CDK 172/vol.36 no.6/September - Oktober 2009
413
TINJAUAN PUSTAKA
CDK 172/vol.36 no.6/September - Oktober 2009
414
TINJAUAN PUSTAKA
INTRODUCTION
Myasthenia gravis is an autoimmune disorder caused by the
presence of autoantibodies specific to human nicotinic acethyl-
choline receptor (AchR), which is concentrated in the post synap-
tic region of the neuromuscular junction
(1)
.
MG is uncommon. Estimated annual incidence is 2 per
1,000,000. The female-to-male ratio is said classically to be 6 : 4,
but as the population aged, the ratio is now equal. MG can
presents at any age
(2)
. Among children population in Hong
Kong the estimated prevalence is 1: 4000
(3)
. Myasthenia gravis
was the commonest type of non inherited NMJ disorders (62%),
mostly ocular type (89%).
Epidemiological study in England(4) found 100 cases in a popu-
lation of 684 000 (prevalence 15 per 100 000 population, 95%
CI: 1218). The commonest presenting symptoms and signs
were ptosis (64%) and diplopia (64%). A population-based
study in Greece found the average annual incidence of seroposi-
tive myasthenia gravis was 7.40/million population/year (women
7.14; men 7.66). The point prevalence rate was 70.63/million
(women 81.58; men 59.39)
(5)
. This review discusses the clinical
aspect, treatment, and prognosis of MG based on previous
current literature.
CASE ILLUSTRATION
A 22 year-old female presented with major complaints of ptosis
and diplopia. Patient felt that the weakness became more severe
in the afternoon and after activities (especially during daylight).
The eyelids had the same width in the morning, but the left
eyelid dropped as day progresses. Double vision became more
severe in the afternoon and after activities like reading, causing
letters look double after 15 minutes. The object become double
in horizontal direction; more pronounced when looking upward.
The symptom improved after rest (nap), and relieved in the
morning (after night sleep). She didn»t have headache, blurred
vision, speech disturbance, swallowing difficulties, extremities
and/or general weakness. The symptoms was slowly progressed
within months. There were no symptoms of malignancy, thyroid
disease, and generalized weakness.
DISCUSSION
Pathophysiology
When an action potential travels down a motor nerve and
reaches the nerve terminal, acetylcholine (Ach) molecules are
released from the presynaptic vesicles and adhere to Ach recep-
tors (AchRs) at the peaks of postsynaptic folds. Channels in the
AchRs open, allowing Na+ and other cations to enter into the
muscle fiber endplate and depolarize it. The multiple depolariza-
tions will sum up, and if large enough, trigger an action potential,
which travels along the muscle fiber to produce contraction
(1).
In MG, there is a reduction of AchRs available at the muscle
endplate and flattening of the postsynaptic folds causing reduc-
tion of available endplates; producing fewer endplate potentials
that might fail to be translated into an action potential. The end
result is an inefficient neuromuscular transmission
(6)
.
MG is Ab-mediated, producing loss of or compromised function
of skeletal muscle nicotinic acetylcholine receptors (AChR»s).
Three mechanisms have been implicated: (a) autoantibodies
against AChR cross-link surface AChR and induce their endocy-
tosis, resulting in their depletion from the postjunctional mem-
brane; (b) the autoantibodies themselves interfere directly with
AChR function by blocking acetylcholine-binding sites; and (c)
the autoantibodies contribute to destruction of endplates with
consequent AChR loss.
Patients become symptomatic once the ACh receptors is
reduced to approximately 30% of normal. The disease does not
affect smooth and cardiac muscle because they have a different
cholinergic receptors antigenicity
(1)
.
The role of thymus in the pathogenesis of MG is not entirely
clear, but 75% of MG patients have some degree of thymus
abnormality (eg, hyperplasia in 85% of cases, thymoma in 15%
of cases). Given the immunologic function of thymus and clinical
improvement following thymectomy, thymus is suspected to be
the site of autoantibody formation. However, the stimulus that
initiates the autoimmune process has not been identified(1).
