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Ann. N.Y. Acad. Sci. ISSN 0077-8923
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
Issue: Myasthenia Gravis and Related Disorders
REVIEW
Developing treatment guidelines for myasthenia gravis
Donald B. Sanders,1,aGil I. Wolfe,2,aPushpa Narayanaswami,3,aand the MGFA Task Force on
MG Treatment Guidance†
1Department of Neurology, Duke University, Durham, North Carolina. 2Department of Neurology, University at Buffalo Jacobs
School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York. 3Department of Neurology,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Address for correspondence: Donald B. Sanders, Department of Neurology, Duke University, DUMC Box 3403, Durham, NC
27710. Donald.Sanders@duke.edu
A task force of the Myasthenia Gravis Foundation of America recently published a formal consensus statement
intended to be a treatment guide for clinicians caring for myasthenia gravis (MG) patients worldwide. Its develop-
ment was stimulated by the fact that there is generally no accepted standard of care for MG, and no one treatment
is best for all MG patients. Also, there are few randomized trials of treatments in current use, and the generaliz-
ability of the few trials that have been successful may be difficult. Fifteen international experts in MG participated
in the consensus process, which used a simple consensus to develop preliminary definitions and the RAND/UCLA
Appropriateness Method to quantify agreement on treatment guidance statements for seven topics: symptomatic and
immunosuppressive treatment, intravenous immunoglobulin and plasma exchange, impending and manifest myas-
thenic crisis, thymectomy, juvenile MG, MG with muscle-specific tyrosine kinase antibodies, and MG in pregnancy.
The executive summary of the guidance statement was published with open access to facilitate access by patients
and healthcare professionals, and the full statement, with extensive background information, is available online. The
guidance statement is a living document that will require updates as new treatments and new information on current
treatments become available.
Keywords: myasthenia gravis; treatment guidelines; consensus process; RAND-UCLA Appropriateness Method
Introduction: why do we need myasthenia
gravis guidance treatment statements?
Several immunosuppressive and immunomodula-
tory treatments are available for myasthenia gravis
aThese authors contributed equally to this manuscript.
†Task Force panelists: Michael Benatar, University of
Miami, Miami, FL; Amelia Evoli, Catholic University,
Rome, Italy; Nils Gilhus, University of Bergen, Bergen,
Norway; Isabel Illa, Hospital de la Santa Creu I Sant
Pau, Barcelona, Spain; Nancy Kuntz, Lurie Children’s
Hospital of Chicago, Chicago, IL; Janice Massey, Duke
University Medical Center, Durham, NC; Arthur Melms,
University of Erlangen, Germany; Hiroyuki Murai, Inter-
national University of Health and Welfare, Narita, Japan;
Michael Nicolle, University Hospital, London, Ontario,
Canada; Jackie Palace, University of Oxford, Oxford, Eng-
land; David Richman, University of California, Davis, CA;
Jan Verschuuren, Leiden University Medical Center, Lei-
den, the Netherlands.
(MG). However, there is significant variation in the
treatment of MG, and there is no accepted standard
of care. This is mainly because large randomized
controlled trials (RCTs) of MG therapies are few,
and the generalizability of the available RCTs may be
limited, largely because of the heterogeneous nature
of the disease. Even the best RCTs cannot balance
all of the information needed to select the most
appropriate treatment for a given patient. Hence,
an effort to develop consensus among international
experts was undertaken to guide clinicians on the
multifaceted approach to managing MG.
Background
Reviews of literature evidence are often used to
inform clinical practice. Narrative reviews are
descriptive reports that summarize the most impor-
tant studies in the field, with perhaps some com-
mentary about their clinical implications. Articles
doi: 10.1111/nyas.13537
95
Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Developing treatment guidelines for MG Sanders et al.
included in a narrative review are typically deter-
mined by the authors and may be influenced by
their subjective opinions of the quality of the study,
availability of full-length articles, and other consid-
erations. Therefore, these reviews may be subject to
selection bias. Moreover, when results of different
studies are inconsistent, with discrepant results, it
is often left to the reader to decide how to address
these inconsistencies.
