Journal of General and Family Medicine 2016, vol. 17, no. 3, p. 211–217.

Review Articles

Myasthenia Gravis: a Review

Hideyuki Matsumoto, MD, PhD1 and Yoshikazu Ugawa, MD, PhD2

1
Department of Neurology, Japanese Red Cross Medical Center, Tokyo, Japan
2
Department of Neurology, School of Medicine, Fukushima Medical University, Fukushima, Japan

Myasthenia gravis (MG) is an auto-immune disorder caused by neuromuscular transmission failure, and is a
representative post-neuromuscular junctional disorder. The most common auto-immune antibody is the anti-
acetylcholine receptor (AChR) antibody, which is detected in approximately 80 to 85% of MG patients. Recently, auto-
immune antibodies against the muscle-specific receptor tyrosine kinase (MuSK) and the LDL-receptor related protein 4
(Lrp4) have also been found. The clinical symptoms and therapeutic responses are highly dependent on the types of
auto-immune antibodies. Thymectomy is a common treatment for MG, although a recent meta-analysis on thymectomy
did not show any clinical benefit. Several new immune-mediated therapies have become available and the therapeutic
strategy is currently changing drastically. In the future, the establishment of a novel therapeutic strategy is expected for
this disorder.

Keywords: myasthenia gravis (MG), anti-acetylcholine receptor (AChR) antibody, anti-muscle-specific receptor
tyrosine kinase (MuSK) antibody, anti-LDL-receptor related protein 4 receptor (Lrp4) antibody, repetitive nerve
stimulation test

Introduction dominant (male:female = 1:1.7). Recently, the number

Myasthenia gravis (MG) is an auto-immune disorder
caused by neuromuscular transmission failure, and is a
representative post-neuromuscular junctional disor-
der.1–3 The most common auto-immune antibody is
the anti-acetylcholine receptor (AChR) antibody, which
targets AChR at the motor end plate over the muscle
membrane (post-neuromuscular junction). This anti-
body is detected in approximately 80 to 85% of MG
patients. In Japan, the prevalence rate is 11.8 per
100,000 and, as far as gender is concerned, it is female
of elderly-onset MG patients over 65 years of age or
late-onset MG patients over 50 yearsof age has been
increasing worldwide.4 The main clinical symptoms are
diplopia, ptosis, dysarthria, dysphagia, and proximal
dominant muscular weakness with easy fatigability.
These symptoms have a daily fluctuation that involves
deterioration in the evening and recovery with rest. The
onset may also involve myasthenic crisis. For example,
the MG patient may initially present with difficulty in
post-surgical ventilator withdrawal. MG patients may

Corresponding author: Hideyuki Matsumoto, MD, PhD

Department of Neurology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan
E-Mail: hideyukimatsumoto.jp@gmail.com
Received for publication 22 December 2014 and accepted in revised form 7 July 2015
© 2016 Japan Primary Care Association