Why the disease afflicts first and predominantly the extraocular
muscles remains unanswered. It probably has to do with the
physiology and antigenicity of the muscles
(6)
.
Symptoms and Signs
The usual initial complaint is specific muscle weakness rather
than generalized. The severity typically fluctuates over hours;
least severe in the morning and worse as the day progresses. It
also varies over the course of weeks or months, with exacerba-
tions and remissions
(1)
.
· Ophthalmic symptoms
Among patients, 75% initially complain of ocular disturbance,
mainly ptosis and diplopia. Eventually, 90% of patients with MG
develop ocular symptoms. Ptosis may be unilateral or bilateral,
and may shift from eye to eye
(6)
.
Ptosis is usually most prominent upon sustained upward gaze or
repeated eyelid closure (blinking). In cases of unilateral ptosis, the
contralateral lid may assume a ptotic position upon occluding
the ptotic eye or lifting the ptotic lid with a finger (Hering pheno-
menon)
(1)
. Extraocular muscle involvement does not follow a
certain pattern. Any acquired ocular motility disturbance with
ptosis, but normally reacting pupils, should raise the clinical
suspicion of MG
(2)
.
· General symptoms and signs
Weakness occur in facial, oropharyngeal, limb, and trunk muscles,
without any other sign of neurologic deficit, such as sensory loss,
change in deep tendon reflexes, or muscle atrophy
(6)
. Weakness
may involve limb musculature with myopathic-like proximal
weakness greater than distal muscle weakness. Isolated limb
muscle weakness as the presenting symptom is rare and occurs
in fewer than 10% of patients
(2)
.
Supporting additional examination
· Fatiguability test
In ocular MG, fatiguability test can be done by asking the patient
to blink repeatedly or gaze upward for an extended time
Simpson test). Increased drooping is a sign of fatigue. The phenomenon
of «enhanced» ptosis can be demonstrated in patients with bilateral
ptosis by elevating and maintaining the more ptotic eyelid in a fixed
position. The opposite eyelid slowly falls and may close completely
(7)
.
The lid-twitch sign is another way to test for fatiguability. The
patient is directed to look down for 10-15 seconds and then to
refixate quickly in the primary position. Observation of an
upward overshoot of the lid with several twitches, followed by
repositioning of the lid to the original ptotic state, identifies the
easy fatiguability and rapid recovery of the muscle. The «peek»
sign occurs when the palpebral fissure widens after a period of
voluntary eyelid closure
(1,7)
.
· Anti-acetylcholine receptor antibody
This test is reliable for diagnosing autoimmune MG. The anti-
AChR antibody (Ab) is positive in 74% of patients. Results are
positive in about 80% of patients with generalized myasthenia
and in 50% of those with pure ocular myasthenia
(2)
.
· Antistriated muscle (anti-SM)
Antistriated muscle (anti-SM) Ab is another important test in patients
with MG. It is present in about 84% of patients with thymoma
younger than 40 years and less often in patients without thymoma(
2)
.
· Tensilon or Prostigmin test
In ocular myasthenia without systemic manifestations, up to 95%
of patients will have a positive Tensilon or Prostigmin test
(7)
.
· Neurophysiological test
Electromyography is used to confirm the diagnosis of MG, but
usually are not available on an emergency basis
(1)
. Repetitive
nerve stimulation (RNS) should lead to a decremental response in
compound action potentials on EMG. A stimulation rate of 1-5
per second should result in a 10% decrease in amplitude by the
fourth action potential. RNS results are less likely to be positive in
patients with ocular MG.
Single fiber electromyography (SFEMG) records action potentials
from single muscle fibers in a motor unit. SFEMG is a substitute
for the RNS in patients with ocular MG, being much more
sensitive. This test is technically demanding and operator depen-
dent. It has a lower specificity, and can give positive results in
other neuromuscular disorders
(6)
.
Other test for diagnosis exclusion
Thyroid function tests are indicated to rule out associated Graves
disease or hyperthyroidism. This is essential especially in patients
with ocular MG where concomitant hyperthyroidism is most
frequent. MRI or CT of mediastinum (thin slices) is indicated to
rule out a thymoma or thymic enlargement
(6)
.
