Gen Thorac Cardiovasc Surg (2015) 63:201215

DOI 10.1007/s11748-015-0518-y

CURRENT TOPICS REVIEW ARTICLE

Perioperative management in myasthenia gravis: republication

of a systematic review and a proposal by the guideline committee
of the Japanese Association for Chest Surgery 2014
Yoshihisa Kadota Hirotoshi Horio Takeshi Mori
Noriyoshi Sawabata Taichiro Goto Shin-ichi Yamashita
Takeshi Nagayasu Akinori Iwasaki

Received: 31 October 2014 / Published online: 22 January 2015

The Japanese Association for Thoracic Surgery 2015

Abstract Thymectomy is regarded as a useful therapeutic

option for myasthenia gravis (MG), though perioperative
management in MG patients is largely empirical. While
evidence-based medicine is limited in the perioperative
management of MG patients, treatment guidelines are
required as a benchmark. We selected issues faced by
physicians in clinical practice in the perioperative management of extended thymectomy for MG, and examined
them with a review of the literature. The present guidelines
have reached the stage of consensus within the Japanese
Association for Chest Surgery.

This article is based on a study first reported in the web site of the
Japanese Association for Chest Surgery; http://www.jacsurg.gr.jp/.

Keywords Myasthenia gravis
Perioperative

management
Thymectomy
Myastenic crisis
Consensus
statement

Introduction
Thymectomy has previously been reported as a useful
therapeutic option for myasthenia gravis (MG) and is now
regarded as a standard therapy. However, because of its
low incidence (1011 cases per 100,000), perioperative
management in MG patients is largely empirical, and
treatment guidelines based on evidence-based medicine
(EBM) have yet to be established. For perioperative management in MG, treatment guidelines are required as a
benchmark. In Japan, Treatment Guidelines for Myasthenia Gravis were prepared by a Joint Committee of the
Japanese Society for Neuroimmunology and the Japanese

This review was submitted at the invitation of the editorial committee.

Y. Kadota
H. Horio
T. Mori
N. Sawabata
T. Goto

S. Yamashita
T. Nagayasu
A. Iwasaki
Guidelines Committees of Japanese Association for Chest
Surgery, Kyoto, Japan
Y. Kadota (&)
Department of General Thoracic Surgery, Osaka Prefectural
Medical Center for Respiratory and Allergic Diseases,
Osaka, Japan
e-mail: kadotay@ra.opho.jp
H. Horio
Department of General Thoracic Surgery, Tokyo Metropolitan
Cancer and Infectious diseases Center Komagome Hospital,
Tokyo, Japan

N. Sawabata
Department of General Thoracic Surgery, Osaka University
Graduate School of Medicine, Osaka, Japan
T. Goto
Department of General Thoracic Surgery, Keio University
School of Medicine, Tokyo, Japan
S. Yamashita
A. Iwasaki
Department of General Thoracic, Breast and Pediatric Surgery,
Fukuoka University School of Medicine, Fukuoka, Japan
T. Nagayasu
Department of Surgical oncology, Nagasaki University Graduate
School of Biomedical Sciences, Nagasaki, Japan

T. Mori
Department of Thoracic Surgery, Kumamoto University
Hospital, Kumamoto, Japan

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Gen Thorac Cardiovasc Surg (2015) 63:201215

Society of Neurological Therapeutics, which also included

guidelines for thymectomy. However, because the publication occurred almost 10 years ago, new knowledge has
been acquired and concepts about the disease have changed. In the perioperative management of extended thymectomy (ET) for myasthenia gravis, we selected issues
faced by physicians in clinical practice and organized them
for examination in these guidelines with a review of the
literature. While EBM is poor in the perioperative management of MG patients, the present guidelines have
reached the stage of consensus within the Japanese Association for Chest Surgery (JACS).