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 Journal of General and Family Medicine
also initially develop myasthenic crisis following the
administration of medications that block neuromuscu-
lar transmission.
In general, according to the clinical symptoms, MG is
classified into two types, ocular MG and generalized
MG. The clinical symptoms of ocular MG are limited
to ocular muscle weakness. If MG patients present with
bulbar or limb symptoms, they are classified as having
generalized MG. Instead of the previously used
Osserman classification, the Myasthenia Gravis Foun-
dation of America (MGFA) classification is currently
used (Table 1).5 MG often involves a concomitant
thymic tumor (Figure 1). Among the thymic tumors,
approximately 20% are thymoma and approximately
60% are thymic hyperplasia. MG often involves other
concomitant auto-immune disorders, such as thyroid
dysfunction, systemic lupus erythematosus, rheumatoid
arthritis, pure red cell aplasia, and alopecia areata.
Recently, auto-immune antibodies against muscle-
specific receptor tyrosine kinase (MuSK) and LDL-
receptor-related protein 4 (Lrp4) have been found.6,7
In this review article, we first describe the two new
auto-immune antibodies, anti-MuSK antibody and anti-
Lrp4 antibody, in MG. Next, we summarize the
examinations, diagnosis, and therapies for MG. For
more detailed information, we recommend reading
“Societas Neurologica Japonica: Practical Guidelines
for Myasthenia Gravis (MG) 2014”.1 This book
contains a wealth of information on MG.
1. Anti-AChR antibody positive MG and anti-
MuSK antibody positive MG
The most common auto-immune antibody is anti-
AChR antibody, which is detected in approximately 80
to 85% of MG patients. Recently, the anti-MuSK
antibody and the anti-Lrp4 antibody have also been
found.6,7 The clinical symptoms and therapeutic
responses are highly dependent on the types of auto-
immune antibodies. Therefore, it is important to
determine the differences in MG among the three
known auto-immune antibodies. The clinical character-
istics in anti-Lrp4 antibody positive MG have not yet
been revealed. Here, we focus on the clinical dif-
ferences between anti-AChR antibody positive MG and
anti-MuSK antibody positive MG.
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2016, vol. 17, no. 3
Table 1. MGFA clinical classification
Class I
Any ocular muscle weakness. All other muscle
strength is normal.
Class II
Mild weakness affecting muscles other than ocular
muscles.
IIa. Predominantly affecting limb, axial muscles, or
both. May also have lesser involvement of
oropharyngeal muscles.
IIb. Predominantly affecting oropharyngeal,
respiratory muscles, or both. May also have
lesser or equal involvement of limb, axial
muscles, or both.
Class III
Moderate weakness affecting muscles other than
ocular muscles.
IIIa. Predominantly affecting limb, axial muscles, or
both. May also have lesser involvementof
oropharyngeal muscles.
IIIb. Predominantly affecting oropharyngeal,
respiratory muscles, or both. May also
havelesser or equal involvement of limb, axial
muscles, or both.
Class IV
Severe weakness affecting muscles other than ocular
muscles.
IVa. Predominantly affecting limb, axial muscles, or
both. May also have lesser involvement of
oropharyngeal muscles.
IVb. Predominantly affecting oropharyngeal,
respiratory muscles, or both. May also have
lesser or equal involvement of limb, axial
muscles, or both.
Class V
Defined as intubation, with or without mechanical
ventilation, except when employed during routine
postoperative management.
(Modified from reference 5)
Table 2 shows the clinical differences between anti-
AChR antibody positive MG and anti-MuSK antibody
positive MG.8 Compared to anti-AChR antibody
positive MG, the clinical characteristics in anti-MuSK
antibody positive MG are as follows: (i) at disease
onset, patients often present with bulbar palsy in
 Myasthenia Gravis: a Review

