Neurology. 2016 Jul 26; 87(4): 419–425.
doi:
10.1212/WNL.0000000000002790
PMCID: PMC4977114
International consensus guidance for management of myasthenia
gravis
Executive summary
Donald B. Sanders, MD, *
Gil I. Wolfe, MD,*
Michael Benatar, MD, PhD,
Amelia Evoli, MD,
Nils E. Gilhus,
MD,
Isabel Illa, MD,
Nancy Kuntz, MD,
Janice M. Massey, MD,
Arthur Melms, M
D, Hiroyuki Murai,
MD,
Michael Nicolle, MD,
Jacqueline Palace, BM, DM,
David P. Richman, MD,
Jan Verschuuren, MD,
and
Pushpa Narayanaswami, MBBS, DM*
Author information ► Article notes ► Copyright and License information ►
See commentary
"Treating myasthenia on consensus guide: Helpful and challenging but still unfinished business." on page 350.
This article has been
cited by other articles in PMC.
Abstract
Objective:
Methods:
Results:
Conclusion:
Acquired myasthenia gravis (MG) is a disorder of neuromuscular transmission, resulting from
binding of autoantibodies to components of the neuromuscular junction, most commonly the
acetylcholine receptor (AChR). The incidence ranges from 0.3 to 2.8 per 1
00,000,1 and it is
estimated to affect more than 700,000 people worldwide.
The increasing use of immunomodulating therapies has been a major factor in improving the
prognosis for patients with MG in recent yea
rs.2 The various treatment options must be
weighed in the context of individual patient factors.
Why do we need MG guidance treatment statements?
Although there is widespread agreement on the use of many treatments for MG, there is no
internationally accepted standard of care. Because MG is heterogeneous, no one treatment
approach is best for all patients. Few physicians treat enough patients with MG to be
comfortable with all available treatments. Given its heterogeneity, the few randomized
controlled trials (RCTs) in MG have limited generalizability, while uncontrolled trials are
limited by potential bias. Hence, an effort to develop consensus among international experts
was undertaken to guide clinicians worldwide on the multifaceted approach to managing MG.
This summary condenses the extensive background information in the full guidance
statements, available on the
Neurology® Web site at
Neurology.org.
Panel constitution and method of expert consensus.
In October 2013, a Task Force of the Myasthenia Gravis Foundation of America (MGFA)
convened a panel of 15 international experts in MG to develop treatment guidance statements
based on formalized consensus. The panel was chosen to represent the breadth of knowledge
and experience and a wide variety of opinions from MG experts internationally.
Development of preliminary definitions.
The panel initially voted on definitions that formed the foundation for subsequent guidance
treatment statements: goals of treatment, remission, ocular MG, impending and manifest
myasthenic crises, and refractory MG.
The Task Force co-chairs (D.B.S., G.I.W.) drafted initial definitions based on available
literature
.3 These were sent by e-mail to the panelists, who were asked to vote yes or no on
each, and to provide modifications if they did not agree. Panelists were instructed not to
discuss the definitions among themselves, and to send their votes only to the facilitator (P.N.).
A simple consensus was used (≥80% of panelists voting yes).
Definitions not achieving consensus were modified based on the panelists' suggestions and the
modified definitions and discussions were shared with the panel for subsequent voting rounds.
Development of guidance treatment statements.
The following were agreed upon a priori:
1. Treatment costs and availability would not be considered, as it is not possible to
make international consensus statements specific for all countries.
2. Clinical examination is assumed to have been performed by physicians skilled in
the evaluation of neuromuscular disease.
3. The MGFA Clinical Classification, including remission, refers to the state of the
patient at the time of evaluation.
A formal systematic review of the literature was not performed. The Task Force co-chairs and
facilitator drafted initial guidance statements based on literature cited in recent national and
regional MG treatment guideline
s,4,–9 supplemented by other literature.
Guidance statements were developed for the following:
1. Symptomatic and immunosuppressive (IS) treatments
2. IV immunoglobulin (IVIg) and plasma exchange (PLEX)
3. Impending and manifest myasthenic crisis
4. Thymectomy
5. Juvenile MG (JMG)
6. MG with antibodies to muscle-specific tyrosine kinase (MuSK-MG)
7. MG in pregnancy
Voting process for consensus guidance treatment statements.
