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REVIEW

CME EDUCATIONAL OBJECTIVE: Readers will recognize the mechanisms, signs, and treatment of myasthenia gravis
CREDIT
YUEBING LI, MD, PhD YEESHU ARORA, MD KERRY LEVIN, MD
Department of Neurology, Neuro- Department of Neurology, Neuro- Chairman, Department of Neurology, Neuro-
muscular Center, Neurological Institute, muscular Center, Neurological Institute, muscular Center, Neurological Institute,
Cleveland Clinic Cleveland Clinic Cleveland Clinic; Professor of Medicine, Cleveland
Clinic Lerner College of Medicine of Case-Western
Reserve University, Cleveland, OH

Myasthenia gravis:
Newer therapies offer sustained
improvement
ABSTRACT
C urrent therapies for myasthenia gravis
can help most patients achieve sustained
improvement. The overall prognosis has dra-
Myasthenia gravis is a prototypical antibody-mediated
autoimmune neuromuscular disorder. Treatments have matically improved over the last 4 decades:
improved over the past 30 years, leading to significantly the mortality rate used to be 75%; now it is
fewer deaths and better quality of life. Future research 4.5%.1
Myasthenia gravis is the most common dis-
should further elucidate its pathogenesis, reveal better
order of neuromuscular junction transmission
ways to diagnose it, and yield new treatments. and is also one of the best characterized au-
KEY POINTS toimmune diseases. However, its symptoms
primarily weaknessvary from patient to pa-
In most cases of myasthenia gravis, the patient has anti- tient, and in the same patient, by time of day
bodies against acetylcholine receptor (AChR) or muscle- and over longer time periods. The variation
specific tyrosine kinase (MuSK). in symptoms can be very confusing to undi-
agnosed patients and puzzling to unsuspect-
ing physicians. Such diagnostic uncertainty
Myasthenia gravis is diagnosed by clinical signs, bedside can give the patient additional frustration and
tests (the ice-pack test or the edrophonium test), sero- emotional stress, which in turn exacerbate his
logic tests for AChR antibodies or MuSK antibodies, and or her condition.
electrophysiologic tests. In this review, we will give an overview of
the pathogenesis, clinical manifestations, di-
Acetylcholinesterase inhibitors are the first-step therapy, agnosis, and treatment of myasthenia gravis.
but patients who have moderate to severe symptoms
require some form of immunomodulating therapy. TWO PEAKS IN INCIDENCE BY AGE

A number of drugs can exacerbate weakness in myasthe- The annual incidence of myasthenia gravis is
approximately 10 to 20 new cases per million,
nia gravis and should be avoided or used with caution.
with a prevalence of about 150 to 200 per mil-
These include penicillamine, interferons, procainamide, lion.2
quinidine, and antibiotics such as quinolones and amino- The age of onset has a bimodal distribution,
glycosides. with an early incidence peak in the second to
third decade with a female predominance and
a late peak in the 6th to the 8th decade with a
male predominance.2
Myasthenia gravis is commonly associated
doi:10.3949/ccjm.80a.13044 with several other autoimmune disorders, in-
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MYASTHENIA GRAVIS