Figure 1. Thymic tumor. sero-negative MG, in which unknown antibodies

Chest computed tomography (CT) shows a low
are speculated to relate to the pathophysiology. To
densitytumor without the enhancement of contrast
media at the anterior mediastinum (arrowhead). This determine the pathophysiology of MG in more detail,
tumor includes a calcification, suggesting thymoma. further investigations into the relationships between
auto-immune antibodies and clinical characteristics are
needed in a large number of MG patients.
MG patients with thymoma may also have striational
antibodies that react with the epitopes on the muscle
protein: titin, ryanodinereceptor (RyR), and voltage-
gated K channel ¡ subunit (Kv1.4).9 The clinical
symptoms in anti-striational antibody positive MG
patients are more severe than those in anti-striational
antibodynegative MG patients. For example, anti-
Kv1.4 antibody positive MG patients may develop
autoimmune myocarditis, which is related to sudden
death. Anti-striational antibodies are expected to
provide additional clinical information.
Table 2. Differences between the two types of MG
Anti-AChR Anti-MuSK 2. Examinations and diagnosis
antibody positive antibody positive The diagnosis of MG is made according to clinical
MG MG symptoms, positive auto-immune antibodies (anti-
Frequency (%) 80–85% 5–10% AChR antibody, anti-MuSK antibody, and anti-Lrp4
Male : Female 1:2 1:3 antibody), specific findings (waning) in repetitive nerve
From ocular type to Ocular and bulbar stimulation tests, and transient improvement of clinical
Symptoms
generalized type palsies from onset
symptoms in the Tensilon test. It is of note that the
Ocular type
20–40% 3% antibody titer does not always reflect clinical symp-
(%)
toms. The most important differential diagnosis is
Muscular
10% 26% Lambert-Eaton myasthenic syndrome (LEMS), which
atrophy (%)
Myasthenic is another auto-immune disorder caused by neuro-
10–20% 33% muscular transmission failure, and is a representative
crisis
Cholinesterase “pre”-neuromuscular junctional disorder (see our re-
Effective Variable
inhibitor view article on LEMS).10
Thymic tumor 20–30% 0%
(Modified from reference 8) 2-1. Repetitive nerve stimulation test
Compound muscle action potentials (CMAPs) are
usually recorded from the nasalis, trapezius, and
addition to ocular symptoms, (ii) with disease progress, abductor pollicis brevis (APB) muscles. As shown in
patients often exhibit muscular atrophy, (iii) patients Figure 2, 3 Hz repetitive electrical stimulation of
often suffer from myasthenic crisis, (iv) the response to peripheral nerves shows a gradual amplitude reduction
cholinesterase inhibitors are poor, and (v) patients of CMAPs (waning). This waning is usually only
never have thymic tumors. detected in weak muscles in all types of MG patients.
The pathophysiological mechanisms of the anti-MuSK The exercise test is useful to sensitively detect waning.
antibody and anti-Lrp4 antibody remain to be solved. In the exercise test, the target muscle is strongly
In the case of MG without any of the three known auto- contracted before electrical stimulation and the CMAPs
immune antibodies, patients are classified as having to repetitive electrical stimulation are recorded every

