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Myasthenia gravis

Diagnosis and management of

myasthenia gravis
Sivakumar Sathasivam MRCP (UK), LLM, PhD

Myasthenia gravis is the most common primary disorder of neuromuscular transmission and
one of the most treatable neurological disorders. In this review, Dr Sathasivam examines
the epidemiology, presentation, aetiology, diagnosis and treatment of myasthenia gravis.

motor
nerve
terminal

presynaptic

VGCC
AChE

LRP4
MuSK

LRP4

intrasynaptic

Dok 7

rapsyn

agrin

MuSK

AChR

AChR
rapsyn
muscle
fibre

AChR

ACh

synaptic
basal lamina

VGSC
VGSC

F-actin
postsynaptic

Figure 1. Normal signalling pathways at the neuromuscular junction of antigen targets

involved in myasthenia gravis
Acetylcholine (ACh) is synthesised by choline acetyltransferase in motor neurones. An action
potential arriving at the motor nerve terminal causes influx of calcium through voltage-gated
calcium channels (VGCCs) and triggers the release of ACh from presynaptic vesicles. ACh
crosses the synaptic basal lamina and binds to acetylcholine receptors (AChRs). Opening of
the AChRs generates an action potential in the postsynaptic muscle fibre via the opening of
voltage-gated sodium channels (VGSCs). ACh is hydrolysed by acetylcholinesterase (AChE).
During development, the assembly of the postsynaptic apparatus is mediated by agrin, which
is released from the motor nerve terminal. Agrin binds to the low-density lipoprotein receptorrelated protein 4 (LRP4) and activates muscle-specific tyrosine kinase (MuSK). Subsequent
downstream signalling requires two intracellular adaptors: (a) docking protein 7 (Dok 7),
which bridges activation of MuSK to downstream signalling pathways, and (b) rapsyn, which
tightly binds to AChRs, attaches them to the contractile protein F-actin and leads to dense
AChR clustering at the top of the junctional folds. Three postsynaptic neuromuscular junction
antigenic target proteins have been identified in myasthenia gravis: AChR, MuSK and LRP4

yasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission.
It is characterised clinically by fluctuating painless
muscle weakness, which worsens with exercise and
6

towards the end of the day, and improves with rest. It

is usually caused by antibodies to postsynaptic proteins, of which three namely nicotinic acetylcholine
receptor (AChR), muscle-specific tyrosine kinase
(MuSK) and low-density lipoprotein receptor-related
protein 4 (LRP4) have been identified. Advances in
pulmonary and ventilatory support in conjunction
with treatments developed based on the understanding of the pathophysiology of the disease have made
MG one of the most treatable neurological disorders.
MG can present to or involve a wide variety of specialists such as internal medicine physicians, GPs, neurologists, ophthalmologists, otorhinolaryngologists,
respirator y physicians, cardiothoracic surgeons,
oncologists and intensive care specialists. Since the
response of MG to treatment is generally favourable,
early recognition and prompt treatment is essential
in reducing morbidity and mortality from MG. The
aim and scope of this review is to provide an up-todate, practical and relevant overview of this eminently
treatable condition.
Epidemiology
The annual incidence of MG is reported to range
between 3 and 30 per million population, with the
rates at the upper end of the range reported by
prospective studies probably providing the most accurate estimates.1 The incidence rates have increased
over time due to greater disease awareness and better diagnostic methods. The prevalence of MG is
reported to be approximately 200 per million population now,2 compared with about 5 per million population between 1915 and 1934.3 This increase can
be explained by an aging population, better detection of the antibodies to postsynaptic proteins and
longer survival from treatment advances.4 The influence of geography on incidence and prevalence is difficult to ascertain as most studies have been carried
out in Europe and North America.1,5
In both females and males, the incidence of MG
increases with age. Some studies report a bimodal dis-