We used the RAND/UCLA Appropriateness Method (RAM) for formal consensus to quantify
agreeme
nt.10 RAM uses a multi-round modified Delphi process to obtain a quantitative
assessment that reflects the judgment of an expert group. Appropriateness refers to the
relative benefit vs harm of the intervention. We obtained anonymous votes and feedback on
each draft statement from the panelists, who rated each for appropriateness on a 9-point scale
(1–3 inappropriate, 4–6 uncertain, and 7–9 appropriate). Panelists responded by e-mail to the
facilitator, who tallied the votes and collated the discussions. Following each round of voting,
statements were modified by the Task Force co-chairs and facilitator based on the panel
feedback. Statements that did not achieve consensus within 3 rounds were excluded.
For statements on symptomatic and IS therapies and thymectomy, an initial round of e-mail
voting was followed by a meeting in Durham, North Carolina, on March 1, 2014. During this
meeting, statements that had undergone prior voting by e-mail were refined with panel input,
and a second round of voting was completed. All subsequent voting was by e-mail.
The level of appropriateness and presence of agreement were determined for each statement
as pe
r RAM.10
Go to:
RESULTS
All definitions below obtained simple consensus and all guidance statements below were
agreed upon as being appropriate by the panel. Literature summaries and tables for
medication dosing guidance and medication cautions are available as supplemental data
at
Neurology.org.
Preliminary definitions.
1. Goals for the treatment of MG.
MGFA Task Force Post-Intervention Status (PIS) classification Minimal Manifestation Status
(MMS) or bette
r,3 with no more than grade 1 Common Terminology Criteria for Adverse
Events (CTCAE) medication side effec
ts.11
MMS: The patient has no symptoms or functional limitations from MG but has some
weakness on examination of some muscles. This class recognizes that some patients who
otherwise meet the definition of remission have mild weakness.
CTCAE grade 1 medication side effects: asymptomatic or only mild symptoms; intervention
not indicated.
2. Definition of remission.
The patient has no symptoms or signs of MG. Weakness of eyelid closure is accepted, but
there is no weakness of any other muscle on careful examination. Patients taking
cholinesterase inhibitors (ChEIs) every day with reasonable evidence to support symptomatic
benefit are therefore excluded from this category.
3. Definition of ocular MG (based on dysfunction due to MG at a specified point
in time, and not dependent upon the duration of disease).
MGFA Class
I3: Any ocular muscle weakness. May have weakness of eye closure. Strength in
all other facial, bulbar, and limb muscles is normal. (It is recognized that some patients report
fatigue when strength testing is normal. The physician should use clinical judgment in
attributing fatigue to generalized MG in the absence of objective nonocular weakness).
4. Definition of impending myasthenic crisis.
Rapid clinical worsening of MG that, in the opinion of the treating physician, could lead to
crisis in the short term (days to weeks).
5. Definition of manifest myasthenic crisis (the concept of crisis focuses on the
clinical implications—it represents a serious, life-threatening, rapid worsening
of MG and potential airway compromise from ventilatory or bulbar
dysfunction).
MGFA Cla
ss V3: Worsening of myasthenic weakness requiring intubation or noninvasive
ventilation to avoid intubation, except when these measures are employed during routine
postoperative management (the use of a feeding tube without intubation places the patient in
MGFA Class IV
B3).
6. Definition of refractory MG.
PI
S3 is unchanged or worse after corticosteroids and at least 2 other IS agents, used in
adequate doses for an adequate duration, with persistent symptoms or side effects that limit
functioning, as defined by patient and physician.
Consensus guidance treatment statements.
Symptomatic and IS treatment of MG.
1. Pyridostigmine should be part of the initial treatment in most patients with MG.
Pyridostigmine dose should be adjusted as needed based on symptoms. The ability to
discontinue pyridostigmine can be an indicator that the patient has met treatment goals
and may guide the tapering of other therapies. Corticosteroids or IS therapy should be
used in all patients with MG who have not met treatment goals after an adequate trial
of pyridostigmine.