Drugs discussed in this article MuSK antibody-positive myasthenia gravis


Like AChR, MuSK is a transmembrane com-
Azathioprine (Imuran) ponent of the postsynaptic neuromuscular
Cyclophosphamide (Cytoxan) junction. During formation of the neuromus-
Cyclosporine (Neoral, Sandimmune) cular junction, MuSK is activated through the
binding of agrin (a nerve-derived proteogly-
Immune globulin (Gammagard) can) to lipoprotein-related protein 4 (LRP4),
Methotrexate (Trexall) after which complicated intracellular signal-
Mycophenolate mofetil (CellCept) ing promotes the assembly and stabilization of
AChR.6
Penicillamine (Cuprimine)
Unlike AChR antibodies, antibodies
Prednisolone against MuSK do not activate the comple-
Prednisone ment system, and complement fixation is not
Procainamide (Pronesty) essential for clinical myasthenic symptoms
to appear.7 Also, myasthenia gravis with
Pyridostigmine (Mestinon, Timespan) MuSK antibodies is rarely associated with
Quinidine thymoma.8
Rituximab (Rituxan) The precise mechanism by which MuSK
antibody impairs transmission at the neuro-
muscular junction has been a mystery until
cluding hypothyroidism, hyperthyroidism, recently. Animal models, including MuSK-
systemic lupus erythematosus, rheumatoid ar- mutant mice and mice injected with MuSK
thritis, vitiligo, diabetes, and, more recently protein or with purified immunoglobulin G
recognized, neuromyelitis optica.3 from patients with this disease, have revealed
a significant reduction of AChR clusters and
ANTIBODIES AGAINST AChR AND MuSK destruction of neuromuscular junction struc-
tures.7,912
Testing again In most cases of myasthenia gravis the patient
In addition, MuSK antibodies produce pre-
612 months has autoimmune antibodies against constitu- synaptic dysfunction, manifesting as a reduc-
ents of the neuromuscular junction, specifical- tion of acetylcholine content. This informa-
later may ly acetylcholine receptor (AChR) and mus- tion is based on studies in mice and on in vitro
detect AChR cle-specific tyrosine kinase (MuSK) (FIGURE 1). electrophysiologic analyses of neuromuscular
junctions from a patient with this disease.7,913
antibody AChR antibody-positive myasthenia gravis Finally, MuSK antibodies may indirectly af-
in about 15% When antibodies bind to AChR on the post- fect the recycling of acetylcholine. After post-
of patients who synaptic membrane, they cross-link neighbor- synaptic activation, acetylcholine is normally
ing AChR units, which are absorbed into the hydrolized by acetylcholinesterase, which is
were initially muscle fiber and are broken up.4 In addition, located in the synaptic cleft but anchored to
seronegative the complement system is activated to mediate MuSK on the postsynaptic membrane. MuSK
further damage on the postsynaptic membrane. antibodies block the binding of MuSK to
AChR antibodies may come from germi- acetylcholinesterase, possibly leading to less
nal centers of the thymus, where clustered accumulation of acetylcholinesterase.14 This
myoid cells express AChR on the plasma process may explain why patients with MuSK
membrane surface.5 About 60% of AChR antibody-positive myasthenia gravis tend to
antibody-positive myasthenia gravis patients respond poorly to acetylcholinesterase inhibi-
have an enlarged thymus, and 10% have a tors (more about this below).
thymomaa tumor of the epithelial cells of
this organ. Conversely, about 15% of patients Seronegative myasthenia gravis
with a thymoma have clinical myasthenia gra- In a series of 562 consecutive patients with
vis, and an additional 20% possess antibodies generalized weakness due to myasthenia gra-
against AChR in the serum without myas- vis, 92% were positive for AChR antibody,
thenic symptoms.5 3% were positive for MuSK antibody, and
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LI AND COLLEAGUES

Myasthenia gravis, an autoimmune disease


Normal

At the neuromuscular junction, motor


neurons release acetylcholine (ACh),
which diffuses across the synaptic
space and binds to receptors on the
muscle cell membrane, designated
AChR. If enough acetylcholine binds
to enough receptors, sodium channels
open, and the muscle depolarizes and
contracts.