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tribution of incidence, especially in females, but this

is an inconsistent finding.1 In young adults, there is a
female preponderance, but the converse is true in
older people.6
Clinical presentation
The extraocular muscles are initially affected in 5060 per cent of cases, but virtually all patients will have
ocular involvement within two years of disease onset.
MG remains purely ocular in 15 per cent of cases.
Only 15 per cent of patients progress from ocular MG
to generalised MG after two years of disease duration.7 When MG generalises, the symptoms of muscle weakness typically progress in a craniocaudal
direction: from the ocular muscles, to the facial muscles, to the lower bulbar muscles, to the truncal muscles, and finally to the limb muscles. Symptom onset
to maximal weakness occurs within the first two years
in more than 80 per cent of cases.3 Despite modern
treatments, at least 20 per cent of patients will experience a myasthenic crisis, defined as weakness necessitating intubation and mechanical ventilation,
usually within the first two years of diagnosis.
Ptosis, due to levator palpebrae weakness, may be
unilateral. Extraocular muscle weakness may mimic
third, fourth or sixth cranial nerve palsies, or internuclear ophthalmoplegia. Difficulty with eye closure
suggests weakness of the orbicularis oculi. Facial muscle weakness may result in an expressionless face, or
a snarl when the patient tries to smile. Jaw weakness
may interfere with mastication. Nasal speech and
nasal regurgitation may occur with palatal weakness,
while dysphagia, dysarthria and choking may result
from weakness of the pharyngeal and tongue musculature. Dysphonia can occur with laryngeal weakness.
In mild disease, neck flexion weakness may be the
only finding. Neck extension weakness causes a head
drop. Upper extremity weakness is commoner than
lower extremity weakness. Mental and physical fatigue
are very common features, and can be debilitating.8
Physical examination should aim to demonstrate
pathological fatigability of muscle strength.
Manoeuvres that may be used include asking the
patient to look up for several minutes (examining for
ptosis or extraocular muscle weakness), counting
aloud to 100 (listening for a nasal or slurred speech),
and repetitively testing the strength of proximal muscles (looking for increasing muscle weakness). If a
patient has generalised muscle weakness with no ocular involvement, the diagnosis of MG should be questioned.
Muscle weakness in MG can be exacerbated by
emotional upset, hot temperature, infection, menwww.progressnp.com

Type of agent

Examples

Anti-infective agents

Aminoglycosides, antimalarials, macrolides,

polymyxins
D-penicillamine, hydroxychloroquine
Beta-blockers, calcium-channel blockers
Non-depolarising drugs, depolarising drugs
Drugs that contain polymyxins, beta-blockers

Antirheumatics
Cardiovascular agents
Neuromuscular blockers
Topical eye preparations

Table 1. Drugs that may exacerbate myasthenia gravis

struation, physical exertion, pregnancy, surgery, thyroid disease (hyperthyroidism or hypothyroidism)

and many classes of drugs (see Table 1).9 In most
cases, the contraindication to drug use is only relative, in which case the drug is best avoided; but when
that is not possible, the patients symptoms should be
closely monitored when the drug is started. Only the
macrolide telithromycin is considered absolutely
contraindicated in MG.10 Live vaccines should not be
given to immunosuppressed patients. D-penicillamine
may induce an immune-mediated MG, which is usually mild, often ocular, and typically remits spontaneously within months of stopping the drug.11
Aetiopathogenesis
Autoantibodies
MG is caused by antibodies against proteins in the
neuromuscular junction postsynaptic membrane (see
Figure 1). Antibodies against AChR are detectable in
50 per cent of MG cases and 85 per cent of generalised MG cases.12 The anti-AChR antibodies are pathogenic because they reduce the number of AChRs at
the neuromuscular junction via three mechanisms:
anti-AChR antibodies bind and crosslink the AChRs,
resulting in increased endocytosis and degradation
of AChRs by the muscle cell;
anti-AChRs bind complement factors at the postsynaptic membrane, leading to focal lysis of the postsynaptic folds at the neuromuscular junction by the
membrane attack complex; and
the destruction of other AChR-associated proteins,
such as utrophin, rapsyn and voltage-gated sodium
channels, impairs neuromuscular transmission as
these proteins are involved in neuromuscular junction formation and maintenance.13
In up to 70 per cent of patients with no detectable
anti-AChR antibodies, antibodies against MuSK, a
transmembrane protein located at the postsynaptic
membrane of the neuromuscular junction, which is
functionally interactive with AChR, have been
detected. 14 The pathogenic mechanisms of antiMuSK antibodies are incompletely understood, but
appear to involve disrupting the membrane ultra-