Myasthenia Gravis: Current Review
Rizaldy Pinzon
Neurology Department, Bethesda Hospital, Yogyakarta, Indonesia
ABSTRACT
Myasthenia gravis (MG) is an acquired autoimmune disorder characterized clinically by weakness of skeletal
muscles and fatigability on exercise. Weakness increases during the day and improves with rest. Extraocular
muscle (EOM) weakness or ptosis is present initially in 50% of patients and 90% occurs during the course of
illness. AChE inhibitors and immunomodulating therapies are the mainstays of treatment. In mild form, AChE
inhibitors are used. Important risk factors for poor prognosis include age older than 40 years, a progressive
disease, and thymoma.
Key words: myasthenia - immunology diagnosis treatment - prognosis
CDK 172/vol.36 no.6/September - Oktober 2009
413
TINJAUAN PUSTAKA
CDK 172/vol.36 no.6/September - Oktober 2009
414
TINJAUAN PUSTAKA
INTRODUCTION
Myasthenia gravis is an autoimmune disorder caused by the
presence of autoantibodies specific to human nicotinic acethyl-
choline receptor (AchR), which is concentrated in the post synap-
tic region of the neuromuscular junction
(1)
.
MG is uncommon. Estimated annual incidence is 2 per
1,000,000. The female-to-male ratio is said classically to be 6 : 4,
but as the population aged, the ratio is now equal. MG can
presents at any age
(2)
. Among children population in Hong
Kong the estimated prevalence is 1: 4000
(3)
. Myasthenia gravis
was the commonest type of non inherited NMJ disorders (62%),
mostly ocular type (89%).
Epidemiological study in England(4) found 100 cases in a popu-
lation of 684 000 (prevalence 15 per 100 000 population, 95%
CI: 1218). The commonest presenting symptoms and signs
were ptosis (64%) and diplopia (64%). A population-based
study in Greece found the average annual incidence of seroposi-
tive myasthenia gravis was 7.40/million population/year (women
7.14; men 7.66). The point prevalence rate was 70.63/million
(women 81.58; men 59.39)
(5)
. This review discusses the clinical
aspect, treatment, and prognosis of MG based on previous
current literature.
CASE ILLUSTRATION
A 22 year-old female presented with major complaints of ptosis
and diplopia. Patient felt that the weakness became more severe
in the afternoon and after activities (especially during daylight).
The eyelids had the same width in the morning, but the left
eyelid dropped as day progresses. Double vision became more
severe in the afternoon and after activities like reading, causing
letters look double after 15 minutes. The object become double
in horizontal direction; more pronounced when looking upward.
The symptom improved after rest (nap), and relieved in the
morning (after night sleep). She didn»t have headache, blurred
vision, speech disturbance, swallowing difficulties, extremities
and/or general weakness. The symptoms was slowly progressed
within months. There were no symptoms of malignancy, thyroid
disease, and generalized weakness.
DISCUSSION
Pathophysiology
When an action potential travels down a motor nerve and
reaches the nerve terminal, acetylcholine (Ach) molecules are
released from the presynaptic vesicles and adhere to Ach recep-
tors (AchRs) at the peaks of postsynaptic folds. Channels in the
AchRs open, allowing Na+ and other cations to enter into the
muscle fiber endplate and depolarize it. The multiple depolariza-
tions will sum up, and if large enough, trigger an action potential,
which travels along the muscle fiber to produce contraction
(1).
In MG, there is a reduction of AchRs available at the muscle
endplate and flattening of the postsynaptic folds causing reduc-
tion of available endplates; producing fewer endplate potentials
that might fail to be translated into an action potential. The end
result is an inefficient neuromuscular transmission
(6)
.
MG is Ab-mediated, producing loss of or compromised function
of skeletal muscle nicotinic acetylcholine receptors (AChR»s).
Three mechanisms have been implicated: (a) autoantibodies
against AChR cross-link surface AChR and induce their endocy-
tosis, resulting in their depletion from the postjunctional mem-
brane; (b) the autoantibodies themselves interfere directly with
AChR function by blocking acetylcholine-binding sites; and (c)
the autoantibodies contribute to destruction of endplates with
consequent AChR loss.
