose im form (2 ml = 5 mg) = 1/30 of oral dose

•
• Immunosuppressive therapy
Immunosuppressive therapy
–
– Indications
Indications
•
• Not adequately controlled by
Not adequately controlled by
anticholinesterase
anticholinesterase drugs and
drugs and sufficently
sufficently
distressing to outweigh the risks of
distressing to outweigh the risks of
possible side effects of
possible side effects of
immunosuppressive drugs in ocular MG
immunosuppressive drugs in ocular MG
•
• Severe but not ready to have surgery
Severe but not ready to have surgery
•
• Not improve after
Not improve after thymectomy
thymectomy: may
: may
delay 3 y after surgery
delay 3 y after surgery
•
• Crisis not respond to plasma exchange or
Crisis not respond to plasma exchange or
IVIg
IVIg
•
• In inactive and burnt
In inactive and burnt-
-out stage
out stage
NEJM 1994

•
–
– Steroid: reduce
Steroid: reduce AchR
AchR-
-Ab
Ab titer
titer
•
• Most use
Most use
•
• Typical dosage is 1 mg/kg daily as a single
Typical dosage is 1 mg/kg daily as a single
oral dose
oral dose
JOAO 2004

•
–
– Steroid:
Steroid:
•
• Start on a low dose and gradually titrate the
Start on a low dose and gradually titrate the
dose up
dose up
–
– 5 mg daily and increased by 5 mg every 4
5 mg daily and increased by 5 mg every 4-
-7 days until
7 days until
clinical benefit achievement;
clinical benefit achievement;
–
– Remain on this dose for 2 mo.
Remain on this dose for 2 mo.
–
– Then, switch to alternate
Then, switch to alternate-
-day therapy
day therapy
–
– Once, the condition stable,
Once, the condition stable, taperd
taperd downward by 5 mg
downward by 5 mg
every month
every month
–
– Patients may relapse after tapered off
Patients may relapse after tapered off
–
– Most patients require long
Most patients require long-
-term low
term low-
-dose
dose
JOAO 2004

•
–
– Steroid:
Steroid:
–
– Have benefit in 6 to 8 weeks after initiation
Have benefit in 6 to 8 weeks after initiation
–
– Adverse effects: acne, bruising, cataracts,
Adverse effects: acne, bruising, cataracts,
electrolyte imbalance,
electrolyte imbalance, hirsutism
hirsutism, hyperglycemia, HT,
, hyperglycemia, HT,
avascular
avascular necrosis of the femoral head, obesity,
necrosis of the femoral head, obesity,
osteoporosis,
osteoporosis, myopathy
myopathy
•
• High
High-
-dose daily
dose daily prednisolone
prednisolone (60
(60-
-80 mg;
80 mg; 1
1-
-1.5
1.5
mg/kg/d
mg/kg/d)
)
–
– Rapid improvement
Rapid improvement
–
– Institution in the first 2
Institution in the first 2-
-3 weeks
3 weeks
–
– Exacerbation of weakness managed by
Exacerbation of weakness managed by ChE
ChE-
-inhibitors
inhibitors
or
or plasmapheresis
plasmapheresis
JOAO 2004

•
–
– Azathioprine
Azathioprine:
:
•
• Most use
Most use
•
• To reduce adverse steroid effects
To reduce adverse steroid effects
•
• To whom steroids are contraindicated
To whom steroids are contraindicated
•
• Starting dose is 50 mg daily for the first week,
Starting dose is 50 mg daily for the first week,
then increased 50 mg every week
then increased 50 mg every week
•
• Titrating up to a maximum of 2
Titrating up to a maximum of 2-
-3 mg/kg/d in
3 mg/kg/d in
two or three divided doses
two or three divided doses
NEJM 1994; JOAO 2004

•
–
– Azathioprine
Azathioprine:
:
•
• Clinical benefit shown in 4
Clinical benefit shown in 4-
-6 months or longer
6 months or longer
(max effect 12
(max effect 12-
-24 mos.)
24 mos.)
•
• Once improvement; maintain as long as 4
Once improvement; maintain as long as 4-
-6 mos.
6 mos.
•
• Adverse effects:
Adverse effects: neutropenia
neutropenia,
, hepatotoxicity
hepatotoxicity;
;
increase risk of malignancy; idiosyncratic
increase risk of malignancy; idiosyncratic
influenza
influenza-
-like reaction
like reaction