2. A nonsteroidal IS agent should be used alone when corticosteroids are
contraindicated or refused. A nonsteroidal IS agent should be used initially in
conjunction with corticosteroids when the risk of steroid side effects is high based on
medical comorbidities. A nonsteroidal IS agent should be added to corticosteroids
when:
o a. Steroid side effects, deemed significant by the patient or the treating
physician, develop;
o b. Response to an adequate trial (table e-1) of corticosteroids is inadequate; or
o c. The corticosteroid dose cannot be reduced due to symptom relapse.
3. Nonsteroidal IS agents that can be used in MG include azathioprine, cyclosporine,
mycophenolate mofetil, methotrexate, and tacrolimus. The following factors should be
considered in selecting among these agents:
o a. There is widespread variation in practice with respect to choice of IS agent
since there is little literature comparing them.
o b. Expert consensus and some RCT evidence support the use of azathioprine as
a first-line IS agent in MG.
o c. Evidence from RCTs supports the use of cyclosporine in MG, but potential
serious adverse effects and drug interactions limit its use.
o d. Although available RCT evidence does not support the use of
mycophenolate and tacrolimus in MG, both are widely used, and one or both
are recommended in several national MG treatment g
uidelines.4,–7
4. Patients with refractory MG should be referred to a physician or a center with
expertise in management of MG. In addition to the previously mentioned IS agents,
the following therapies may also be used in refractory MG:
o a. Chronic IVIg and chronic PLEX (see IVIg and PLEX, no. 6);
o b. Cyclophosphamide;
o c. Rituximab, for which evidence of efficacy is building, but for which formal
consensus could not be reached.
5. IS agent dosage and duration of treatment
o a. Once patients achieve treatment goals, the corticosteroid dose should be
gradually tapered. In many patients, continuing a low dose of corticosteroids
long-term can help to maintain the treatment goal.
o b. For nonsteroidal IS agents, once treatment goals have been achieved and
maintained for 6 months to 2 years, the IS dose should be tapered slowly to the
minimal effective amount. Dosage adjustments should be made no more
frequently than every 3–6 months (table e-1).
o c. Tapering of IS drugs is associated with risk of relapse, which may
necessitate upward adjustments in dose. The risk of relapse is higher in patients
who are symptomatic, or after rapid taper.
o d. It is usually necessary to maintain some immunosuppression for many years,
sometimes for life.
6. Patients must be monitored for potential adverse effects and complications from IS
drugs. Changing to an alternative IS agent should be considered if adverse effects and
complications are medically significant or create undue hardship for the patient.
IVIg and PLEX.
1. PLEX and IVIg are appropriately used as short-term treatments in patients with MG
with life-threatening signs such as respiratory insufficiency or dysphagia; in
preparation for surgery in patients with significant bulbar dysfunction; when a rapid
response to treatment is needed; when other treatments are insufficiently effective; and
prior to beginning corticosteroids if deemed necessary to prevent or minimize
exacerbations.
2. The choice between PLEX and IVIg depends on individual patient factors (e.g.,
PLEX cannot be used in patients with sepsis and IVIg cannot be used in renal failure)
and on the availability of each.
3. IVIg and PLEX are probably equally effective in the treatment of severe
generalized MG.
4. The efficacy of IVIg is less certain in milder MG or in ocular MG.
5. PLEX may be more effective than IVIg in MuSK-MG.
6. The use of IVIg as maintenance therapy can be considered for patients with
refractory MG or for those in whom IS agents are relatively contraindicated.
Impending and manifest myasthenic crisis.
Impending and manifest myasthenic crisis are emergent situations requiring aggressive
management and supportive care.
Although cholinergic crises are now rare, excessive ChEI cannot be completely excluded as a
cause of clinical worsening. Also, ChEIs increase airway secretions, which may exacerbate
breathing difficulties.
PLEX and IVIg are the mainstay of management in myasthenic crisis.
1. Impending crisis requires hospital admission and close observation of respiratory
and bulbar function, with the ability to transfer to an intensive care unit if it progresses
to manifest crisis. Myasthenic crisis requires admission to an intensive care or step-
down unit to monitor for or manage respiratory failure and bulbar dysfunction.
2. PLEX and IVIg are used as short-term treatment for impending and manifest
myasthenic crisis and in patients with significant respiratory or bulbar dysfunction.