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structure and electrophysiological function of MuSK,

and the disassembly of AChR clusters.15 The prevalence of anti-MuSK antibody-positive MG is higher in
countries nearer the equator.16 Anti-MuSK antibodies
appear to produce a distinct clinical phenotype, with
patients more commonly female, a predominance of
cranial and bulbar muscle involvement with a higher
frequency of respiratory crises, less limb involvement
and being uncommonly associated with long-term
pure ocular MG.17,18
Approximately 15 per cent of all patients with generalised MG have no detectable serum anti-AChR or
anti-MuSK antibodies. These patients are considered
to have seronegative MG.19 In up to two-thirds of
seronegative MG patients, low-affinity anti-AChR antibodies have been demonstrated on a special cellbased assay where the AChRs are clustered together
with the protein rapsyn.19
Recently, a new antigen target at the neuromuscular junction, known as low-density lipoprotein
receptor-related protein 4 (LRP4), has been identified. LRP4 is an agrin receptor and is required for
agrin-induced activation of MuSK, AChR clustering
and neuromuscular junction formation.20 The pathogenic role of anti-LRP4 antibodies appears to involve
inhibiting interactions between agrin and LRP4, and
reducing AChR clustering.21 The frequency of antiLRP4 antibodies in patients with MG appears to vary
depending on geographical location, ranging from 2
per cent in Japan21 to 50 per cent in Germany.22 A
proportion of patients have both anti-LRP4 and antiMuSK antibodies.21 It has been reported that the
major clinical features of anti-LRP4 antibody-positive
MG are not very different from those of anti-AChR
antibody-positive MG.22 About 5 per cent of generalised MG patients who continue to have undetectable antibodies probably have pathogenic
antibodies against as yet undefined muscle membrane
proteins that interact with AChRs.
Up to 30 per cent of anti-AChR antibody-positive
MG patients have additional antibodies that bind to
epitopes on skeletal and heart muscle tissue, known
as anti-striational antibodies.23 Anti-striational antibodies to the sarcomeric protein titin, the sarcoplasmic calcium channel r yanodine receptor and the
a-subunit of the muscular voltage-gated potassium
channel (Kv1.4) have been extensively investigated.
Anti-striational antibodies do not have a major pathogenic role, but are markers for thymoma and lateonset disease. They are also associated with
autoimmune myocarditis and myositis, and lethal
arrhythmias.24 Although MG patients with anti-Kv1.4
antibodies have been associated with severe disease
8

in a Japanese population, a recent study in a

Caucasian population demonstrated that the presence of these antibodies was associated with mild MG,
suggesting different clinical phenotypes between the
two populations.25
Thymus
The thymus is thought to play an important pathogenic
role in anti-AChR antibody-positive MG, with thymic
hyperplasia present in 65 per cent of cases and thymoma present in 10 per cent of cases.26 Furthermore,
MG occurs in 30 per cent of patients with a thymoma
as a paraneoplastic phenomenon.27 A large body of
evidence implicates the thymus as the main site of
autosensitisation. AChR expression by myoid cells in
the thymus, in the presence of the inflammatory environment within the thymus, is thought to lead to the
induction and maintenance of the anti-AChR autoimmune response in MG.28,29 In anti-MuSK antibodypositive patients, there are minimal thymic changes,
suggesting no pathogenic role of the thymus in this
subtype. In anti-LRP4 antibody-positive MG patients,
no thymus disorder has been established thus far.
Genetic and environmental factors
Certain human leukocyte antigen (HLA) loci and several common variants in HLA-unlinked genes have
been associated with MG susceptibility.30 Many of
these risk-associated genes are widely distributed
among other autoimmune diseases, suggesting shared
pathogenic pathways. Indeed, first-degree relatives of
MG patients have a higher incidence of other autoimmune diseases.31
Several pathogens, such as the Epstein-Barr virus
and poliovirus, have been suggested as potential candidates for driving and perpetuating autoimmunity
in MG. However, many of the studies give contradictory and inconsistent results.15
Diagnostic investigations
The differential diagnosis of MG is wide (see Table
2). A detailed history and physical examination in
conjunction with investigations is often needed to
provide diagnostic clues. A systematic review examining the utility of diagnostic tests in MG concluded that
only anti-AChR antibody testing and single-fibre
electromyography (SFEMG) were adequately validated. However, the anti-MuSK antibody test was not
evaluated in this study.32
Antibody tests
All patients with suspected MG should be tested for
anti-AChR antibodies. The sensitivity of this test is 70-