•
• Plasmapheresis
Plasmapheresis (plasma exchange)
(plasma exchange)
and
and IVIg
IVIg: Indications
: Indications
–
– Severe MG and exacerbations
Severe MG and exacerbations
–
– Preparing for
Preparing for thymectomy
thymectomy or post
or post
operative period
operative period
–
– Covering period before
Covering period before
immunosuppressive therapy becomes
immunosuppressive therapy becomes
fully active
fully active
INDAPS 2004

•
• Plasmapheresis
Plasmapheresis (plasma exchange):
(plasma exchange):
double filtration plasma exchange and
double filtration plasma exchange and
immunoadsorption
immunoadsorption plasmaphoresis
plasmaphoresis
–
– Undergoing a 2
Undergoing a 2-
-week course of 5
week course of 5-
-6
6
exchanges (1 plasma volume = 40
exchanges (1 plasma volume = 40-
-50 ml/kg;
50 ml/kg;
2
2-
-3 liters each)
3 liters each)
–
– Effective but transient in its response:
Effective but transient in its response:
Improvement in the third exchange and
Improvement in the third exchange and
lasts 6
lasts 6-
-8 weeks
8 weeks
–
– To remove the circulating immune
To remove the circulating immune
complexes and
complexes and AchR
AchR-
-Ab
Ab
NEJM 1994; Neurologic clinics 1997; JOAO 2004

•
• Plasmapheresis
Plasmapheresis (plasma exchange):
(plasma exchange):
–
– Limitation: too small or fragile venous
Limitation: too small or fragile venous
access
access
–
– Complications (catheters):
Complications (catheters): pneumothorax
pneumothorax,
,
bleeding, sepsis,
bleeding, sepsis,
–
– Adverse effects: hypotension,
Adverse effects: hypotension,
hypercoagulation
hypercoagulation,
, hypoalbuminemia
hypoalbuminemia,
,
hypocalcemia
hypocalcemia, pulmonary embolism,
, pulmonary embolism,
arrhythmia, (frequent exchanges) anemia,
arrhythmia, (frequent exchanges) anemia,
low platelets
low platelets

•
• IVIg
IVIg therapy
therapy
–
– Dose: 2 g/kg over 2
Dose: 2 g/kg over 2-
-5 days
5 days
–
– Clinical improvement in 1
Clinical improvement in 1-
-2 weeks and lasts
2 weeks and lasts
weeks to months
weeks to months

•
• IVIg
IVIg: Side effect profile(some product
: Side effect profile(some product
contain
contain IgA
IgA)
)
–
– Allergic
Allergic response:low
response:low grade fever, chills,
grade fever, chills,
myalgia
myalgia
–
– Diaphoresis, fluid overload, HT
Diaphoresis, fluid overload, HT
–
– Nausea, vomiting, rash,
Nausea, vomiting, rash, neutropenia
neutropenia
–
– Headache, aseptic meningitis
Headache, aseptic meningitis
–
– Hyperviscosity
Hyperviscosity: stroke, MI, ATN (most
: stroke, MI, ATN (most
serious with
serious with compromized
compromized renal
renal glomerular
glomerular
filtration; DM)
filtration; DM)

•
• IVIg
IVIg: Side effect profile
: Side effect profile
–
– Anaphylactic reaction: with
Anaphylactic reaction: with IgA
IgA deficiency
deficiency
–
– Transmission with (very low)
Transmission with (very low)
•
• Hepatitis
Hepatitis
•
• HIV
HIV

•
• Surgical intervention
Surgical intervention
–
– Thymectomy
Thymectomy
•
• Acetylcholine
Acetylcholine-
-receptor antibody levels fall
receptor antibody levels fall
after
after thymectomy
thymectomy
•
• Mechanisms
Mechanisms
–
– Eliminate a source of continued antigenic stimulation
Eliminate a source of continued antigenic stimulation
–
– Subside immune response
Subside immune response
–
– Correct a disturbance of immune regulation
Correct a disturbance of immune regulation
NEJM 1994

•
• Surgical intervention
Surgical intervention
–
– Thymectomy
Thymectomy
•
• Not recommended in
Not recommended in
–
– Patients with purely ocular MG
Patients with purely ocular MG
–
– Childhood, some do not recommended because of less
Childhood, some do not recommended because of less
severity than in adults and common remission
severity than in adults and common remission
spontaneously
spontaneously
–
– Late
Late-
-onset
onset
Neurologic clinics 1994; NEJM 1994