Pathogenesis of MG and surgical indication

Pathogenesis of MG
MG is an autoimmune disease that is caused by autoantibodies against acetylcholine receptors (AChRs) in neuromuscular junctions (NMJs). MG is characterized by easy
fatigability and improvement with rest [1]. Because these
antibodies are specific for the nicotinic AChRs, AChRs in
the heart, bladder, and intestine remain unaffected. MG
symptoms are usually characterized by ocular, bulbar, and
systemic symptoms. Respiratory failure can also develop

during acute exacerbation (MG crisis). Diagnostic criteria

for MG have been established by the Neuroimmunological
Disorders Research Committee of Japan [2].
Clinical symptoms can be evaluated based on the Osserman classification and Myasthenia Gravis Foundation of
America (MGFA) classification [3] (Table 1). Severity is
evaluated using scoring systems such as the Quantitative
MG Score for Disease Severity (QMG score) and the MG
Activities of Daily Living profile (MG-ADL) (Table 2). To
decide on surgical indications and evaluate perioperative
MG status, physician interviews regarding physical findings are important [4].
Anti-AChR antibodies, the direct cause of the symptoms,
are specific for MG and are rarely detected in otherwise
healthy individuals. However, the absolute titers of these
antibodies do not correlate well with MG severity. Moreover,
1015 % of MG patients are negative for AChR antibodies,
which is called seronegative MG (SNMG) [5, 6].
In addition to the above serological findings (presence or
absence of anti-AChR antibodies), classification into subgroups with different background factors, such as epidemiological factors (age at onset) and pathological factors
(presence or absence of complication by thymoma or thymic hyperplasia), is also important to understand the
pathogenesis and pathology of MG and also determine the
surgical indications [4].

Table 1 Osserman and MGFA clinical classification

Osserman classification
I

Ocular myasthenia

IIA

Mild generalized myasthenia with slow progression: no crises, responsive to drugs

IIB

Moderately severe generalized myasthenia: severe skeletal and bulbar involvement but no crises; drug response less
than satisfactory

III

Acute fulminating myasthenia, rapid progression of severe symptoms, with respiratory crises and poor drug response

IV

Late severe myasthenia, same as III but progression over 2 years from class I to II

MGFA clinical classification

Class I

Any ocular muscle weakness. May have weakness of eye closure. All other muscle strength is normal

Class II

Mild weakness affecting areas other than ocular muscles. May also have ocular muscle weakness of any severity

IIa

Predominantly affecting limb or axial muscles, or both. May also have lesser involvement of oropharyngeal muscles

IIb

Predominantly affecting oropharyngeal or respiratory muscles, or both. May also have lesser or equal involvement of
limb or axial muscles, or both

Class III

Moderate weakness affecting areas other than ocular muscles. May also have ocular muscle weakness of any severity

IIIa

Predominantly affecting limb or axial muscles, or both. May also have lesser involvement of oropharyngeal muscles

IIIb

Predominantly affecting oropharyngeal or respiratory muscles, or both. May also have lesser or equal involvement of
limb or axial muscles, or both

Class IV

Severe weakness affecting areas other than ocular muscles. May also have ocular muscle weakness of any severity

IVa

Predominantly affecting limb or axial muscles, or both. May also have lesser involvement of oropharyngeal muscles

IVb

Predominantly affecting oropharyngeal or respiratory muscles, or both. May also have lesser or equal involvement of
limb or axial muscles, or both

Class V

Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative
management. The use of a feeding tube without intubation places the patient in class IVb

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203

Table 2 MG Activities of Daily Living profile and Quantitative MG score

MG Activities of Daily Living (MG-ADL) profile
Grade

1. Talking

Normal

Intermittent slurring or
nasal speech

Constant slurring or nasal, but

can be understood

Difficult to
understand speech

2. Chewing

Normal

Fatigue with solid food

Fatigue with soft food

Gastric tube

3. Swallowing

Normal

Rare episodes of choking

Frequent choking necessitating

changes in diet

Gastric tube

4. Breathing

Normal

Shortness of breath with

exertion

Shortness of breath at rest

Ventilator dependence

5. Impairment of ability to brush

teeth or comb hair

None

Extra effort, but no rest

periods needed

Rest periods needed

Cannot do one of
these functions

6. Impairment of ability to rise

from a chair

None

Mild, sometimes uses

arms

Moderate, always uses arms

Severe, requires
assistance

7. Double vision

None

Occurs, but not daily

Daily, but not constant

Constant

8. Eyelid droop

None

Occurs, but not daily

Daily, but not constant

Constant

Score
(0, 1,
2, or 3)

MG-ADL score total

(range 024)
Quantitative MG score (QMG)
Test items weakness (score)