Myasthenia gravis Antibodies to AChR Antibodies to MuSK

Antibody
Antibody

Above middle, most people with myasthenia gravis have antibodies that block, alter, or destroy AChR (the last by cross-linking
neighboring receptors so that they are absorbed and destroyed, and also by complement activation). The result is less transmis-
sion of nerve impulses, leading to muscle weakness.
Above right, a minority of myasthenic patients have antibodies to another constituent of the neuromuscular junction, muscle-
specific tyrosine kinase (MuSK), leading to reduction of AChR clustering and to release of acetylcholinesterase (AChE). Others
have no detectable antibodies to either AChR or MuSK. CCF
Medical Illustrator: Amanda Mendelsohn 2013

Figure 1

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MYASTHENIA GRAVIS

TABLE 1 radioimmunoassays in a solution phase. With


a sensitive cell-based immunofluorescence
Major symptoms of myasthenia gravis assay, low-affinity antibodies to clustered
AChRs were detected in 66% of patients
Location Symptoms
with generalized myasthenia gravis and in
Ocular Ptosis, sometimes alternating from one eye to the 50% of those with ocular myasthenia gravis
other who were seronegative on standard assays.19,20
Diplopia These low-affinity AChR antibodies can also
Weakness of eye closure activate complement in vitro, increasing the
Bulbar Dysarthria with nasal speech
likelihood that they are pathogenic. However,
Dysphagia with nasal regurgitation assays to detect low-affinity AChR antibodies
Facial weakness are not yet commercially available.
Within the past year, three research groups
Cervical Neck flexor weakness causing head-lag upon lifting up independently reported detecting antibodies
from lying down to LRP4 in 2% to 50% of seronegative myas-
Neck extensor weakness manifesting as posterior neck thenia gravis patients. This wide variation in
pain and head-drop
the prevalence of LRP4 antibodies could be
Limb Proximal limb weakness, arm more than leg related to patient ethnicity and methods of
Finger extensor weakness detection.2123 LRP4 is a receptor for agrin and
is required for agrin-induced MuSK activation
Respiratory Intercostal and diaphragm muscle weakness causing and AChR clustering. LRP antibodies can acti-
respiratory failure
Accessory muscle usage sometimes not prominent
vate complement; therefore, it is plausible that
LRP4 antibody binding leads to AChR loss
on the postsynaptic membrane. However, ad-
5% were seronegative (possessing neither an- ditional study is needed to determine if LRP4
tibody).15 In contrast, about 50% of patients antibodies are truly pathogenic in myasthenia
with purely ocular myasthenia gravis (ie, with gravis.
Muscle isolated weakness of the levator palpebrae
weakness superioris, orbicularis oculi, or oculomotor A DISORDER OF FATIGABLE WEAKNESS
muscles) are seropositive for AChR antibody.
is often worse Only a few ocular MuSK antibody-positive Myasthenia gravis is a disorder of fatigable
later in the day cases have been described, leaving the rest weakness producing fluctuating symptoms.
seronegative. Rarely, both antibodies can be Symptoms related to the involvement of spe-
or after detected in the same patient.16 cific muscle groups are listed in TABLE 1. Muscle
exercise In patients who are negative for AChR weakness is often worse later in the day or af-
antibodies at the time of disease onset, sero- ter exercise.
conversion may occur later during the course. Ocular myasthenia gravis accounts for
Repeating serologic testing 6 to 12 months about 15% of all cases. Of patients initially
later may detect AChR antibodies in approxi- presenting with ocular symptoms only, two-
mately 15% of patients who were initially se- thirds will ultimately develop generalized
ronegative.15,17 symptoms, most within the first 2 years.24
The clinical presentation, electrophysio- No factor has been identified that predicts
logic findings, thymic pathologic findings, and conversion from an ocular to a generalized
treatment responses are similar in AChR an- form.
tibody-positive and seronegative myasthenia Several clinical phenotypes of MuSK an-
gravis.17 Muscle biopsy study in seronegative tibody-positive myasthenia gravis have been
cases demonstrates a loss of AChR as well.18 described. An oculobulbar form presents with
Based on these observations, it has been diplopia, ptosis, dysarthria, and profound atro-
proposed that seronegative patients may phy of the muscles of the tongue and face. A
have low-affinity antibodies that can bind to restricted myopathic form presents with prom-
tightly clustered AChRs on the postsynaptic inent neck, shoulder, and respiratory weakness
membrane but escape detection by routine without ocular involvement. A third form is
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LI AND COLLEAGUES