•
• Future treatment
Future treatment
–
– B
B-
-cell
cell-
-directed approaches
directed approaches
•
• B
B-
-cells produce pathogenic antibodies
cells produce pathogenic antibodies
–
– T
T-
-cell
cell-
-directed approaches
directed approaches
•
• Pivotal role in autoimmune antibody
Pivotal role in autoimmune antibody
response
response
NEJM 1994

Preparation for
Preparation for thymectomy
thymectomy

Preparation for
thymectomy
•
• No emergency performance of
No emergency performance of
thymectomy
thymectomy
•
• Preoperative preparation
Preoperative preparation
–
– Optimized strength and respiratory
Optimized strength and respiratory
function
function
–
– Avoided immunosuppressive agents (risk of
Avoided immunosuppressive agents (risk of
infection)
infection)
–
– If VC < 2 liters,
If VC < 2 liters, plasmapheresis
plasmapheresis carried out
carried out
NEJM 1994

Preparation for
thymectomy
•
• Postoperative management
Postoperative management
–
– May have weakness
May have weakness
•
• Pain
Pain
•
• Myasthenic
Myasthenic crisis:
crisis: ChE
ChE-
-Is withdrawal
Is withdrawal
•
• Cholinergic crisis: disease improvement
Cholinergic crisis: disease improvement
•
• May test with
May test with tensilon
tensilon
–
– ChE
ChE inhibitors may be reduced for a few
inhibitors may be reduced for a few
days after
days after thymectomy
thymectomy
–
– Postoperative
Postoperative ChE
ChE medication given IV at a
medication given IV at a
dose of
dose of ¾
¾ of the preoperative requirement
of the preoperative requirement
NEJM 1994

Anaesthetic
Anaesthetic management in MG
management in MG

Anaesthetic
management in MG
•
• Local and regional
Local and regional anaesthesia
anaesthesia should be
should be
employed
employed
•
• GA requires meticulous pre and
GA requires meticulous pre and
perioperative
perioperative care
care
BJA 2002

Anaesthetic
management in MG
•
• Preoperative consideration: major
Preoperative consideration: major
elective surgical procedures
–
– Admitted 48 hrs prior to surgery
Admitted 48 hrs prior to surgery
–
– Assessment and monitoring of respiratory
Assessment and monitoring of respiratory
(FVC) and bulbar function
(FVC) and bulbar function
–
– Adjustment of
Adjustment of ChE
ChE inhibitors and steroid if
inhibitors and steroid if
indicated
indicated
–
– Chest physiotherapy started
Chest physiotherapy started
–
– Plasma exchange or
Plasma exchange or IvIg
IvIg if necessary
if necessary
BJA 2002

Anaesthetic
management in MG
•
• Preoperative consideration: major
Preoperative consideration: major
–
– Sedative medications save if no respiratory
Sedative medications save if no respiratory
comprimise
comprimise
–
– Antimuscarinic
Antimuscarinic agents helpful in reducing
agents helpful in reducing
secretions
secretions
–
– Steroid continued pre
Steroid continued pre-
-operatively
operatively
–
– Hydrocortisone administered on the day of
Hydrocortisone administered on the day of
surgery
surgery
–
– ChE
ChE inhibitors withheld on the morning of
inhibitors withheld on the morning of
surgery
surgery
BJA 2002

Anaesthetic
management in MG
•
• Induction and maintenance of
Induction and maintenance of
anaesthesia
anaesthesia
–
– Routine monitoring
Routine monitoring
–
– Supplement with invasive blood pressure
Supplement with invasive blood pressure
measurement
measurement
–
– Nasotracheal
Nasotracheal tube is
tube is prefered
prefered
–
– Patients more sensitive to neuromuscular
Patients more sensitive to neuromuscular
blocking agents
blocking agents
BJA 2002

Anaesthetic
management in MG
•
• Postoperative management
Postoperative management
–
– Nursed in a high dependency area and
Nursed in a high dependency area and
adequate analgesia provided: NSAID and
adequate analgesia provided: NSAID and
parenteral
parenteral opioids
opioids
–
– ChE
ChE inhibitors restarted at a reduce dose
inhibitors restarted at a reduce dose
in the immediate post
in the immediate post-
-operative period and
operative period and
increasing if necessary
increasing if necessary
BJA 2002