None (0)

Mild (1)

Moderate (2)

Severe (3)

1. Double vision on lateral gaze right or

left, s

61

1160

110

Spontaneous

2. Ptosis (upward gaze), s

61

1160

110

Spontaneous

3. Facial muscles

Normal lid
closure

Complete, weak,
some resistance

Complete, without
resistance

Incomplete

4. Swallowing 4 oz./120 ml of water

Normal

Minimal coughing
or throat clearing

Severe coughing/
choking
or nasal regurgitation

Cannot swallow
(test not
attempted)

5. Speech following counting aloud from 1

to 50 (onset of dysarthria)

None at #50

Dysarthria at
#3049

Dysarthria at #1029

Dysarthria at #9

6. Right arm outstretched (90 sitting), s

240

90239

1089

09

7. Left arm outstretched (90 sitting), s

240

90239

1089

09

8. Vital capacity (% predicted) mouthpiece

or facemask (best of 3)

C80 %

6579 %

5064 %

\50 %

Male

C45

1544

514

04

Female

C30

1029

59

04

Male

C35

1534

514

04

Female

C25

1024

59

04

11. Head, lifted (45 supine), s

120

30119

129

12. Right leg outstretched (45 supine), s

100

3199

130

13. Left leg outstretched (45 supine), s

100

3199

130

Item score
(0, 1, 2, or 3)

9. Right hand grip: (best of 2), KgW

10. Left hand grip: (best of 2), KgW

0
Total QMG score
(range 039)

SNMG patients are usually not associated with thymoma, and about 50 % of them are anti-MuSK antibodypositive [4, 5]. Most of the SNMG patients with anti-MuSK

antibody-positivity do not have thymic hyperplasia, so

there is no aggressive indication for thymectomy. Moreover, because patients with ocular-type MG sometimes

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Table 3 Classification of
myasthenia gravis

Gen Thorac Cardiovasc Surg (2015) 63:201215

Clinicopathological classification
Thymomatous MG

Early-onset MG
Late-onset MG

2
3

Juvenile MG

Anti-MuSK antibody-positive MG (anti-MuSK MG)

Anti-MuSK antibody-negative MG (double-seronegative MG)

Ocular MG (without bulbar or systemic symptom)

Generalized MG (with bulbar or systemic symptom)

[26]

Non-thymomatous MG

Serological classification
Anti-AChR antibody-positive MG
Anti-AChR antibody-negative MG (seronegative MG)

Classification with symptoms

resolve spontaneously, there is no aggressive indication for

thymectomy. MG is classified from the clinicopathological
findings, serological findings, and symptoms (Table 3).
From a practical standpoint, generalized non-thymomatous
MG is classified into five subgroups: 2 in Table 1, and
when thymomatous MG and ocular MG are also included,
they are classified into seven subgroups: 17 in Table 1. In
addition to these classifications, MG symptom severity is
evaluated by the MGFA classification and QMG score [4].
Effectiveness and adverse effects of thymectomy
Thymectomy for MG was first reported by Sauerbruch
(1912) and Blalock (1944) in cases where MG symptoms
improved after thymectomy [79]. This surgical treatment
has been empirically developed, and while various possibilities have been suggested as a theoretical basis for MG
improvement, none has yet been confirmed [1017]. Many
reports have suggested a positive relationship between
thymectomy and MG prognosis, so thymectomy is currently regarded as a standard treatment for MG. However,
because the onset of remission after thymectomy takes a
few months to a few years, medical treatment is required to
improve and maintain ADL during this time [18, 19]. In
thymomatous MG, thymectomy is required for treatment of
thymoma. The effectiveness of this approach is thus discussed in terms of treatment outcomes in non-thymomatous MG patients.