Patients become symptomatic once the ACh receptors is
reduced to approximately 30% of normal. The disease does not
affect smooth and cardiac muscle because they have a different
cholinergic receptors antigenicity
(1)
.
The role of thymus in the pathogenesis of MG is not entirely
clear, but 75% of MG patients have some degree of thymus
abnormality (eg, hyperplasia in 85% of cases, thymoma in 15%
of cases). Given the immunologic function of thymus and clinical
improvement following thymectomy, thymus is suspected to be
the site of autoantibody formation. However, the stimulus that
initiates the autoimmune process has not been identified(1).
Why the disease afflicts first and predominantly the extraocular
muscles remains unanswered. It probably has to do with the
physiology and antigenicity of the muscles
(6)
.
Symptoms and Signs
The usual initial complaint is specific muscle weakness rather
than generalized. The severity typically fluctuates over hours;
least severe in the morning and worse as the day progresses. It
also varies over the course of weeks or months, with exacerba-
tions and remissions
(1)
.
· Ophthalmic symptoms
Among patients, 75% initially complain of ocular disturbance,
mainly ptosis and diplopia. Eventually, 90% of patients with MG
develop ocular symptoms. Ptosis may be unilateral or bilateral,
and may shift from eye to eye
(6)
.
Ptosis is usually most prominent upon sustained upward gaze or
repeated eyelid closure (blinking). In cases of unilateral ptosis, the
contralateral lid may assume a ptotic position upon occluding
the ptotic eye or lifting the ptotic lid with a finger (Hering pheno-
menon)
(1)
. Extraocular muscle involvement does not follow a
certain pattern. Any acquired ocular motility disturbance with
ptosis, but normally reacting pupils, should raise the clinical
suspicion of MG
(2)
.
· General symptoms and signs
Weakness occur in facial, oropharyngeal, limb, and trunk muscles,
without any other sign of neurologic deficit, such as sensory loss,
change in deep tendon reflexes, or muscle atrophy
(6)
. Weakness
may involve limb musculature with myopathic-like proximal
weakness greater than distal muscle weakness. Isolated limb
muscle weakness as the presenting symptom is rare and occurs
in fewer than 10% of patients
(2)
.
Supporting additional examination
· Fatiguability test
In ocular MG, fatiguability test can be done by asking the patient
to blink repeatedly or gaze upward for an extended time
Simpson test). Increased drooping is a sign of fatigue. The phenomenon
of «enhanced» ptosis can be demonstrated in patients with bilateral
ptosis by elevating and maintaining the more ptotic eyelid in a fixed
position. The opposite eyelid slowly falls and may close completely
(7)
.
The lid-twitch sign is another way to test for fatiguability. The
patient is directed to look down for 10-15 seconds and then to
refixate quickly in the primary position. Observation of an
upward overshoot of the lid with several twitches, followed by
repositioning of the lid to the original ptotic state, identifies the
easy fatiguability and rapid recovery of the muscle. The «peek»
sign occurs when the palpebral fissure widens after a period of
voluntary eyelid closure
(1,7)
.
· Anti-acetylcholine receptor antibody
This test is reliable for diagnosing autoimmune MG. The anti-
AChR antibody (Ab) is positive in 74% of patients. Results are
positive in about 80% of patients with generalized myasthenia
and in 50% of those with pure ocular myasthenia
(2)
.
· Antistriated muscle (anti-SM)
Antistriated muscle (anti-SM) Ab is another important test in patients
with MG. It is present in about 84% of patients with thymoma
younger than 40 years and less often in patients without thymoma(
2)
.
· Tensilon or Prostigmin test
In ocular myasthenia without systemic manifestations, up to 95%
of patients will have a positive Tensilon or Prostigmin test
(7)
.
· Neurophysiological test
Electromyography is used to confirm the diagnosis of MG, but
usually are not available on an emergency basis
(1)
. Repetitive
nerve stimulation (RNS) should lead to a decremental response in
compound action potentials on EMG. A stimulation rate of 1-5
per second should result in a 10% decrease in amplitude by the
fourth action potential. RNS results are less likely to be positive in
patients with ocular MG.