Seronegative
Seronegative MG
MG

Seronegative
Seronegative MG
MG
•
• Found in approximately 15% of patients
Found in approximately 15% of patients
with generalized MG
with generalized MG
•
• Clinically indistinguishable from
Clinically indistinguishable from AchR
AchR-
-
Ab
Ab-
-positive
positive patients
patients
•
• Be diagnosed using SFEMG
Be diagnosed using SFEMG
•
• 70% of SNMG patients have
70% of SNMG patients have Ab
Ab to the
to the
muscle
muscle-
-specific receptor tyrosine
specific receptor tyrosine kinase
kinase
(
(MuSK
MuSK)
)
Curr Opin Neurol 2001

Thymoma
Thymoma-
-associated MG
associated MG
•
• Muscle antibodies predict the presence
Muscle antibodies predict the presence
of
of thymoma
thymoma
Sens
Sens. Spec.
. Spec.
–
– Ryanodine
Ryanodine receptor
receptor Ab
Ab 70%
70%
–
– Titin
Titin Ab
Ab 95%
95%
–
– Both
Both 70%
70% 70%
70%
Curr Opin Neurol 2001

Late
Late-
-onset MG
onset MG
•
• Onset after the age of 50
Onset after the age of 50
•
• Male = female
Male = female
•
• Most are
Most are nonthymoma
nonthymoma
•
• More severe than early
More severe than early-
-onset MG
onset MG
•
• Having circulating
Having circulating Ab
Ab to
to AchR
AchR but lower
but lower
conc. than in early
conc. than in early-
-onset MG
onset MG
•
• Titin
Titin Ab
Ab associates with severity
associates with severity
•
• Difficulty in treatment
Difficulty in treatment
Archives of Neurol 1999

Late
Late-
-onset MG
onset MG
•
• Difficulty in treatment
Difficulty in treatment
–
– Temporary response to
Temporary response to ChE
ChE-
-inhibitors
inhibitors
–
– Plasma exchange produces more
Plasma exchange produces more
complications
complications
–
– Thymectomy
Thymectomy gives poorer results
gives poorer results
–
– Steroids give many complications
Steroids give many complications
–
– Treatment has to be tailored
Treatment has to be tailored
Archives of Neurol 1999

MG and pregnancy
MG and pregnancy

MG and pregnancy
MG and pregnancy
•
• Pregnancy is associated with physiologic
Pregnancy is associated with physiologic
immunosuppression
immunosuppression: depress leukocyte
: depress leukocyte
function
function
•
• Pregnancy aggravates MG
Pregnancy aggravates MG
•
• So, clinical course unpredictable: rule of
So, clinical course unpredictable: rule of
three
three
•
• One pregnancy not predict the course in
One pregnancy not predict the course in
subsequent pregnancies
subsequent pregnancies
•
• Exacerbation occur equally in all trimesters
Exacerbation occur equally in all trimesters
•
• Therapeutic termination not demonstrate a
Therapeutic termination not demonstrate a
consistent benefit in cases of first trimester
consistent benefit in cases of first trimester
exacerbation
exacerbation

MG and pregnancy
MG and pregnancy
•
• Use
Use minimual
minimual dosage of drugs
dosage of drugs
•
• ChE
ChE-
-inhibitors: in creased uterine contraction
inhibitors: in creased uterine contraction
•
• Avoid other immunosuppressive drugs except
Avoid other immunosuppressive drugs except
steroid
steroid
•
• Normal delivery done
Normal delivery done
•
• No problems in breast feeding
No problems in breast feeding
•
• Transient neonatal myasthenia:
Transient neonatal myasthenia:
–
– Found by 9
Found by 9-
-30%
30%
–
– Good response to
Good response to ChE
ChE-
-inhibitors
inhibitors
–
– Complete recovery in 2
Complete recovery in 2-
-4 mo
4 mo

Myasthenic
Myasthenic crisis
crisis

Myasthenic
Myasthenic crisis
crisis
•
• Rarely at the initial presentation
Rarely at the initial presentation
•
• Known MG may reach a crisis
Known MG may reach a crisis
•
• Defined as sudden worsening of
Defined as sudden worsening of
respiratory function and/or profound
respiratory function and/or profound
muscle weakness
muscle weakness
•
• Being a
Being a neurologic
neurologic emergency
emergency
•
• Causes: concurrent infection,
JOAO 2004