have yet been reached [20]. At present, therefore, no evidence-based effectiveness has been confirmed.
The American Academy of Neurology conducted a
meta-analysis based on 21 cohort studies in 28 articles on
postoperative course and outcomes after thymectomy,
which classified the MG outcome into complete remission,
asymptomatic status, and improvement [21]. The study has
shown the superiority of surgical treatment to non-surgical
treatment, of which the median relative rates were 2.1 in
complete remission, 1.6 in asymptomatic status, and 1.7 in
improvement. Regardless of differences in selection criteria and outcome assessment in each study, 18 of the 21
cohort studies showed the superiority of surgical treatment
to the non-surgical treatment [21]. Therefore, there is no
clear evidence for the effectiveness of thymectomy, it has
been generally recommended as one option that may lead
to MG remission or improvement for non-thymomatous
MG [21]. The results of the RCT by the NIH are eagerly
anticipated [20].
Adverse effects of thymectomy
The mortality rate associated with thymectomy, even in
cases of inadequately controlled MG symptoms, is B1 %
[22]. Complications associated with thymectomy include
crisis (6 %), infections (11 %), and recurrent laryngeal
nerve/phrenic nerve injury (2 %) [23].
Approach and extent of thymectomy

Effectiveness of thymectomy
The effectiveness of thymectomy in non-thymomatous MG
patients is currently being investigated in a randomized
controlled trial (RCT) by the National Institutes of Health
(NIH) in the United States, that is, thymectomy combined
with prednisone vs. prednisone alone, but no conclusions

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The surgical approach for thymectomy is classified by

MGFA (2000) [3, 24] into transcervical, videoscopic,
transsternal, and transcervical and transsternal thymectomy. Regarding the extent of thymectomy, it has been
classified into simple, extended, and maximal thymectomy.
Extended thymectomy is the most commonly used

Gen Thorac Cardiovasc Surg (2015) 63:201215

procedure [19, 25]. Maximal thymectomy, namely, extended thymectomy with the dissection of neck fatty tissue, is
the most extensive procedure [24]. However, it is well
known that maximal thymectomy causes postoperative
complications more frequently than the extended thymectomy. Besides, because no RCTs comparing extended
thymectomy and maximal thymectomy have been conducted, no superiority of the former in terms of the outcome has been shown. Therefore, in Japan, extended
thymectomy is now mainly performed rather than the
maximal thymectomy [19, 25]. Thoracoscopic extended
thymectomy has recently been performed, the results of
which are comparable to those by a median sternotomy
approach [26, 27].
In patients with invasive thymoma, combined resection
of invaded organs is sometimes necessary. In cases of
pleural dissemination, extrapleural pneumonectomy may
also be considered. Such cases need to be evaluated on an
individual basis when planning surgery.
Indications for thymectomy
Currently, the effectiveness of thymectomy based on evidence remains unclear. Data regarding indications thus
remain limited to those based on the results of casecontrol
studies about pathological findings of the thymus and
postoperative course and outcomes.
Thymomatous MG
Thymectomy is performed for the treatment of thymoma.
In unresectable thymomas, medical treatment is indicated.
MG remission and improvement rates in patients with
thymoma have been reported to be similar or slightly worse
than those without [19, 28].
Non-thymomatous MG (anti-AChR antibody-positive)
Non-thymomatous MG with positivity for anti-AChR
antibody in adults is classified by the onset of MG, namely,
early and late types. The borderline between the early and
late onset of MG is usually around 50 years old for the
following reasons: (1) the sex ratio in MG patients reverses
at this age; and (2) this age is just between the two peaks of
early onset and late onset [29, 30]. However, some
researchers have described that the boundary should be at
40 years old based on the thymus pathology, while others
have set it at 60 years old based on HLA and the autoantibody profile [31, 32]. Patients with an onset at older than
65 years old are usually called elderly-onset MG.
Early-onset MG: ocular type Because early-onset MG of
the ocular type resolves spontaneously in 1128 % of

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cases, the treatment of choice is usually conservative [33].