Treatment guidelines are used not only by clin-
icians but also by third-party payers (insurance
companies, Medicare, and Medicaid), governmen-
tal health organizations, and institutional review
boards. In 2011, the National Academy of Medicine
(NAM), then known as the Institute of Medicine,
defined clinical practice guidelines (CPGs), often
synonymous with evidence-based guidelines, as
“statements that provide recommendations to opti-
mize patient care, informed by a systematic review
of the evidence and an assessment of the benefits
and harms of alternative care options.”1The NAM
further established standards for development of
CPGs, one of which is that they are developed from
a systematic review (SR) of all the available evidence
to inform a clinical question. An important step in
the SR process is measurement of the risk of bias of
each study that informs the CPG. Bias or systematic
error is the tendency of a study to measure the effect
of the intervention on the outcome in a way that
deviates from the true value. This cannot be mea-
sured directly. However, principles of study design
can be used to estimate the risk of bias of a study. On
the basis of these principles, RCTs have the lowest
risk of bias, and case studies have the highest.
ThereareseveralsituationsinwhichRCTsarenot
available, and it is not possible to develop an SR or
CPG because of the high risk of bias in the available
literature. High-quality studies are difficult to per-
form in some conditions and are therefore unlikely
to be available. This is particularly true with rare
diseases like MG, where recruitment of sufficient
numbers of subjects for clinical trials is difficult. An
additional factor in MG is that immunosuppressive
treatments require a long time to demonstrate effi-
cacy. Financial constraints and study limitations,
such as dropouts over time, may preclude high-
quality studies, and the use of placebo controls may
not be feasible or ethical. However, clinical and pol-
icy decisions must still be made, and patients may
have questions about the options available to them.
When good evidence is lacking, there is even more
uncertainty about the value of differing options, and
there is usually considerable practice variation.
When high-level evidence is not available to
inform a CPG, guidance for practice can be based
on consensus methods, using the available literature
and experience supplemented by the knowledge and
opinions of expert clinicians. Group decisions are
based on the assumption that a group is less likely
than an individual to arrive at a wrong conclusion.
Groups can provide a broad range of knowledge
and experience. Group interaction encourages
debate and scrutiny of multiple opinions, chal-
lenges preconceived opinions, and stimulates
new ideas. Group discussion therefore serves to
integrate judgments when uncertainty and differing
opinions exist, to identify areas of agreement, and
to determine areas where agreement is lacking.2
Informal consensus refers to the collective opin-
ions developed in unstructured meetings or com-
mittees with few formal rules or methods. Members
in these groups are not instructed in any specific
method, although simple directions may be pro-
vided, such as to not derogate input from other
members.2
The following disadvantages of group consensus
must be recognized: (1) only one person can speak
at a time, limiting the number of ideas discussed; (2)
there is social pressure to agree with the majority or
apowerfulvoice;and(3)adesiretoreachagreement
may result in premature closure without attention
to all options. Formal consensus methods have been
developed to minimize some of these disadvantages
by providing a structured decision-making process
(e.g., by adopting rating methods to represent the
extent of agreement). Performance in groups is
affected in various ways by the presence of other
members. In formal consensus methods, there is a
degree of anonymity in the process, which reduces
the effect of wanting to please a senior or dominant
member or to conform to judgments of the group.
The group opinion is integrated, discussed, and used
to refine recommendations. A structured consen-
sus process, with formal rules and procedures, also
conveys authority and rationality to the ultimate
product, leading to scientific credibility. The RAND-
UCLA Appropriateness Method (RAM), developed
in the 1980s by the RAND Corporation and the Uni-
versity of California Los Angeles, is one of the better
known methods of formal consensus.3
96 Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Sanders et al. Developing treatment guidelines for MG
Methods
In October 2013, the Myasthenia Gravis Foundation
of America appointed a task force, co-chaired by
Donald Sanders and Gil Wolfe, to develop guidance
statements for the treatment of autoimmune MG.