Myasthenic
Myasthenic crisis
crisis
•
• DDx
DDx from cholinergic crisis
from cholinergic crisis
–
– Abdominal pain, diarrhea,
Abdominal pain, diarrhea, hypersecretion
hypersecretion,
,
pinpoint pupil
pinpoint pupil
–
– Negative or worse by
Negative or worse by tensilon
tensilon test
test
•
• Hold
Hold ChE
ChE-
-Is
Is
•
• Atropine 2 mg/hr
Atropine 2 mg/hr
–
– Tensilon
Tensilon test to consider the need of
test to consider the need of ChE
ChE-
-
Is
Is

Myasthenic
Myasthenic crisis
crisis
•
• Management
Management
–
– Stop every medications
Stop every medications
–
– Assisted ventilation
Assisted ventilation
•
• Respiratory support required if
Respiratory support required if
–
– Negative
Negative inspiratory
inspiratory force of less than
force of less than -
-20 cm H
20 cm H2
2O
O
–
– Tidal volume of less than 4mL/kg
Tidal volume of less than 4mL/kg
–
– Force vital capacity < 15
Force vital capacity < 15 mL
mL/kg (normal 50
/kg (normal 50-
-60 [f], 70
60 [f], 70
[m])
[m])
–
– Treating
Treating ppf
ppf.
.
–
– Tensilon
Tensilon test to estimate
test to estimate ChE
ChE-
-Is requirement
Is requirement
–
– If not improve
If not improve
•
• IVIg
IVIg or
or plasmapheresis
plasmapheresis
JOAO 2004

Myasthenia Gravis: Etiology
Myasthenia Gravis: Etiology
•
• Immunopathogenesis
Immunopathogenesis
–
– MG is due to antibody
MG is due to antibody-
-mediated processes
mediated processes
•
• Ab
Ab is present
is present
•
• Ab
Ab interacts with the target antigen,
interacts with the target antigen,
acetylcholine receptor
acetylcholine receptor
•
• Passive transfer reproduces disease feature
Passive transfer reproduces disease feature
•
• Immunization with the antigen produces a model
Immunization with the antigen produces a model
disease
disease
•
• Reduction of antibody levels ameliorates the
Reduction of antibody levels ameliorates the
disease
disease
NEJM 1997

Myasthenia Gravis: Investigation
Myasthenia Gravis: Investigation
•
• For associated diseases
For associated diseases
–
– Autoimmune
Autoimmune thyroiditis
thyroiditis
–
– Grave
Grave’
’s disease
s disease
–
– SLE
SLE
–
– CXR
CXR
–
– CT chest scan: may miss small
CT chest scan: may miss small thymoma
thymoma
nodules
nodules
•
• Rule out genetic MG, Lambert
Rule out genetic MG, Lambert-
-Eaton
Eaton
myasthenic
myasthenic syndrome
syndrome
JOAO 2004

•
• Ocular MG
Ocular MG
–
– Good response to
Good response to pyridostigmine
pyridostigmine
–
– Starting with 30 mg every 4 to 6 hours
Starting with 30 mg every 4 to 6 hours
–
– Titrated depending on clinical symptoms
Titrated depending on clinical symptoms
and patient tolerability
and patient tolerability
–
– Adverse effects: abdominal cramping,
Adverse effects: abdominal cramping,
increased salivation, nausea and diarrhea
increased salivation, nausea and diarrhea
–
– Lowest amount, maximum benefit
Lowest amount, maximum benefit
–
– Usually spontaneous remission
Usually spontaneous remission
JOAO 2004

•
• Ocular MG
Ocular MG
–
– If spread out, will occur in 1
If spread out, will occur in 1-
-2 years
2 years
after onset
after onset
–
– So, closed follow up in the first 2
So, closed follow up in the first 2
years is necessary to detect
years is necessary to detect
weakness early
weakness early –
– thymectomy
thymectomy is
is
recommended
recommended