Corticosteroids or other IS agents are often started at the same time to achieve a
sustained clinical response. (Because corticosteroids may cause transient worsening of
myasthenic weakness, it may be appropriate to wait several days for PLEX or IVIg to
have a beneficial effect before starting corticosteroids).
3. Although clinical trials suggest that IVIg and PLEX are equally effective in the
treatment of impending or manifest myasthenic crisis, expert consensus suggests that
PLEX is more effective and works more quickly. The choice between the 2 therapies
depends on patient comorbidity (e.g., PLEX cannot be used in sepsis and IVIg is
contraindicated in hypercoagulable states, renal failure, or hypersensitivity to
immunoglobulin) and other factors, including availability. A greater risk of
hemodynamic and venous access complications with PLEX should also be considered
in the decision (many complications of PLEX are related to route of access and may
be minimized by using peripheral rather than central venous access).
Thymectomy in MG.
1. In non-thymomatous MG, thymectomy is performed as an option to potentially
avoid or minimize the dose or duration of immunotherapy, or if patients fail to respond
to an initial trial of immunotherapy or have intolerable side-effects from that therapy.
Because of the long delay in onset of effect, thymectomy for MG is an elective
procedure. It should be performed when the patient is stable and deemed safe to
undergo a procedure where postoperative pain and mechanical factors can limit
respiratory function.
2. The value of thymectomy in the treatment of prepubertal patients with MG is
unclear, but thymectomy should be considered in children with generalized AChR
antibody–positive MG:
o a. If the response to pyridostigmine and IS therapy is unsatisfactory; or
o b. In order to avoid potential complications of IS therapy.
For children diagnosed with seronegative generalized MG, the possibility of a congenital
myasthenic syndrome or other neuromuscular condition should be entertained, and evaluation
at a center specializing in neuromuscular diseases is of value prior to thymectomy.
3. With rare exceptions, all patients with MG with thymoma should undergo surgery
to remove the tumor. Removal of the thymoma is performed to rid the patient of the
tumor and may not produce improvement in MG. All thymus tissue should be
removed along with the tumor. Further treatment of thymoma will be dictated by
histologic classification and degree of surgical excision. Incompletely resected
thymomas should be managed after surgery with an interdisciplinary treatment
approach (radiotherapy, chemotherapy).
4. In elderly or multimorbid patients with thymoma, palliative radiation therapy can be
considered in the appropriate clinical setting. Small thymomas may be followed
without treatment unless they are enlarging or become symptomatic.
5. Endoscopic and robotic approaches to thymectomy are increasingly performed and
have a good track record for safety in experienced centers. Data from randomized,
controlled comparison studies are not available. Based on comparisons across studies,
less invasive thymectomy approaches appear to yield similar results to more
aggressive approaches.
6. Thymectomy may be considered in patients with generalized MG without
detectable AChR antibodies if they fail to respond adequately to IS therapy, or to
avoid/minimize intolerable adverse effects from IS therapy. Current evidence does not
support an indication for thymectomy in patients with MuSK, LRP4, or agrin
antibodies.
Juvenile MG (see also Thymectomy in MG, no. 2).
1. Children with acquired autoimmune ocular MG are more likely than adults to go
into spontaneous remission. Thus, young children with only ocular symptoms of MG
can be treated initially with pyridostigmine. Immunotherapy can be initiated if goals of
therapy are not met.
2. Children are at particular risk of steroid side effects, including growth failure, poor
bone mineralization, and susceptibility to infection, due in part to a delay in live
vaccinations. Long-term treatment with corticosteroids should use the lowest effective
dose to minimize side effects.
3. Maintenance PLEX or IVIg are alternatives to IS drugs in JMG.
MG with MuSK antibodies.
1. Many patients with MuSK-MG respond poorly to ChEIs, and conventional
pyridostigmine doses frequently induce side effects.
2. Patients with MuSK-MG appear to respond well to corticosteroids and to many
steroid-sparing IS agents. They tend to remain dependent on prednisone despite
concomitant treatment with steroid-sparing agents.
3. MuSK-MG responds well to PLEX, while IVIg seems to be less effective.
4. Rituximab should be considered as an early therapeutic option in patients with
MuSK-MG who have an unsatisfactory response to initial immunotherapy.