A panel of 12 international experts in the treatment
of MG was recruited, and Pushpa Narayanaswami
agreed to serve as the nonvoting facilitator and
moderator of the consensus process. The panel was
chosen by the task force co-chairs to represent the
breadth of knowledge and experience and a wide
variety of opinions from MG experts internation-
ally. All panel members are MG experts who have
participated in regional/national guidelines, have
interests, and have published in specific areas of MG
treatment, or both.
The RAM was used to develop the consensus
guidance statements for the treatment of MG.3RAM
was initially developed to evaluate overuse/underuse
of medical or surgical procedures. It uses a multi-
round modified Delphi process to arrive at a consen-
sus that reflects the judgment of a group of experts
on the basis of two concepts: appropriateness and
agreement. RAM uses an explicit method for aggre-
gating the views of the individual members of a
group (i.e., mathematical rules are used to combine
opinions).
The initial step in RAM is to define the appropri-
ateness level of draft statements. Appropriateness is
a judgment regarding the relative harm versus ben-
efit of a given intervention, and it is rated by each
member of the panel on a 9-point scale: 1–3, inap-
propriate (risks >benefit); 4–6, uncertain (risks ࣈ
benefit); 7–9, appropriate (benefit >risks).
The median score of the panel is calculated. A
median that falls in between the 3-point ranges is
included in the higher appropriateness category. The
range of panel scores provides an idea of disper-
sion within the panel. The second step is to quan-
tify agreement or disagreement of the full panel for
the appropriateness level of the statement (i.e., to
measure the degree of acceptance by the panel of a
given statement). This is done mathematically and
depends on the number of panel members. For a
panel of 14 members, agreement is defined as no
more than four panelists rating the statement out-
side the 3-point region containing the median score
(i.e., most panel members scored the statement in
the same 3-point region that contains the median
score). Disagreement is defined as at least five pan-
elists rating the statement in the 1–3 region and at
least five panelists rating it in the 7–9 region (i.e.,
there is wide variation, and the scores are dispersed
from the median).
A statement is considered to be appropriate if the
median rating is 7–9 without disagreement, and
inappropriate if the median rating is 1–3 without
disagreement. It is rated as uncertain if the median
rating is 4–6 or if there is disagreement. Thus, there
can be agreement that a recommendation is appro-
priate, inappropriate, or even uncertain.
Appropriateness ratings are used to define prac-
tice recommendations. Disagreements and uncer-
tainty ratings assist in determining “gray” areas for
future research. Panel consensus is not forced. The
degree of agreement is used to define the strength
of the recommendations. Cost and availability con-
siderations are not used in this process to decide
appropriateness; all options are assumed to be
affordable and freely available. RAM uses an initial
rating round without panel interactions followed by
a face-to face meeting.
AformalSRoftheliteraturewasnotperformed.
The task force co-chairs and facilitator drafted
guidance statements for the initial round of voting
on the basis of literature cited in recent national
and regional guidelines and supplemented by other
literature.
An initial round of e-mail voting was followed
by a 1-day face-to-face meeting in Durham, North
Carolina on March 1, 2014. All but two of the
panel members attended the initial meeting, during
which a second round of voting was completed
on statements that had previously been voted on
by e-mail. Definitions were also developed during
that meeting for the following five terms to be used
during the subsequent deliberations: (1) goals of
MG treatment; (2) remission; (3) ocular MG; (4)
myasthenic crisis, impending and manifest; and (5)
refractory MG.
Most of these terms had been previously defined
in the MG literature, and those definitions formed
a foundation for further refinement by the panel.