•
–
– Cyclosporine
Cyclosporine
•
• Inhibits T
Inhibits T-
-cell activation
cell activation
•
• For failure to respond to combination therapy
For failure to respond to combination therapy
with
with prednisolone
prednisolone and
and azathioprine
azathioprine or
or
intolerability of
intolerability of azathioprine
azathioprine
•
• Starting dose: 25 mg twice daily
Starting dose: 25 mg twice daily
•
• Titrating up to 3
Titrating up to 3-
-6 mg/kg/d
6 mg/kg/d

•
–
– Cyclosporine
Cyclosporine
•
• Combination therapy is more efficacious;
Combination therapy is more efficacious;
reduced dosage and fewer adverse effects
reduced dosage and fewer adverse effects
•
• Time to onset of effect: 2
Time to onset of effect: 2-
-12 wk
12 wk
•
• Time to maximal effect: 3
Time to maximal effect: 3-
-6 mo
6 mo
•
• Adverse effects:
Adverse effects: nephrotoxicity
nephrotoxicity, HT
, HT

•
–
– Cyclophosphamide
Cyclophosphamide
•
• Used only others failed or not tolerated
Used only others failed or not tolerated
•
• Starting dose: 25 mg daily
Starting dose: 25 mg daily
•
• Gradually increased up to 2
Gradually increased up to 2-
-5 mg/kg/d
5 mg/kg/d
•
• Adverse effect: hemorrhagic cystitis
Adverse effect: hemorrhagic cystitis
JOAO 2004

•
–
– Mycophenolate
Mycophenolate Mofetil
Mofetil
•
• Novel agent, benefit in transplantation
Novel agent, benefit in transplantation
medicine
medicine
•
• Starting at 250 mg twice daily
Starting at 250 mg twice daily
•
• Standard daily dosage: 1
Standard daily dosage: 1-
-2 g.
2 g.
•
• CBC checked every week for the first
CBC checked every week for the first
month; every two weeks for the next 6
month; every two weeks for the next 6-
-8
8
weeks; and monthly thereafter
weeks; and monthly thereafter
JOAO 2004

•
• Generalized MG with onset in adult life
Generalized MG with onset in adult life
–
– Mild: no symptoms related to breathing,
Mild: no symptoms related to breathing,
coughing and swallowing
coughing and swallowing
•
• ChE
ChE inhibitors
inhibitors
•
• If optimal dosage,
If optimal dosage, thymectomy
thymectomy to be
to be
considered
considered
•
• Or additional
Or additional prednisolone
prednisolone, if no remission in 1
, if no remission in 1
year
year -
- thymectomy
thymectomy
–
– Balbar
Balbar involvement
involvement
•
• ChE
ChE inhibitors + high dose
inhibitors + high dose prednisolone
prednisolone
•
• Thymectomy
Thymectomy to be considered
to be considered

•
• Generalized MG
Generalized MG
–
– Combination with
Combination with pyridostigmine
pyridostigmine and
and
prednisolone
prednisolone
•
• Starting with low dose
Starting with low dose
•
• Starting with high dose: 1
Starting with high dose: 1-
-1.5 mg/kg/d
1.5 mg/kg/d
–
– Patients be worse
Patients be worse
–
– Should be admitted for 2 weeks
Should be admitted for 2 weeks
–
– Clinical benefit in 1
Clinical benefit in 1-
-2 months afterward
2 months afterward
–
– Adverse effects: acne, bruising, cataracts,
Adverse effects: acne, bruising, cataracts,
electrolyte imbalance,
electrolyte imbalance, hirsutism
hirsutism, hyperglycemia, HT,
, hyperglycemia, HT,
avascular
avascular necrosis of the femoral head, obesity,
necrosis of the femoral head, obesity,
osteoporosis,
osteoporosis, myopathy
myopathy
JOAO 2004

•
• Generalized MG with onset in childhood
Generalized MG with onset in childhood
–
– Distiquishing
Distiquishing acquired autoimmune MG from
acquired autoimmune MG from
genetic MG
genetic MG –
– not respond to immunotherapy
not respond to immunotherapy
–
– Seronegative
Seronegative in acquired MG possible
in acquired MG possible
–
– Positive treatment response with plasma
Positive treatment response with plasma
exchange,
exchange, IvIg
IvIg is autoimmune disease; but
is autoimmune disease; but
negative not excluded
negative not excluded
–
– More benign than in adult; less associated with
More benign than in adult; less associated with
thymoma
thymoma, and remit spontaneously
, and remit spontaneously
–
– ChE
ChE inhibitors only apply otherwise disabling
inhibitors only apply otherwise disabling
signs exist, steroid will be recommended
signs exist, steroid will be recommended
–
– Thymectomy
Thymectomy if not respond to
if not respond to prednisolone
prednisolone