TABLE 2
Differential diagnoses of myasthenia gravis
Main Differential Clinical features distinct from Ancillary testing features distinct
symptom diagnoses autoimmune myasthenia gravis from autoimmune myasthenia
gravis
Ptosis Thyroid Stable restricted ophthalmopathy Enlarged extraocular muscles on imaging
and ophthalmopathy
diplopia
Mitochondrial Chronic progressive ptosis and Muscle biopsy revealing ragged red fibers,
myopathy ophthalmoparesis, diplopia rare, slow presence of specific mutations
saccadic movement
Oculopharyngeal Autosomal dominant inheritance Muscle biopsy revealing intranuclear
dystrophy Slowly progressive ptosis and dyspha- inclusion
gia in 4th and 5th decades Mutations in PABPN1 gene
Myotonic dystrophy Autosomal dominant inheritance Electromyogram revealing myotonia
Characteristic facial features, distal Mutations in DMPK or CNBP gene
weakness, myotonia

Dysarthria Brainstem mass lesion Hyperreflexia, nonfluctuating Brainstem imaging findings


and or encephalitis symptoms
dysphagia
Motor neuron disease Progressive course, spastic dysarthria, Electromyogram revealing widespread
tongue atrophy, hyperreflexia, asym- denervation or reinnervation
metrical weakness, fasciculations

Proximal Lambert-Eaton Leg more than arm weakness, bulbar Positive voltage-gated calcium channel
muscle myasthenic syndrome symptoms rare, autonomic dysfunction antibody, facilitation on electrophysiologic
weakness (dry mouth, erectile dysfunction) testing
Congenital myasthenic Positive family history, early childhood Lack of AChR or MuSK antibody,
syndromes onset with slow and steady progres- presence of specific mutations
sion
Botulism Prominent autonomic features Facilitation on electrophysiologic testing
Guillain-Barr syndrome Hyporeflexia, sensory loss, ataxia High cerebrospinal fluid protein
Chronic inflammatory Nerve conduction study showing features
demyelinating suggesting acquired demyelination
polyneuropathy
Myopathy or limb-girdle Nonfluctuating weakness, ocular Creatine phosphokinase elevation, muscle
dystrophy findings rare biopsy revealing myopathic changes

a combination of ocular and proximal limb positive patients demonstrated no response,


weakness, indistinguishable from AChR anti- poor tolerance, or cholinergic hypersensitiv-
body-positive disease.25 ity to these agents.25 Fortunately, most MuSK
MuSK antibody-positive patients do not antibody-positive patients have a favorable
respond as well to acetylcholinesterase inhibi- response to immunosuppressive therapy
tors as AChR antibody-positive patients do. sometimes a dramatic improvement after plas-
In one study, nearly 70% of MuSK antibody- mapheresis.8
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MYASTHENIA GRAVIS