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Disease

Differentiating clinical features

Botulism
Congenital myasthenic syndromes

Autonomic and pupillary involvement

Onset in infancy or childhood; seronegative; no response to
immunotherapy
Clinical features occur in distribution of the affected cranial nerves
Ascending pattern of muscle weakness; autonomic involvement;
areflexia; sensory signs and symptoms
No ocular muscle weakness except in orbital myositis; constitutional
manifestations common, eg fever, anorexia, weight loss
Ocular muscles usually spared; hyporeflexia, autonomic involvement
No fluctuation of muscle weakness; often no diplopia in presence of
severe ophthalmoplegia
Upper motor neurone features; no ocular involvement; muscle wasting
Dysphagia typically noticed for solid foods before liquids; tongue
weakness and atrophy
Proptosis

Cranial nerve palsies

Guillain-Barr syndrome
Inflammatory myopathies
Lambert Eaton myasthenic syndrome
Mitochondrial cytopathies
Motor neurone disease
Oculopharyngeal muscular dystrophy
Thyroid eye disease
Table 2. Differential diagnoses of myasthenia gravis

95 per cent for generalised MG and 50-75 per cent

for ocular MG.33 Anti-AChR antibody concentrations
do not reliably predict disease severity in individual
patients. If anti-AChR antibodies are negative, antiMuSK antibodies should be tested. In seronegative
patients, there is a seroconversion rate of 15 per cent
after one year.34 Immunosuppression can occasionally lead to disappearance of antibodies.34 Detection
of anti-striational antibodies may give an indication
of the disease phenotype and prognosis.
Neurophysiology
Repetitive nerve stimulation (RNS) and SFEMG are
the most commonly used neurophysiological tests.
Results can be misleading in patients on chronic highdose acetylcholinesterase inhibitors. If there is doubt,
then it is better, if possible, to stop these drugs for up
to a week before the tests. Detailed descriptions of
the methodology behind RNS and SFEMG are
beyond the scope of this article, but a brief overview
of the main principles of these tests, including their
sensitivities and specificities are discussed.
RNS at stimulation rates of 3-10 Hz typically produces a progressive decrement in the amplitude of
the compound muscle action potential. The test is
approximately 80 per cent positive in generalised MG,
but may be negative in 50 per cent of ocular MG.
Overall, sensitivity is approximately 75 per cent.35 The
specificity of RNS is variable and depends partly on
which nerve is tested.
SFEMG is the most sensitive diagnostic test in MG
and should be performed if RNS is normal and a
neuro muscular junction disorder is suspected. It
shows increased jitter (trial-to-trial variation in the
latency from stimulus to response) and intermittent
www.progressnp.com