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 Journal of General and Family Medicine
Figure 2. Repetitive nerve stimulation test.
Three hertz repetitive nerve stimulation test for the
abductor pollicis brevis muscle is performed during
relaxation (A) and 3 minutes after exercise (B).
During relaxation (A), the amplitude of the fourth
compound muscle action potential (CMAP) is 18%
smaller than that of the first CMAP, suggesting
waning (waning is defined as a more than 10%
CMAP amplitude reduction). Three minutes after
exercise (B), the amplitude of the fourth CMAP is
24% smaller than that of the first CMAP, showing
waning more clearly. In MG patients, acetylcholine is
normally released from nerve terminals. However,
in anti-AChR antibody positive MG, the antibody
prevents acetylcholine from reaching the acetylcho-
line receptor (AChR), leading to neuromuscular
transmission failure. Similar mechanisms are specu-
lated in MG without the anti-AChR antibody.
Immediately after exercise, abundant acetylcholine
is released. Therefore, the waning is diminished. On
the other hand, one minute after exercise, acetylcho-
line is depleted. Therefore, the waning appears more
clearly. The exercise test is useful to sensitively
detect the failure of neuromuscular transmission in
repetitive nerve stimulation test for MG patients.
minute after the muscular contraction (from one to
three minutes). One or two minutes after the contrac-
tion, if waning appears or is exaggerated, the diagnosis
of MG is supported. Here, we must caution that waning
is also observed in LEMS although the EMG findings
differ considerably between MG and LEMS.
2-2. Tensilon test
The Tensilon test involves the intravenous adminis-
tration of 10 mg of edrophonium chloride (Antirexµ),
a cholinesterase inhibitor that transiently blocks the
action of acetylcholinesterase. It is of note that this test
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2016, vol. 17, no. 3
can be false positive because of the placebo effect.11 To
precisely determine the effects of edrophonium chlo-
ride, a comparison of the effects between edrophonium
chloride and placebo is helpful. First, saline is
gradually injected as a placebo test. Next, 2 mg of
edrophonium chloride is gradually injected, and side-
effects such as bradycardia, dyspnea, and abdominal
pain are checked for. If no side-effects appear, the
remaining 8 mg of edrophonium chloride is gradually
injected. If severe side-effects appear, atropine sulface
hydrate (atropinesulface injectionµ), an anticholinergic
drug, is injected. In order to handle potential side-
effects, emergency carts should always be prepared for
this test. Clinical symptoms are transiently improved in
anti-AChR antibody positive MG, but not always in
anti-MuSK antibody positive MG. Anti-MuSK anti-
body positive MG patients also tend to show hyper-
reactivity to the Tensilon test, e.g., fasciculation of
muscles. Due to the side-effects of edrophonium
chloride, this test is not always required.
3. Treatment
The first approach in conventional therapeutic strategy
for generalized MG was thymectomy regardless of the
presence of thymic tumor. However, none of the anti-
MuSK antibody positive MG patients had any thymic
tumors, which brings into question the significance of a
thymectomy. A meta-analysis on thymectomy did not
show clear positive therapeutic responses.12 In partic-
ular, the necessity of thymectomy for late-onset MG
patients is questioned due to the risks of surgery: if
immunotherapy is sufficiently administered to late-
onset MG patients, thymectomy may not be the first
choice. Currently, a provisional therapeutic guideline
for late-onset MG patients over 50 years of age is
proposed.9 In this guideline, the indication of thymec-
tomy in late-onset MG patients is less than that in
early-onset MG patients and the combination of a small
dosage of corticosteroids and immunosuppressive
agents is recommended for late-onset MG patients.
Here, we note the current standard treatment of MG:
thymectomy, cholinesterase inhibitor, immunotherapy
with steroids and immunosuppressive drugs, plasma-
pheresis, intravenous immunoglobulin (IVIg), and
rituximab. In addition to these treatments, rehabilitation
 Myasthenia Gravis: a Review
is also an important therapy to maintain muscle forces.
MG patients should be careful about exacerbation risk
factors such as infection, fatigue, mental stress, and
inadequate medications blocking neuromuscular trans-
mission.13 Finally, since MG is one of the intractable
diseases, MG patients should be supported by various
social services.
3-1. Thymectomy
Thymic tumors should be surgically resected regardless
of the presence of MG. If a thymic tumor is completely
resected without any invasions, the prognosis is good.
On the other hand, in cases of metastasis, radiotherapy
and chemotherapy are required. Surgery is not always
required for thymic hyperplasia and involution. A
meta-analysis showed no clear efficacy for thymec-
tomy, although the analysis did not completely rule out
all efficacies. Current opinion holds that thymectomy
should be considered as a therapeutic option for MG.
The surgery should be considered on a case-by-case
basis. In particular, for late-onset MG, the therapeutic
strategy tends to give preference to immunotherapy
over thymectomy. As an adverse effect, thymectomy
may prevent MG patients from ventilator withdrawal
due to myasthenic crisis. Therefore, thymectomy
should be performed while clinical symptoms such as
bulbar palsy and respiratory dysfunction are well
controlled.
3-2. Cholinesterase inhibitor
A cholinesterase inhibitor prevents the acetylcholines-