MG in pregnancy.
1. Planning for pregnancy should be instituted well in advance to allow time for
optimization of myasthenic clinical status and to minimize risks to the fetus.
2. Multidisciplinary communication among relevant specialists should occur
throughout pregnancy, during delivery, and in the postpartum period.
3. Provided that their myasthenia is under good control before pregnancy, the majority
of women can be reassured that they will remain stable throughout pregnancy. If
worsening occurs, it may be more likely during the first few months after delivery.
4. Oral pyridostigmine is the first-line treatment during pregnancy. IV ChEIs may
produce uterine contractions and should not be used during pregnancy.
5. Thymectomy should be postponed until after pregnancy as benefit is unlikely to
occur during pregnancy.
6. Chest CT without contrast can be performed safely during pregnancy, although the
risks of radiation to the fetus need to be carefully considered. Unless there is a
compelling indication, postponement of diagnostic CT until after delivery is
preferable.
7. Prednisone is the IS agent of choice during pregnancy.
8. Current information indicates that azathioprine and cyclosporine are relatively safe
in expectant mothers who are not satisfactorily controlled with or cannot tolerate
corticosteroids. Current evidence indicates that mycophenolate mofetil and
methotrexate increase the risk of teratogenicity and are contraindicated during
pregnancy. (These agents previously carried Food and Drug Administration [FDA]
Category C (cyclosporine), D (azathioprine and mycophenolate mofetil), and X
(methotrexate) ratings. The FDA has recently discontinued this rating system, and
replaced it with a summary of the risks of using a drug during pregnancy and
breastfeeding, along with supporting data and “relevant information to help health care
providers make prescribing and counseling decisi
ons”12).
Although this statement achieved consensus, there was a strong minority opinion
against the use of azathioprine in pregnancy. Azathioprine is the nonsteroidal IS of
choice for MG in pregnancy in Europe but is considered high risk in the United States.
This difference is based on a small number of animal studies and case reports.
9. PLEX or IVIg are useful when a prompt, although temporary, response is required
during pregnancy. Careful consideration of both maternal and fetal issues, weighing
the risks of these treatments against the requirement for use during pregnancy and
their potential benefits, is required.
10. Spontaneous vaginal delivery should be the objective and is actively encouraged.
11. Magnesium sulfate is not recommended for management of eclampsia in MG
because of its neuromuscular blocking effects; barbiturates or phenytoin usually
provide adequate treatment.
12. All babies born to myasthenic mothers should be examined for evidence of
transient myasthenic weakness, even if the mother's myasthenia is well-controlled, and
should have rapid access to neonatal critical care support.
Go to:
DISCUSSION
We have developed international guidance statements for the management of JMG and adult
MG. We utilized recent national guidelines and a regional European guideline to assemble a
foundation of literature, supplementing their comprehensive literature reviews with additional
articles identified by panelists. After reaching agreement on the treatment goals, a 3-round
anonymous modified Delphi voting process was used to obtain consensus on guidance
statements.
A limitation of consensus-based processes is that subconscious or conscious selection of like-
minded panel members may result in opinions that are not representative of MG experts. This
issue was addressed by selecting an international panel with variations in practice and by
using a formal consensus process.
Recognizing the variability of practice patterns and availability of treatment modalities, these
statements are not absolute recommendations for management, but are intended as a guide for
the clinician. They are also not intended for establishing payment policies or drug tiering by
payers.
This is a living document that will require updates as the MG treatment theater continues to
evolve. Despite the limitations of consensus-based methods, these guidance statements reflect
an up-to-date expert consensus to guide clinicians worldwide who strive to optimize function
and quality of life for their patients with MG, especially for those who practice in parts of the
world that do not have the resources to develop local treatment guidelines. Any future trial of
treatment that provides relevant information will merit review of these guidance statements.
Go to:
Supplementary Material
Data Supplement: Click here to view.
Accompanying Editorial: Click here to view.
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ACKNOWLEDGMENT
The authors thank MGFA Board member Jurgen Venitz, MD, PhD, for providing insight from
the patients' perspective.