impulse blocking (failure of excitation of muscle

fibers) in MG. Sensitivity of SFEMG is as high as 99
per cent in generalised MG and is approximately 80
per cent in ocular MG.36 The specificity of SFEMG is
variable and an abnormal test can be seen in other
conditions such as mitochondrial cytopathy, motor
neurone disease or radiculopathy.
Edrophonium test
The edrophonium or tensilon test is a bedside test in
which edrophonium chloride, a short-acting acetylcholinesterase inhibitor, is administered. The aim is to
demonstrate reversibility of muscle weakness and can
only be performed if there is unequivocal weakness
present that can be measured objectively. It should be
performed double-blind and placebo-controlled. The
sensitivity of the test is as high as 88 per cent for generalised MG and 92 per cent for ocular MG, with specificities of 97 per cent for both disease forms.37 It is
prudent to administer atropine prophylactically
because of the risk of bradykinesia and cardiac arrest.
It is probably best to avoid doing the test in the elderly.
Ice pack test
A quick method to distinguish ptosis due to MG from
other causes is the ice pack test. An ice cube is placed
over the drooping eyelid for about two minutes, and
if there is improvement in the ptosis, it suggests a
neuromuscular transmission disorder. Results pooled
from six studies gave this test a sensitivity of 89 per
cent and a specificity of 100 per cent.38
Imaging
All MG patients should have computed tomography
(CT) or magnetic resonance imaging (MRI) of the

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thorax to screen for thymoma or thymic hyperplasia.

Imaging of the mediastinum should be repeated in
the context of a MG relapse after a period of stable
disease to exclude the development of a thymoma,
which can occur later in the disease course.
Treatment
In MG, treatment strategies tend to vary even among
different physicians practising within the same countr y. There are no UK guidelines and treatment
depends on the experience and familiarity of the
treating physician to a particular regimen. Figure 2
depicts a general treatment flowchart that I regularly
use, but it is important to note that treatment regimens should be individualised as no single treatment
strategy is appropriate for every patient. The present
day prognosis of MG is excellent with current treatment regimens having reduced the disease mortality
from 70 per cent between 1915 and 19343 to less than
5 per cent now.39 The quality of the scientific evidence
for the use of the various treatments in MG is variable
(see Table 3).40
Symptomatic treatment
The first-line symptomatic treatment is acetylcholinesterase inhibitors, usually pyridostigmine.41,42

Other acetylcholinesterase inhibitors are rarely used

because of their inferior pharmacodynamic profiles
and tolerability. Two observational studies concluded
that pyridostigmine was more effective than neostigmine with fewer adverse events.43,44
Increasing tolerance to pyridostigmine over time
may necessitate dose escalation. Anti-MuSK antibodypositive patients tend to show non-responsiveness to
pyridostigmine.45 High doses of pyridostigmine may
lead to desensitisation of AChRs, inducing muscle
weakness leading to a cholinergic crisis, which can be
difficult to distinguish from a myasthenic crisis. If
there is any concern, pyridostigmine can be temporarily withdrawn and the patient monitored for improvement. The majority of MG patients will fail to achieve
adequate response on pyridostigmine alone and will
require further immunosuppression.
Short-term immunosuppression
Oral prednisolone is the most commonly used firstline short-term immunosuppressant.46,47 Two double-blind trials of corticosteroids versus placebo gave
conflicting results, 48,49 while one open-label randomised trial comparing high-dose corticosteroid versus low-dose corticosteroid showed no significant
difference in efficacy.50 Prednisolone is typically used

IVIG or PE in
emergency

Myasthenia
gravis

Thymoma

Complete
response

Acetylcholinesterase
inhibitor

Thymectomy

Complete
response

Incomplete
response

Add prednisolone +
azathioprine (or other
immunosuppressants)

Incomplete
response

Young, fit and

anti-AChR positive

Figure 2. A treatment flowchart for the management of myasthenia gravis. IVIG, intravenous immunoglobulin; PE, plasma exchange
10

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z Review

Treatment

Mode of action

Evidence
class*

Serious adverse
events

Recommendation

Symptomatic
Pyridostigmine

Inhibits acetylcholinesterase

Class III

Cholinergic crisis

First line

Class II

Cushingoid features, diabetes,

hypertension, osteoporosis,
psychiatric disorders

First line

Class I

Haematopoietic suppression,
hepatotoxicity, malignancy,
pancreatitis
Hypertension, malignancy,
nephrotoxicity

First line

Short-term immunosuppression
Prednisolone
Inhibits T-cell activation and
impairs function of cells from
the monocyte/macrophage
lineage
Long-term immunosuppression
Azathioprine
Purine antagonist that inhibits
DNA synthesis and cell
proliferation
Ciclosporin
Calcineurin-mediated inhibition
of T-cell interleukin-2 production