•
• Generalized MG
Generalized MG
–
– To reduce adverse steroid effects
To reduce adverse steroid effects
–
– Add with or switch to
Add with or switch to azathioprine
azathioprine
JOAO 2004

•
• Ocular MG
Ocular MG
–
– If not good response to
If not good response to pyridostigmine
pyridostigmine:
:
not lead to normal social and working life
not lead to normal social and working life
•
• Add low dose
Add low dose prednisolone
prednisolone: 10
: 10-
-30 mg/d for 2
30 mg/d for 2-
-
3 months or incrementing dose; after
3 months or incrementing dose; after
•
• If not effective, getting along with
If not effective, getting along with
dysfunction; maneuvers and simple mechanical
dysfunction; maneuvers and simple mechanical
devices used
devices used
•
• Or high
Or high-
-dose daily
dose daily prednisolone
prednisolone with/without
with/without
azathioprine
azathioprine or even
or even thymectomy
thymectomy
•
• If
If ptosis
ptosis is fixed; surgical shortening of the
is fixed; surgical shortening of the
eyelid to be considered
eyelid to be considered
JOAO 2004; Neurologic clinics 1994

Myasthenia Gravis:
Pathophysiology

Myasthenia Gravis:
Pathophysiology
•
• Serum concentration of acetylcholine
Serum concentration of acetylcholine-
-
receptor antibody not correlate with
receptor antibody not correlate with
the clinical severity
the clinical severity
•
• Degree of reduction of acetylcholine
Degree of reduction of acetylcholine
receptors correlate with the severity
receptors correlate with the severity
NEJM 1997

•
• Immunopathogenesis
Immunopathogenesis
–
– Antibody negative MG
Antibody negative MG
•
• Found in 10
Found in 10-
-20%
20%
•
• Causes:
Causes:
–
– Too low an affinity for detection in the
Too low an affinity for detection in the
soluble assay system
soluble assay system
–
– Antibody may be directed at
Antibody may be directed at epitopes
epitopes not
not
present in the soluble acetylcholine
present in the soluble acetylcholine-
-receptor
receptor
extract
extract
NEJM 1997
Myasthenia Gravis:
Pathophysiology

MG
MG
•
• Anti
Anti-
-infective Agents
infective Agents
–
– Aminoglycosides
Aminoglycosides
–
– Kanamycin
Kanamycin sulfate
sulfate
–
– Ampicillin
Ampicillin sodium
sodium
–
– Erythromycin
Erythromycin
–
– Ciprofloxacin HCL
Ciprofloxacin HCL
–
– Imipenem
Imipenem
–
– Pyrantel
Pyrantel
JOAO 2004

MG
MG
•
• Cardiovascular Agents
Cardiovascular Agents
–
– Propanolol
Propanolol HCL
HCL
–
– Acebutolol
Acebutolol HCL
HCL
–
– Oxyprenolol
Oxyprenolol HCL
HCL
–
– Practolol
Practolol
–
– Timolol
Timolol maleate
maleate (
( β
β blocker)
blocker)
–
– Quinidine
Quinidine (anti
(anti-
-arrhythmic)
arrhythmic)
–
– Procainamide
Procainamide HCL
HCL (anti
(anti-
-arrhythmic)
arrhythmic)
–
– Propafenone
Propafenone HCL
HCL (anti
(anti-
-arrhythmic)
arrhythmic)
JOAO 2004

MG
MG
•
• Other Agents
Other Agents
–
– Chloroquine
Chloroquine
–
– Corticosteroids
Corticosteroids
–
– D
D-
-penicillamine
penicillamine
–
– Interferon
Interferon α
α
–
– Mydriatics
Mydriatics
–
– Phenytoin
Phenytoin sodium
sodium
–
– Trihexyphenidyl
Trihexyphenidyl HCL
HCL (
(artane
artane)
)
–
– Trimethadione
Trimethadione
–
– Verapamil
Verapamil HCL
HCL
JOAO 2004

J med Assoc Thai 2001
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Diagnosis and Management of Myasthenia Gravis

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