terase enzyme from breaking down the acetylcholine
released from nerve terminals. The medicine increases
the concentration of acetylcholine at the synaptic cleft,
enhancing the muscular contraction. This is a sympto-
matic therapy, although it is remarkably effective for
anti-AChR antibody positive MG. It is not overly
effective for anti-MuSK antibody positive MG, which
may also show the hyper-reactivity. Pyridostigmine
bromide (Mestinonµ; up to three tablets/day) or
ambenoiumchloride (Mytelaseµ; 1.5 tablets/day) is
often used. The half-life of the former is shorter than
that of the latter. As for side-effects, clinicians must
remain vigilant for bradycardia, dyspnea, abdominal
pain, diarrhea, and cholinergic crisis.
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3-3. Immunotherapy
3-3-1. Steroids
Steroids suppress the immune system and prevent
abnormal auto-immune antibodies from being made.
Prednisolone (Predonineµ) is often used as an oral
glucocorticosteroid therapy. This medicine is usually
administered on consecutive or alternate days. Imme-
diately after steroid administration, an initial deterio-
ration occurs in 40% of MG patients. Previously,
to avoid this initial deterioration, prednisolone was
gradually increased to a dosage of 1 mg/kg/day,
maintained at the same high dosage for a certain
period, and then gradually reduced to the maintenance
dosage needed to prevent the deterioration of clinical
symptoms. Currently, however, for late-onset MG, to
avoid the side-effects of high-dosage steroids, a low
dosage of prednisolone (under 10 mg/day) is recom-
mended for patients with mild symptoms and a
moderate dosage (20–30 mg/day) for patients with
severe symptoms. To improve clinical symptoms,
generalized MG patients often need a higher dosage
than ocular MG patients. Clinicians should be aware of
the many side-effects, including infection, gastric
ulcers, diabetes mellitus, insomnia, psychosis, and
osteoporosis. Preventive medicines for these major
side-effects should be considered.
Steroid pulse therapy (methylprednisolone, Solumedrolµ,
1 g/day © 3 days) is reported to be effective in MG
patients presenting with acute exacerbation and can be
used to shorten the therapeutic period with high-dosage
oral steroid therapy. However, clinicians should be aware
of the initial deterioration.
3-3-2. Immunosuppressive drugs
In Japan, tacrolimus (Prograf µ) and cyclosporine
(Neoralµ) are available. The usual dosage of tacrolimus
is 3 mg/day. The trough level should be under 20
ng/ml. The dosage (3 mg) is markedly low for MG
compared to the dosage used in organ transplantation.
Side-effects such as diabetes mellitus and hyperkalemia
should be monitored for. The initial dosage of cyclo-
sporine is 5 mg/kg/day and the maintenance dosage is
3 mg/kg/day. For late-onset MG, the initial dosage
should be the maintenance dosage. As for side-effects,
clinicians should monitor for renal failure, hyper-
tension, and malignant tumors. The trough level should
 Journal of General and Family Medicine
be under 200 ng/ml during the initial period and under
150 ng/ml during the maintenance period. Immuno-
suppressive drugs are often used for the reduction of
steroids, but the efficacy of monotherapy has not yet
been determined. As for other medicines, azathioprine
(Imuranµ), cyclophosphamide (Endoxanµ), and myco-
phenolate mofetil (CellCeptµ) can be used.
3-3-3. Plasmapheresis
Plasmapheresis is expected to improve the clinical
symptoms drastically, although the efficacy is tempo-
rary (two or three weeks). Therefore, plasmapheresis is
mainly used for myasthenic crisis. It is also used for
shortening the duration of high-dosage steroid therapy
in late-onset MG. Three types of therapies — plasma
exchange (PE), double filtration plasmapheresis
(DFPP), and immunoadsorption therapy (IAPP) — are
available. PE is the most effective. The advantage
of DFPP is that it enables a reduced dosage of albumin
transfusion. IAPP is effective for anti-AChR antibody
positive MG, whereas it is ineffective for anti-MuSK
antibody positive MG.
3-3-4. Intravenous immunoglobulin (IVIg)
µ
IVIg (Venoglobulin-IH ) is mainly used for shortening
the duration of high-dosage steroid therapy and for
steroid-resistant MG in addition to myasthenic crisis.
The temporal efficacy of IVIg is almost the same as
that of PE. This infusion therapy is more convenient
than plasmapheresis.
3-3-5. Rituximab
Rituximab (Rituxanµ) is a genetically engineered
chimeric murine/human monoclonal IgG1 kappa anti-
body directed against the CD20 antigen. Although
efficacy has been shown for refractory MG patients, the
therapy currently has no indication for MG.
4. Current problems and future expectations
As a clinical problem for MG, the measurements of
anti-Lrp4 antibody is not commercially available.
Another problem is that, because the efficacy of
thymectomy is ambiguous, the therapeutic strategy is
confusing. Currently, to investigate the efficacy of
thymectomy, a thymectomy trial for non-thymomatous
MG patients receiving prednisone (the MGTX study)
is underway. Sixteen countries, including Japan, are
involved in this study. The results of the MGTX study
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2016, vol. 17, no. 3
in addition to novel immunotherapy will provide new
information on the role of thymectomy. Several new
immune-mediated therapies have also become avail-
able. In the future, the establishment of a novel
therapeutic strategy is expected for this disorder.
Conflicts of interest
The authors declare no conflicts of interest with respect
to this article.
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