Class I

Cyclophosphamide

DNA-alkylating agent that

blocks cell proliferation

Class I

Bladder toxicity, haematopoietic

suppression, infertility, malignancy,
opportunistic infections

Methotrexate

Folate antagonist that inhibits de

novo synthesis of purines and
pyrimidines
Inhibits T-cell proliferation
by blocking purine synthesis

Class II

Haematopoietic suppression,
hepatotoxicity, pneumonitis

Class I

Chimeric monoclonal
antibody against the B-cell
surface marker CD20
Calcineurin-mediated
inhibition of T-cell
interleukin 2 production

Class IV

Haematopoietic suppression,
hepatotoxicity, opportunistic
infections, progressive multifocal
leukoencephalopathy
Neutropaenia, opportunistic
infections, progressive multifocal
leukoencephalopathy
Hyperglycaemia, hypertension,
malignancy, nephrotoxicity

Mycophenolate
mofetil

Rituximab

Tacrolimus

Rapid short-term immunomodulation

Immunoglobulin
Interference of signalling via Fc
receptors, neutralisation of
activated complement, suppression
of idiotypic antibodies, modulation
of proinflammatory cytokines
Plasma exchange
Removes circulating antibodies,
cytokines, immune complexes,
and other inflammatory
mediators
Long-term immunomodulation
Thymectomy
Disrupts B-cells producing
anti-AChR antibodies

Class I

To be considered in patients
intolerant of or unresponsive
to azathioprine, methotrexate,
mycophenolate mofetil or tacrolimus
To be considered in patients
intolerant of or unresponsive
to azathioprine, methotrexate,
mycophenolate mofetil, tacrolimus
or ciclosporin
Second line in patients intolerant
of or unresponsive to azathioprine
Third line in patients intolerant
of or unresponsive to azathioprine,
methotrexate or tacrolimus
To be considered only in patients
with severe refractory MG
unresponsive to other treatments
Third line in patients intolerant
of or unresponsive to azathioprine,
methotrexate or mycophenolate
mofetil

Class I

Aseptic meningitis, solute-induced

renal failure, thrombotic
complications, volume overload

First line

Class I

Air embolism, disturbances in acidbase homeostasis, hypocalcaemia,

hypotension, infection, pneumothorax,
thrombosis, volume overload

First line

Class II

General risks of surgery

Always indicated in patients with a

thymoma; in non-thymomatous
anti-AChR antibody-positive
patients, to be considered if MG is
not controlled adequately with
medical treatment

*Evidence

Class I - randomised controlled trials available; Class II - controlled trials without randomisation or randomised trials with small patient number;
Class III - uncontrolled trials; Class IV - case series

Table 3. Treatment options and recommendations in myasthenia gravis

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as an interim measure while titrating up doses of

other immunosuppressants and waiting for those to
have maximum effect. A steroid dip due to a temporary worsening of MG four to ten days after starting prednisolone may occur if prednisolone is started
at a high dose. To avoid this, it is recommended that
prednisolone be started at a low dose on alternate
days51 and gradually titrated upwards.52 In certain
cases, a daily prednisolone regimen may be more suitable, for example in diabetic patients or those intolerant to the fluctuations inherent to an alternate day
regimen. Premature or rapid tapering of cortico steroids should be avoided as this is likely to lead to a
relapse of symptoms.
Long-term immunosuppression
Several different immunosuppressants are used as
long-term corticosteroid-sparing agents in MG.46,53
Azathioprine is the most frequently used. A randomised unblinded trial of azathioprine plus initial
prednisolone versus prednisolone alone, 54 and
another randomised double-blind trial of azathioprine plus prednisolone versus prednisolone plus
placebo55 have established the efficacy of azathioprine in MG. When azathioprine is not tolerated or if
the MG remains difficult to control, alternative
immunosuppressants can be used including
methotrexate (commonly used second line),
mycophenolate mofetil or tacrolimus.
A single-blind trial of methotrexate versus azathioprine demonstrated similar efficacy between the two
drugs.56 Two randomised controlled trials failed to
show that mycophenolate mofetil plus prednisolone
was more effective than prednisolone plus
placebo.57,58 Several reasons have been suggested for
these negative results: the generally mild disease status of patients, the better than expected response to
prednisolone and the relatively short duration of the
trials. 59 A randomised double-blind placebo-controlled trial of tacrolimus plus prednisolone versus
prednisolone plus placebo, 60 and another randomised unblinded non-placebo controlled trial of
tacrolimus plus corticosteroids with or without plasma
exchange versus no tacrolimus plus corticosteroids
with or without plasma exchange, 61 have demonstrated that tacrolimus is efficacious in the treatment
of MG.
Ciclosporin or cyclophosphamide are reserved for
severe cases of MG refractory to the other previously
mentioned immunosuppressants, but their use is
limited by potentially serious adverse events.40,46 A
randomised double-blind trial of ciclosporin
monotherapy versus placebo, 62 and another ran12