Single fiber electromyography (SFEMG) records action potentials
from single muscle fibers in a motor unit. SFEMG is a substitute
for the RNS in patients with ocular MG, being much more
sensitive. This test is technically demanding and operator depen-
dent. It has a lower specificity, and can give positive results in
other neuromuscular disorders
(6)
.
Other test for diagnosis exclusion
Thyroid function tests are indicated to rule out associated Graves
disease or hyperthyroidism. This is essential especially in patients
with ocular MG where concomitant hyperthyroidism is most
frequent. MRI or CT of mediastinum (thin slices) is indicated to
rule out a thymoma or thymic enlargement
(6)
.
Myasthenia Gravis: Current Review
Rizaldy Pinzon
Neurology Department, Bethesda Hospital, Yogyakarta, Indonesia
ABSTRACT
Myasthenia gravis (MG) is an acquired autoimmune disorder characterized clinically by weakness of skeletal
muscles and fatigability on exercise. Weakness increases during the day and improves with rest. Extraocular
muscle (EOM) weakness or ptosis is present initially in 50% of patients and 90% occurs during the course of
illness. AChE inhibitors and immunomodulating therapies are the mainstays of treatment. In mild form, AChE
inhibitors are used. Important risk factors for poor prognosis include age older than 40 years, a progressive
disease, and thymoma.
Key words: myasthenia - immunology diagnosis treatment - prognosis
TINJAUAN PUSTAKA
CDK 172/vol.36 no.6/September - Oktober 2009
416
Diagnosis
Myasthenia gravis diagnosed from clinical characteristics. An array
of biological, pharmacological, and instruments test can assist
diagnosis. A negative result does not definitely exclude MG
(8)
.
Table 1. Myasthenia gravis classification (Osserman and Gerkins)
Differential diagnosis
Disorders of neuromuscular junction [NMJ] are clinically hetero-
geneous. The clinical expressions of these disorders are myasthenic
features in the form of variable muscle weakness and fatigability.
The name myasthenic syndromes [MS] is given to a group of
disorder of NMT with different pathophysiology from acquired
autoimmune myasthenia gravis
(9,10)
.
· Lambert-Eaton myasthenic syndrome (LEMS)
Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition
caused by abnormality of acetylcholine (ACh) release at the neuro-
muscular junction. Cancer is eventually found in 40% of patients
with LEMS; usually small cell lung cancer (SCLC), although LEMS
also has been associated with other cancers(11). A comparative study
of clinical pattern between MG and LEMS from 101 patients
showed that LEMS do not affect ocular weakness in all cases
(12)
.
· Botulism
The effects of the toxin are limited to blockade of peripheral
cholinergic nerve terminals, including those at neuromuscular
junctions, postganglionic parasympathetic nerve endings, and
peripheral ganglia. This blockade produces a characteristic bilateral
descending paralysis of the muscles innervated by cranial, spinal,
and cholinergic autonomic nerves but no impairment of adrenergic
or sensory nerves. Botulism has severe, progressive, and symmetric
pattern
(13)
.
Treatment
The aim of MG treatment is to achieve three essential objectives :
(1) Optimise neuromuscular transmission, (2) Reduce or neutralise
the consequences of the autoimmune reaction, and (3) modify
the natural history of MG by inducing remission, defined as per-
manent condition of absence of symptoms without treatment(8).
AChE inhibitors and immunomodulating therapies are the
mainstays of treatment. In the mild form of the disease, AChE
inhibitors are initially used. Most patients with generalized MG
require additional immunomodulating therapy
(2)
.
Other novel treatments for MG are Plasma Exchange, Immuno-
globulin, and thymectomy. Plasmapheresis or plasma exchange
is effective, especially in preparation for surgery or as short-term
management of an exacerbation.