DIAGNOSIS OF MYASTHENIA GRAVIS antibodies are present in 80% to 90% of pa-


tients with generalized myasthenia gravis and
The common differential diagnoses for myas- 50% of those with ocular myasthenia gravis.
thenia gravis are listed in TABLE 2. Testing for blocking and modulating AChR
The essential feature of myasthenia gravis is antibodies increases the sensitivity by less
fluctuating muscle weakness, often with fatigue. than 5% when added to testing for binding
Many patients complain of weakness of specific antibodies.
muscle groups after their repeated usage. Pain is AChR antibody titers correlate poorly with
generally a less conspicuous symptom, and gen- disease severity between patients. However, in
eralized fatigue without objective weakness is individual patients, antibody titers tend to go
inconsistent with myasthenia gravis. down in parallel with clinical improvement.
Signs of muscle weakness may include MuSK antibody is detected in nearly half
droopy eyelids, diplopia, inability to hold the of myasthenia gravis patients with generalized
head straight, difficulty swallowing or chew- weakness who are negative for AChR antibody.
ing, speech disturbances, difficulty breathing,
and difficulty raising the arms or rising from Electrophysiologic tests
the sitting position. A historical pattern of Electrophysiologic tests can usually confirm
ptosis alternating from one eye to the other is the diagnosis of seronegative myasthenia gra-
fairly characteristic of myasthenia gravis. vis. They are also helpful in seropositive pa-
The weakness of orbicularis oculi is easily tients who have unusual clinical features or a
identified on examination by prying open the poor response to treatment.
eyes during forced eye closure. Limb weakness Repetitive nerve stimulation studies use
is usually more significant in the arms than in a slow rate (25 Hz) of repetitive electrical
the legs. An often-neglected feature of myas- stimulation. The study is positive if the motor
thenia gravis is finger extensor weakness with response declines by more than 10%. How-
a relative sparing of other distal hand muscles.2 ever, a decremental response is not specific
The ice-pack test is performed by placing for myasthenia gravis, as it may be seen in
Two-thirds a small bag of ice over the ptotic eye for 2 to 5 other neuromuscular disorders such as motor
of patients minutes and assessing the degree of ptosis for neuron disease or Lambert-Eaton myasthenic
any noticeable improvement. This test is not syndrome.
who present very helpful for assessing ocular motor weak- This test is technically easier to do in dis-
initially only ness. tal muscles than in proximal muscles, but less
The edrophonium (Tensilon) test can be sensitive. Therefore, proximal muscles such
with ocular used for patients with ptosis or ophthalmopa- as the trapezius or facial muscles are usually
symptoms resis. Edrophonium, a short-acting acetylcho- also sampled to maximize the yield. To further
eventually linesterase inhibitor, is given intravenously maximize the sensitivity, muscles being tested
while the patient is observed for objective im- should be warm, and acetylcholinesterase in-
develop provement. The patients cardiovascular sta- hibitors should be withheld for 12 hours before.
generalized tus should be monitored for arrhythmias and Repetitive nerve stimulation studies in dis-
hypotension. Atropine should be immediately tal muscles are positive in approximately 75%
symptoms available in case severe bradycardia develops. of patients with generalized myasthenia gravis
The ice-pack test and the edrophonium and in 30% with ocular myasthenia gravis.26
test can give false-negative and false-positive Single-fiber electromyography is more
results, and the diagnosis of myasthenia gravis technically demanding than repetitive nerve
must be verified by other diagnostic tests. stimulation and is less widely available. It is
usually performed with a special needle elec-
Testing for antibodies trode that can simultaneously identify action
Testing for circulating AChR antibodies, potentials arising from individual muscle fi-
MuSK antibodies, or both is the first step in the bers innervated by the same axon.
laboratory confirmation of myasthenia gravis. Variability in time of the second action
There are three AChR antibody subtypes: potential relative to the first is called jitter.
binding, blocking, and modulating. Binding Abnormal jitter is seen in more than 95%
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LI AND COLLEAGUES