domised double-blind trial of ciclosporin plus prednisolone versus prednisolone plus placebo 63 have
clearly shown that ciclosporin is effective in MG.
Cyclophosphamide was shown to be effective in a randomised double-blind trial of intravenous pulsed
cyclophosphamide plus prednisolone versus prednisolone plus placebo.64 Rituximab is a useful option
in severe refractory MG unresponsive to other treatments,65 but this treatment is very expensive.
Rapid short-term immunomodulation
Intravenous immunoglobulin (IVIG) or plasma
exchange (PE) is used in acute severe exacerbations
of generalised MG or to optimise muscle strength
prior to surgery.66-68 IVIG and PE are equal first-line
treatments because they have similar efficacy.
However, because IVIG is easier to administer and
associated with fewer adverse events than PE, the former is often preferred. Two randomised controlled
trials comparing IVIG with placebo established the
efficacy of this treatment in acute severe MG.69,70 Two
randomised controlled trials comparing IVIG to PE
showed no significant differences between the two
treatments in acute exacerbation of MG 71 or in
chronic moderate-to-severe MG.72 One randomised
controlled trial of IVIG versus corticosteroids,67 and
another of PE versus corticosteroids did not reveal significant differences between the treatments tested.73
Long-term immunomodulation
Thymectomy is always indicated in patients with a thymoma because of its malignant potential.74 However,
tumour removal does not always lead to remission of
MG. Indeed, MG in thymomatous patients is commonly more severe than in non-thymomatous
patients.
Thymectomy has been a mainstay of treatment for
non-thymomatous MG for over 50 years. However,
randomised trials of thymectomy versus medical treatment are lacking. A rigorous evidence-based analysis
of 28 studies published between 1953 and 1998 concluded that it only might improve the chance of
remission as the benefit of surger y was generally
small.75 Thymectomy within the first three years of
diagnosis may lead to a better response. The procedure is commonly restricted to patients under the age
of 60-65 years because older patients usually have an
atrophic thymus. Anti-MuSK antibody-positive
patients tend to have a poorer response, probably
explained by the lack of typical thymus pathology in
these patients. There is controversy as to whether a
minority of seronegative MG patients benefit from
thymectomy. An ongoing international thymectomy

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trial in non-thymomatous patients may help clarify

further the right candidates for thymectomy.
Conclusion
Advances in our understanding of the pathophysiology of MG have led to more effective treatments for
this condition. Earlier disease recognition combined
with prompt appropriate treatment are key factors in
improving the prognosis of MG. Therefore, the need
to educate and improve disease awareness is important in the diagnosis and management of this eminently treatable neurological disorder.
Declaration of interests
None declared.
Dr Sathasivam is a Consultant Neurologist at The Walton
Centre NHS Foundation Trust, Liverpool
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1. McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis:
a systematic literature review. Neuroepidemiology 2010;34:171-83.
2. Phillips LH 2nd. The epidemiology of myasthenia gravis. Ann NY Acad
Sci 2003;998:407-12.
3. Grob D, Brunner N, Namba T, et al. Lifetime course of myasthenia
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