A consensus meeting on IVIg concluded that IVIg treatment (2g/
kgBW) was most useful in acute deteriorating disease, minimising
the risk of bulbar or respiratory weakness requiring intensive care
support. It was also useful temporarily in patients with severe
condition when other treatments had not yet effective. Use in chronic
condition and as a primary treatment was not recommended.
No significant difference was found in an randomised controlled
trial comparing plasmapheresis and IVIg treatment. Mechanism
of Immunoglobulin Therapy are: (1) Microbial and toxin inhibition,
(2) Complement deactivation, (3) Receptor Blockade, (4) Anti
Idiotypes, and (5) Modulating Cytokine Production
(14)
.
Thymectomy is an important treatment option in MG, especially
if a thymoma is present. It has been proposed as a first-line
therapy in most patients with generalized myasthenia. Thymec-
tomy may induce remission. American Association of Neurology
recommended thymectomy for nonthymomatous autoimmune
MG patients. Thymectomy is recommended as an option to
increase the probability of remission or improvement
(15)
.
Prognosis
In ocular MG, >50% of cases evolve to generalised MG within a
year, spontaneous remission in < 10%(8). Approximately 15-17%
of patients will remain having strictly ocular symptoms over a
mean follow-up period of 17 years. Those patients are referred
as ocular MG. The rest develop a generalized weakness and are
referred as generalized MG
(6).
A study of 37 patients MG showed
that the presence of thymoma associated with poorer outcome.
REFERENCE
1. Newton E. Myasthenia Gravis, eMedicine Journal, December 2001
2. Shah AK. Myasthenia Gravis, eMedicine Journal, August 2002
3. Chung WY, Wong HY, The Epidemiology of Myasthenia Gravis in Hongkong, HK Medicine 2000; 12
4. Robertson NP, Deans J, Compston DAS, Myasthenia Gravis: a Population Based Epidemiological Study
in Cambridgeshire, England. J Neurol Neurosurg Psychiatry; 1998; 65:492496
5. Poulas K, Tsibri E, Kokla E, Papanastasiou D, Tsouloufis T, Marinou M, Tsantili P, Papapetropoulos T,
Tzartos SJ, Epidemiology of seropositive myasthenia gravis in Greece. J Neurol Neurosurg Psychiatry
2001;71:352356
6. Awwad S. Myasthenia Gravis, eMedicine Journal, September 2001
7. Skorin L. Testing for Myasthenia Gravis. Optometry Today 1999
8. Cornelio F. Myasthenia Gravis. European Neurological Society 12th meeting, Berlin 2002.
9. Aleem MA, Raveendran S, Saddique S, Manivannan R. Myasthenic Syndromes, Indegene Publ. Co . 2000
10. Bromberg MK. Myasthenia Gravis and Myasthenic Syndromes. MGnyc.org , 2000
11. Sanders DB. Lambert-Eaton Myasthenic Syndrome, eMedicine Journal, March 2001
12. Wirtz PW, Sotodeh M et al. Difference in Distribution of Muscle Weakness between Myasthenia Gravis
and The LambertEaton Myasthenic Syndrome, J Neurol Neurosurg Psychiatry 2002;73:766768
13. Kim J. Botulism. eMedicine Journal, October 2001
14. Wiles CM, Brown P, Chapel H, et.al. Intravenous Immunoglobulin in Neurological Disease: A Specialist
Review. J Neurol Neurosurg Psychiatr. 2002, 72:440448
15. Gronseth GS, Barohn RJ. Practice parameter: Thymectomy for autoimmune myasthenia gravis (an
evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of
Neurology,
Neurology
2000;55:715
16. Kalita RJ, Misra UK, Kar D, Agarwal A,. Misra SK. A Study of Myasthenia Gravis in Patients with and
without
Thymoma.
Neurol
India
2000;48
:
343-346
Degree
Symptoms and signs
I
Purely ocular (ptosis and diplopia)
II A
Mild generalized (ocular and extremities, no prominent
bulbar
sugns)
II B
Moderate generalized (ocular and/ or bulbar signs, variable
limb muscle involvement, no crises
III
Acute fulminating generalized signs with prominent
bulbar involvement and crises
IV
Late severe generalized and prominent bulbar signs
and
crises