The concept of impending crisis was novel but was
felt by the panel to be critical to properly formulate
treatment statements pertaining to aggressive man-
agement in emergent scenarios. Impending crisis
was defined as “rapid clinical worsening of MG
that, in the opinion of the treating physician, could
lead to crisis in the short term (days to weeks).”4
97
Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Developing treatment guidelines for MG Sanders et al.
The following list of seven treatment topics to be
addressed was developed by the panel at the meet-
ing: (1) symptomatic and immunosuppressive treat-
ment of MG; (2) intravenous immunoglobulin and
plasma exchange; (3) management of impending
and manifest myasthenic crisis; (4) thymectomy in
MG; (5) juvenile MG; (6) MG with MuSK antibod-
ies; and (7) MG in pregnancy.
Draft guidance statements for each topic, along
with relevant literature reviews, were prepared by
the co-chairs and facilitator and sent to each panel
member for anonymous rating via email. Panel
members were asked to not discuss the topics
directly with other members in order to reduce the
risk of undue influence by one or more panel mem-
bers. The nonvoting facilitator tallied the votes and
summarized panel comments and discussion after
each round. Statements modified by the co-chairs
and facilitator on the basis of panel feedback were
then sent to the panel, along with the discussion for
the next round of voting. This was repeated until
consensus was achieved; all statements achieved
consensus within three rounds of voting.
Consensus on all topics was completed in May
2015, and the final report was completed in July
2015. The executive summary of the guidance state-
ment was published in Neurology in August 20164
with open access to facilitate access by patients and
healthcare professionals. A comprehensive version
with extensive background information was pub-
lished online.
Examples of the consensus process
There was considerable difference in the ease with
which consensus was reached among the different
topics (Table 1). For example, consensus on the
topic of immunotherapy in MG was relatively
straightforward.
Immunotherapy in MG
The round 1 statement argued: “If high steroid doses
are needed chronically to achieve or maintain an
adequate response, a steroid-sparing agent should
be added, typically along with the steroid, to per-
mit subsequent reduction of the steroid dose to the
lowest necessary to maintain an adequate response.”
Round 1 voting resulted in a median of 9 and a range
of 6–9, indicating agreement and appropriateness.
Consensus on this topic was achieved after one
round of votes. However, on the basis of panel
input and discussion, we modified the statement
and revoted.
The round 2 statement read: “A non-steroid
immunosuppressive agent (IS) should be used alone
when steroids are contraindicated or refused. A non-
steroid IS should be used initially in conjunction
with steroids when the risk of steroid side effects
is high based on medical co-morbidities. A non-
steroid IS should be added to steroids when steroid
side effects deemed significant by the patient or the
treating physician, develop, response to an adequate
trial of steroids is inadequate, or symptoms relapse
upon steroid taper.” Round 2 voting resulted in a
median of 9 and a range of 8–9, indicating agree-
ment and appropriateness.
Here, round 2 was performed to address panel
comments and discussion and not because there
was lack of consensus in round 1.
Thymectomy in childhood myasthenia
In contrast, consensus on the topic of thymectomy
in childhood myasthenia required extensive dis-
cussion and modifications. The round 1 statement
was: “In children and adolescents aged 5–10 years,
thymectomy should be considered only after fail-
ure of symptomatic therapy and immunotherapy.”
Round 1 voting produced a median of 6 and a range
of 1–9, indicating that the statement was considered
uncertain and that agreement was equivocal.
A modified round 2 statement was created on the
basis of discussion: “A. In patients under 15 years
of age, thymectomy should be considered in gen-
eralized MG after unsatisfactory response to acetyl-
cholinesterase (AChE) inhibitors and immunother-
apy. B. There is wide consensus that thymectomy is
indicated in peripubertal and postpubertal children
with moderate to severe AChR-ab+MG. C. Pub-
lished reports also suggest that early thymectomy
(within the first 12 months of onset of symptoms)
is more effective than delayed thymectomy. D. For
seronegative children, thereis always a risk that some
will have a congenital myasthenic syndrome and
not immune-mediated juvenile MG. E. Evaluation
at a center specializing in childhood neuromuscular
diseases should be considered before recommend-
ing thymectomy in young patients with seronegative
MG.” Voting in round 2 resulted in a median of 8
and a range of 2–9; four panelists rated it 2–4, and
the rest in the 7–9 range. Thus, there was still dis-
agreement and no consensus.