of patients with generalized myasthenia gra- tion are penicillamine, interferons, procain-
vis and in 85% to 90% of those with ocular amide, quinidine, and antibiotics, including
myasthenia gravis.26,27 However, abnormal quinolones and aminoglycosides. A more
jitter can also be seen in other neuromuscu- comprehensive list of medications that may
lar diseases such as motor neuron disease or exacerbate myasthenia gravis symptoms can
in neuromuscular junctional disorders such as be found in a review by Keesey.2
Lambert-Eaton myasthenic syndrome.
Rapid induction immunotherapies:
Imaging studies PLASMAPHERESIS, IMMUNE GLOBULIN
Chest computed tomography or magnetic
resonance imaging with contrast should be Both plasmapheresis and intravenous immune
performed in all myasthenia gravis patients to globulin act quickly over days, but in most pa-
look for a thymoma. tients their effects last only a few weeks. Both
are used as rescue therapies for myasthenic cri-
TREATMENT OF MYASTHENIA GRAVIS ses, bridging therapy to slow-acting immuno-
therapeutic agents, or maintenance treatment
Acetylcholinesterase inhibitors for poorly controlled cases.
As a reasonable first therapy in mild cases of Several retrospective studies have con-
myasthenia gravis, acetylcholinesterase inhib- firmed the efficacy of plasmapheresis in more
itors slow down the degradation of acetylcho- than 80% of patients with generalized symp-
line and prolong its effect in the neuromuscular toms.28,29
junction, but they are not disease-modifying
In a randomized trial in patients with gen-
and their benefits are mild. eralized therapies, intravenous immune globu-
Pyridostigmine is the usual choice of acetyl- lin improved muscle strength in the group of
cholinesterase inhibitor. Its onset of action is patients with severe symptoms.30 The effective
rapid (15 to 30 minutes) and its action lasts dosage of intravenous immune globulin varies
for 3 to 4 hours. For most patients, the effec- from 1 to 2 g/kg without observed difference
tive dosage range is 60 mg to 90 mg every 4 to between doses.31 Trials comparing the efficacy CT or MRI
6 hours. A long-acting form is also available of intravenous immune globulin and plasma- with contrast
and can be given as a single nighttime dose. pheresis in acute and severe myasthenia gravis
did not reveal a difference in efficacy.32,33 In- should be
Immunomodulating therapy travenous immune globulin at a minimal dose done in all
Patients who have moderate to severe symp- of 0.4 g/kg every 3 months has been success-
toms require some form of immunomodulat- fully used as a long-term maintenance mono-
myasthenia
ing therapy. therapy, and such a role could be expanded to gravis patients
Plasmapheresis or intravenous immune more patients with further studies.34 to look for
globulin is reserved for patients with severe or The choice between plasmapheresis and
rapidly worsening disease because their benefi- intravenous immune globulin is often based a thymoma
cial effects can be seen within the first week of on the ability of a patient to tolerate each
treatment. treatment and on the availability of the plas-
Longer-acting immunotherapies (cortico- mapheresis procedure. Intravenous immune
steroids, azathioprine, mycophenolate mofetil globulin is easier to administer, is associated
and others) have a slower onset of responses with fewer adverse events related to vascular
but provide sustained benefits. Which drug to access, and is therefore more appropriate than
use depends on factors such as comorbidity, plasmapheresis in some centers.
side effects, and cost.
CHRONIC MAINTENANCE
Drugs to avoid IMMUNOMODULATING TREATMENT
A number of medications can exacerbate
weakness in myasthenia gravis and should Corticosteroids
be avoided or used with caution. The list is Prednisone, the most commonly used agent,
long, but ones that deserve the most atten- leads to remission or marked improvement in
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MYASTHENIA GRAVIS