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GLOSSARY
AChR
acetylcholine receptor
ChEI
cholinesterase inhibitor
CTCAE Common Terminology Criteria for Adverse Events
FDA
Food and Drug Administration
IS
immunosuppressive
IVIg
IV immunoglobulin
JMG
juvenile myasthenia gravis
MG
myasthenia gravis
MGFA Myasthenia Gravis Foundation of America
MMS
minimal manifestation status
MuSK muscle-specific tyrosine kinase
PIS
Post-Intervention Status
PLEX
plasma exchange
RAM
RAND/UCLA Appropriateness Method
RCT
randomized controlled trial
Go to:
Footnotes
Supplemental data at
Neurology.org
Editorial, page
350
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AUTHOR CONTRIBUTIONS
D.B. Sanders: study concept and design, grant application and management, acquisition of
data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the
manuscript for important intellectual content, study supervision. G.I. Wolfe: study concept
and design, acquisition of data, analysis or interpretation of data, drafting/revising the
manuscript, critical revision of the manuscript for important intellectual content, study
supervision. M. Benatar: acquisition of data, drafting/revising the manuscript, critical revision
of the manuscript for important intellectual content. A. Evoli: acquisition of data,
drafting/revising the manuscript, critical revision of the manuscript for important intellectual
content. N.E. Gilhus: acquisition of data, critical revision of the manuscript for important
intellectual content. I. Illa: acquisition of data, critical revision of the manuscript for important
intellectual content. N. Kuntz: acquisition of data, drafting/revising the manuscript, critical
revision of the manuscript for important intellectual content. J.M. Massey: acquisition of data,
drafting/revising the manuscript, critical revision of the manuscript for important intellectual
content. A. Melms: acquisition of data, critical revision of the manuscript for important
intellectual content. H. Murai: acquisition of data, critical revision of the manuscript for
important intellectual content. J. Palace: acquisition of data, drafting/revising the manuscript,
critical revision of the manuscript for important intellectual content. M. Nicolle: acquisition of
data, drafting/revising the manuscript, critical revision of the manuscript for important
intellectual content. D.P. Richman: acquisition of data, critical revision of the manuscript for
important intellectual content. J. Verschuuren: acquisition of data, critical revision of the
manuscript for important intellectual content. P. Narayanaswami: study concept and design,
acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical
revision of the manuscript for important intellectual content, study supervision.
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STUDY FUNDING
Supported by a grant from the Myasthenia Gravis Foundation of America (MGFA).
Go to:
DISCLOSURE
D. Sanders: consultant for Accordant Health Services, Cytokinetics, GlaxoSmithKline, and
Jacobus Pharmaceutical Co. G. Wolfe: advisory board for Grifols, Baxter, CSL Behring, and
Syntimmune; and research support from Alexion. M. Benatar: research support from the FDA
(R01FD003710), NIH (U01NS084495), and Alexion. A. Evoli: scientific award jury member
for Grifols. N. Gilhus: speaker's honoraria from Octopharma, Baxter, and Merck Serono. I.
Illa: research funding from Grifols and speaking fees and travel grants from Genzyme and
Pfizer; and consultant for Alexion, UCB, and Grifols. N. Kuntz and J. Massey report no
disclosures relevant to the manuscript. A. Melms: advisory board, UCB. H. Murai: research
funding from Biogen, Novartis, Bayer, Tanabe Mitsubishi, and the Japan Blood Products
Organization. J. Palace: consultant for Merck Serono, Biogen Idec, Novartis, Teva, Chugai
Pharma, Alexion, and Bayer Schering; research funding from Merck Serono, Novartis,
Biogen Idec, and Bayer Schering. M. Nicolle reports no disclosures relevant to the
manuscript. D. Richman: research funding from the Muscular Dystrophy Association,
Myasthenia Gravis Foundation of California, and the Myasthenia Gravis Foundation of
Illinois. J. Verschuuren: research support by NIH, FP7 European grant (#602420), consultant
for Tyr pharma, and arGEN-X. The LUMC receives royalties from IBL for antibody tests. P.
Narayanaswami: serves on the Medical and Scientific Advisory Board, Myasthenia Gravis
Foundation of America (MGFA), and Medical Advisory Board, MGFA, New England
Chapter. Go to
Neurology.org for full disclosures.
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