98 Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Sanders et al. Developing treatment guidelines for MG
Tab l e 1. Selected examples of consensus statements and voting rounds for each of the seven topics
Statement Round 1 (median, range) Round 2 (median, range)
Round 3
(median, range)
I. Symptomatic and immunosuppressive
treatment of MG
1. Pyridostigmine should be part of the initial
treatment in most MG patients.
Pyridostigmine dose should be adjusted as
needed on the basis of 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 and/or IS therapy
should be used in all MG patients who have
not met treatment goals afteran adequate
trial of pyridostigmine.
Multiple suggestions and
consensus statements in this
round were combined into one
statement in the next round.
Individual statement votes:
9, 2–9: appropriate,aagreement;b
8, 5–8: appropriate, agreement;
8, 4–9: equivocal;
8, 5–9: appropriate, agreement;
8, 2–9: equivocal;
7, 3–9: equivocal
Revote on combined, modified
statement:
8, 4–9: appropriate, agreement
2. Nonsteroidal IS agents that can be used in
MG include azathioprine, cyclosporine,
mycophenolate mofetil, methotrexate, and
tacrolimus.
Multiple suggestions and
consensus statements in this
round were combined into one
statement in the next round.
Individual statement votes:
8, 2–9: appropriate, agreement;
7, 3–8: equivocal;
7, 2–8: equivocal
Revote on combined, modified
statement:
8, 6–9: appropriate, agreement
II. Intravenous immunoglobulin (IVIg) and
plasma exchange (PLEX)
1. PLEX and IVIg are appropriately used as
short-term treatments in MG patients 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 before
beginning corticosteroids if deemed
necessary to prevent or minimize
exacerbations.
Multiple suggestions in this round
were combined in the next
round.
9, 6–9: appropriate, agreement.
Revote on combined, modified
statement:
9, 7–9: appropriate, agreement
III. Impending and manifest myasthenic crisis
1. 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 two therapies depends on patient
comorbidity and other factors, including
availability. A greater risk of hemodynamic
and venous access complicati ons with PLEX
should also be considered in the decision.
Multiple suggestions and
consensus statements in this
round were combined into one
statement in the next round.
Individual statement votes:
8, 2–9: equivocal;
9, 6–9: appropriate, agreement
Revote on combined, modified
statement:
9, 2–9: appropriate, agreement
IV. Thymectomy in MG
1. In nonthymomatous 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.
Multiple suggestions and
consensus statements in this
round were combined into one
statement in the next–round.
Individual statement votes:
8, 1–9, equivocal;
8, 5–9, equivocal
Revote on combined, modified
statement:
8, 2–9: appropriate, agreement
2. The value of thymectomy in the treatment of
prepubertal MG patients is unclear, but
thymectomy should be considered in
children with generalized AChR-antibody
positive MG either (a) if the response to
pyridostigmine and IS therapy is
unsatisfactory or (b) in order to avoid
potential complications of IS therapy.
Multiple suggestions and
consensus statements in this
round were combined into one
statement in the next round.
Individual statement votes:
6, 1–9: equivocal;
6, 1–9: equivocal
Revote on combined, modified
statement:
8, 2–9: equivocal
Revote on modifie d
statement:
8, 7–9: appropriate,
agreement
Continued
99
Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Developing treatment guidelines for MG Sanders et al.
Tab l e 1. Continued
Statement Round 1 (median, range) Round 2 (median, range)
Round 3
(median, range)
V. Juvenile MG (JMG)a
1. Maintenance PLEX or IVIg are alternatives to
IS drugs in JMG.