70% to 80% of patients with ocular or gener- months, and it often reaches its maximal ef-
alized myasthenia gravis.35 It may also reduce ficacy only after 1 to 2 years of treatment.38
the progression of ocular myasthenia gravis to In a study of 78 myasthenia gravis patients,
the generalized form.36 91% improved when treated with azathioprine
The effective dose of prednisone depends on alone or together with prednisone.39 In anoth-
the severity and distribution of symptoms. Some er study using azathioprine and prednisolone
patients may need up to 1.0 mg/kg/day (usually for generalized myasthenia gravis, nearly two-
50 to 80 mg per day). In patients with mild to thirds of patients came off prednisolone while
moderate symptoms, a lower maximal dosage maintaining remission for 3 years.38
such as 20 to 40 mg per day can be sufficient. A typical maintenance dose is 2 to 3 mg/
Within 1 to 2 weeks after starting high-dose kg/day. Common side effects are nausea, vom-
prednisone, up to 50% of patients may develop iting, and malaise. Less frequent side effects
a transient deterioration, including possible include hematologic abnormalities, abnor-
precipitation of a myasthenic crisis.37 For this mal liver function, and pancreatitis. Monthly
reason, high-dose prednisone is commonly monitoring of complete blood cell counts and
started only in hospitalized patients who are liver function tests is warranted for the first 6
also receiving plasmapheresis or intravenous months, then less often.
immune globulin. Otherwise, an outpatient One in 300 people in the general popula-
dose-escalation protocol can be used to achieve tion is homozygous for a mutant allele in the
a target dose over several weeks. thiopurine methyltransferase (TPMT) gene.
Prednisone tapering can begin after the Patients with this genotype should not receive
patient has been on the maximal dose for 1 azathioprine because of the risk of life-threat-
to 2 months and significant improvement is ening bone marrow suppression.40 A slightly in-
evident. A monthly tapering of 5 to 10 mg creased risk of various forms of lymphoma has
is preferred, then more slowly after the daily been documented.41
dose reaches 30 mg. The usual maintenance
dose averages about 5 mg daily. Mycophenolate mofetil
Many drugs Common side effects of prednisone in- A well-tolerated medication with few side
can exacerbate clude weight gain, cushingoid features, easy effects, mycophenolate mofetil is being used
bruising, cataracts, glaucoma, hypertension, more in myasthenia gravis. The results of two
myasthenia diabetes, dyslipidemia, and osteoporosis. Pa- recent randomized trials suggested that it is
gravis: eg, tients are advised to take supplemental calci- not effective in improving myasthenia gravis
um (1,500 mg per day) and vitamin D (400 to symptoms or sparing prednisone dosage when
penicillamine, 800 IU per day). For those most at risk of os- used for 90 days or 36 weeks.42,43 However, ex-
interferons, teoporosis, treatment with a bisphosphonate tensive clinical experience supports its long-
procainamide, should be considered. term efficacy in myasthenia gravis.
Other immunotherapeutic agents are In a retrospective study of 85 patients with
quinidine, often needed, either to replace the cortico- generalized myasthenia gravis, mycophenolate
quinolones, steroid or to permit use of lower doses of it. at doses of 1 to 3 g daily improved symptoms
Because of their delayed onset of action, start- in 73% and produced remission in 50%. Ste-
and amino- ing such corticosteroid-sparing agents early in roid dosage was reduced in 71% of patients.44
glycosides the course is often necessary. These agents are Another retrospective study, with 102
often initially combined with high-dose pred- patients, verified a slow development of
nisone, with an eventual goal of weaning off clinical benefit after months of mycopheno-
prednisone entirely. This strategy offers the late therapy alone or in combination with
advantage of relatively rapid induction while prednisone. Approximately 50% of patients
avoiding the long-term adverse effects of cor- achieved a minimal manifestation status after
ticosteroid treatment. 6 to 12 months of mycophenolate treatment.
Eventually, at 24 months of treatment, 80%
Azathioprine of patients had a desirable outcome of mini-
Azathioprine doesnt begin to show a ben- mal clinical manifestation or better, 55% of
eficial effect in myasthenia gravis for 6 to 12 patients were able to come off prednisone en-
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LI AND COLLEAGUES