Multiple suggestions in this round
were combined in the next
round.
8, 5–9: equivocal
Revote on modified statement:
8, 6–9: appropriate, agreement
VI. MG with MuSK antibodies
1. Many MuSK–MG patients respond poorly to
ChEIs, and conventional pyridostigmine
doses frequently induce side effects.
9, 6–9: appropriate, agreement
VII. MG in pregnancy
1. 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.
Although consensus with
agreement was reached during
this round, minor modifications
were suggested by the panel.
9, 7–9: appropriate, agreement
Revote on minor modifications:
9, 7–9: appropriate, agreement
2. 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 inc rease the risk of
teratogenicity and are contraindicated
during pregnancy.
Multiple suggestions and
consensus statements in this
round were combined in the
next round.
Individual statement votes:
5, 2–9: equivocal;
8, 3–9: appropriate, agreement;
9, 6–9: appropriate, agreement
Revote on combined, modified
statement:
8, 1–9: appropriate, agreement
aA statement is considered to be appropriate if the median rating is 7–9 without disagreement, and inappropriate if the median rating
is 1–3 without disagreement.
bAgreement: For a panel of 14 members, agreement is defined as no more than four panelists rating the statement outside the 3-point
region containing the median score (i.e., most votes are in the same 3-point region that contains the median score).
A round 3 statement was generated by the dis-
cussion: “A. The value of thymectomy in the treat-
ment of pre-pubertal MG patients is unclear, but
thymectomy should be considered in children with
generalized AChR-ab+MG either if the response to
AChE inhibitor and immunosuppressive is unsatis-
factory, or if there is a need/desire to avoid poten-
tial complications of immunosuppressive therapy.
B. For children diagnosed as seronegative general-
ized MG, the possibility of a congenital myasthenic
syndrome or other neuromuscular condition should
be entertained, and evaluation at a center special-
izing in neuromuscular diseases is of value before
thymectomy.” Round 3 voting produced a median
of 8, and a range of 7–9; indicating that a consensus
agreement statement was appropriate.
Limitations of consensus-based processes
The major disadvantage of consensus-based state-
ments is that the recommendation depends on the
makeup of the expert panel and the personalities
involved. Two groups with different experts may
arrive at different conclusions. This is in contrast to
the evidence-based method for developing CPGs,
where the conclusions and recommendations will
be relatively similar across different panels, because
they are linked to the evidence from the SR. How-
ever, in the evidence-based method, a recommen-
dation may not be possible if there is no high-level
evidence. It is therefore important for the reader to
be familiar with the method used to develop any
practice guidance statement and to be aware of the
strength and weaknesses of each method.
Looking to the future
This first international consensus guidance for MG
management is not a static document; it will require
updates as treatments for MG continue to evolve.
In general, treatment recommendation statements
should be reviewed every 2–5 years to determine
whether an update is needed.1,5,6 The NAM does
not provide a timeframe for updates but recom-
mends regular review of the literature to determine
whether new evidence dictates a needed change in
100 Ann. N.Y. Acad. Sci. 1412 (2018) 95–101 C2018 New York Academy of Sciences.
Sanders et al. Developing treatment guidelines for MG
the guideline statements.1A policy of the American
College of Physicians is that statements that have
not been vetted or updated at least every 5 years are
withdrawn.5
The most important reason for an update is pub-
lication of results of a new trial that would change a
guidance statement. As an example, results from
the thymectomy trial in nonthymomatous MG7
were embargoed when the MG consensus guidance
statements were published and could not be used
to inform those statements. This study produced
strong evidence that, in nonthymomatous AChR
antibody+MG, thymectomy should be considered
early in treatment decisions to avoid or minimize
the dose or duration of immunotherapy and to
improve clinical status. These results will require the
RAM approach to obtain panel consensus before any
modification of the guidance statement is officially
adopted.
Competing interests
The authors declare no competing interests.
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