tirely, and 75% were taking less than 7.5 mg of effect that lasts for years.
prednisone per day.45 The standard dosage is 375 mg/m2 per
Common side effects of mycophenolate week for 4 consecutive weeks. Peripheral B
include nausea, diarrhea, and infections such cells tend to be depleted within 2 weeks after
as urinary tract infections and herpes reactiva- the first infusion, while T-cell populations re-
tion. The complete blood cell count needs to be main unchanged.50
monitored frequently during the first 6 months A minimal infusion reaction such as flush-
of therapy. Leukopenia can occur but rarely ne- ing and chills can be seen with the first infu-
cessitates stopping mycophenolate. Long-term sion. Patients may be more susceptible to cer-
safety data are lacking, but so far there has been tain infections such as reactivation of herpes
no clearly increased risk of malignancy. zoster, but overall rituximab is well tolerated.
Mycophenolate exposure in pregnancy re- Rare cases of progressive multifocal leukoen-
sults in a high incidence of major fetal mal- cephalopathy have been reported in patients
formations. Therefore, its use in pregnant taking it, but none have occurred so far in my-
patients is discouraged, and women of child- asthenia gravis treatment.
bearing age should use effective contracep-
tion.46 Cyclophosphamide
Cyclophosphamide is an alkylating agent that
Cyclosporine reduces proliferation of both B and T cells.
A randomized trial in a small number of pa- It can be effective in myasthenia gravis, but
tients suggested that cyclosporine is fairly ef- potentially serious side effects limit its use. It
fective as monotherapy.47 Its onset of action should be reserved for the small percentage
in myasthenia gravis is faster than that of of cases that are refractory to other immuno-
other corticosteroid-sparing agents, and clini- therapies.
cal benefit can often be observed as early as
1 to 2 months. A dose of 5 mg/kg/day and a Thymectomy
maintenance serum level of 100 to 150 ng/mL Surgical treatment should be considered for
are generally recommended. However, renal, patients with thymoma. If the tumor cannot Prognosis of
hepatic, and hematologic toxicities and inter- be surgically resected, chemoradiotherapy can myasthenia
actions with other medications make cyclo- be considered for relief of myasthenic symp-
sporine a less attractive choice. toms and for prevention of local invasion. gravis has
Thymomas recur in a minority of patients dramatically
Methotrexate many years after the initial resection, some-
A randomized trial evaluated the utility of times without myasthenia gravis symptoms. A
improved
methotrexate as a steroid-sparing agent com- recurrence of symptoms does not necessarily over the last
pared with azathioprine.48 At 24 months, its indicate a recurrence of thymoma. The lack of 4 decades
steroid-sparing effect was similar to that of correlation between myasthenia gravis symp-
azathioprine, and the prednisone dosage had toms and thymoma recurrence highlights the
been reduced in more than 50% of patients. importance of radiologic follow-up in these
Another phase II trial studying the effi- patients.
cacy of methotrexate in myasthenia gravis is For patients without thymoma, many ex-
under way.49 perts believe that thymectomy is beneficial in
patients under age 60 who have generalized
Rituximab myasthenia gravis. The likelihood of medica-
Rituximab is a monoclonal antibody against tion-free remission is about twice as high, and
B-cell membrane marker CD20. A growing the likelihood of becoming asymptomatic is
number of case series support its efficacy in about one and a half times higher after thymec-
patients with severe generalized myasthenia tomy.51 However, it takes up to several years for
gravis refractory to multiple immunosuppres- the benefits of thymectomy to manifest, and
sants.16,50 It seems particularly effective for thymectomy does not guarantee protection
MuSK antibody-positive disease, reducing from developing AChR antibody-positive my-
MuSK antibody titers and having a treatment asthenia gravis in the future.
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MYASTHENIA GRAVIS

The optimal timing of thymectomy is AChR antibody-positive and seronegative


not well established; however, the proce- patients. In general, thymectomy for MuSK
dure is usually recommended within the antibody-positive patients has not been ef-
first 3 years of diagnosis.52 The response fective, and its role in ocular myasthenia
rates from thymectomy are similar for gravis is unclear.2,53

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ADDRESS: Yuebing Li, MD, PhD, Department of Neurology, Neuromus-


cular Center, Neurological Institute, S90, Cleveland Clinic, 9500 Euclid
Avenue, Cleveland, OH 44195; e-mail: Liy@ccf.org

CORRECTION

Paget disease of bone


(July 2013)

In the article Paget disease of bone: Diagnosis and drug


therapy in the July 2013 issue, an error occurred on
page 458, under the subheading Intravenous bisphos-
phonates. The text read, Pamidronate was approved
in 1994. Although it does not contain nitrogen, it is
quite effective in many patients with Paget disease.
Pamidronate in fact does contain nitrogen.
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