While conflicting results regarding the effectiveness of
thymectomy for early-onset MG patients with the ocular
type have been reported [19, 3436], thymectomy has been
recommended for cases with resistance to immunosuppressive therapy, including steroids, and high serum levels
of the anti-AChR antibody [37].
Early-onset MG: generalized type It is well known that
patients with early-onset MG of the systemic type often
have thymic hyperplasia. Better prognosis has been
reported with a shorter interval between MG onset and
thymectomy, so thymectomy is recommended [6, 19, 38,
39].
Late-onset MG Because the number of patients with lateonset MG has been increasing recently, the choice of
treatment is becoming an important issue [40, 41]. A study
involving pathological examination with autopsy reported
that patients over 60 years old show little thymic hyperplasia, and they might not respond to thymectomy [42].
Therefore, in MG patients C60 years old, surgical indications should be prudently considered. Because a relatively
long time is required until MG improves after thymectomy,
its surgical damage and the life expectancy should be
considered for determination of the surgical indication for
these patients. Some reports recommend thymectomy only
for refractory cases in patients C60 years old [43].
On the other hand, several researchers have reported the
effectiveness of thymectomy in elderly patients [4347].
Although thymectomy may be a treatment option even in
elderly patients, the indications need to be carefully considered in each individual case [41]. In practice, thymectomy in elderly patients could be indicated in those with
thymic abnormality suggesting hyperplasia in the thymus
in imaging studies, rapid progression of MG symptoms, or
resistance to medical treatment. For elderly MG patients
with ocular type or with negativity for anti-AChR antibody,
medical treatment is the standard approach [41].
Regarding thymectomy in elderly patients without thymoma, a questionnaire study from 251 institutions in Japan
was conducted by the Japanese Society of Neurology/
Japanese Association for Research on the Thymus (2010),
showing that C90 % of the institutions performed thymectomy in patients B69 years old, while 58 % of them
performed thymectomy even in patients C70 years old
[48]. While thymectomy for elderly patients is still controversial, it should be applied more prudently than in
younger patients.
Juvenile MG In juvenile MG, the remission rate with
medical treatment is higher than in adult MG. In cases with
initial onset at B11 years old, thymectomy has been

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reported not to affect MG remission [49]. In contrast, with

the onset at C12 years old, some reports suggested that the
remission rate with thymectomy is better than that without
it, so they recommended early thymectomy for severe MG
[50].

Gen Thorac Cardiovasc Surg (2015) 63:201215

rate remains B1 % [22]. However, in surgery when MG is

poorly controlled, postoperative mechanical ventilation
may be required for a long time, and the risk of crisis after
extubation may be increased. Therefore, the timing of
surgery in severe MG should be determined based on the
condition of each patient.

Anti-AChR antibody-negative MG [seronegative MG

(SNMG)]
MG medications used perioperatively
Anti-AChR antibody-negative MG can be divided, based
on the serological findings, into anti-MuSK antibodypositive MG (anti-MuSK MG) and MG in which there is
neither anti-AChR antibody nor anti-MuSK antibody
(double-seronegative MG) [4].
Anti-MuSK MG The pathological features of anti-MuSK
MG are that thymoma is usually not associated and that the
rate of thymic hyperplasia is low [5]. In anti-MuSK MG,
because the rate of MG remission is reported to be low with
thymectomy, medical treatment is usually the first choice
[5, 11].
Anti-AChR antibody and anti-MuSK antibody double-negative MG In patients with negativity for both anti-AChR
antibody and anti-MuSK antibody (double-seronegative
MG), trace amounts of anti-AChR antibody and antiMuSK antibody, or other unknown autoantibodies, are
presumed to be involved in the pathogenesis. A recent
study showed that a high proportion of SNMG patients
have anti-AChR antibody below the limit of detection [51].
Several studies have reported that some double-negative
MG patients have thymic hyperplasia upon pathological
examination, and their symptoms could be improved by
thymectomy. Similar to anti-AChR-positive MG, generalized MG in double-seronegative MG has been reported as
an indication for thymectomy [52, 53]. In ocular-type
double-negative MG patients, there is no aggressive indication for surgery, as for the ocular type with anti-AChR
antibody.
It is thought that MuSK forms a dimer with low-density
lipoprotein receptor-related protein 4 (Lrp4), and is
involved in the signal transduction of NMJ by inducing
AChR clustering. Recently, autoantibodies to Lrp4 have
been reported in Japan [54]. This has attracted attention for
clarifying further the pathogenesis of SNMG.

Pharmacotherapy is essential for the control of MG

symptoms, and anticholinesterase drugs, steroids, and
immunosuppressive drugs are used. However, their perioperative use is more complicated than their maintenance
use. Expert opinions and experience for their perioperative
use are introduced here.
Anticholinesterase drugs
Anticholinesterase drugs, by blocking the degradation of
Ach and increasing the Ach concentration at NMJs,
increase muscle contraction [55, 56]. However, cholinergic
crisis can occur with an overdose [33]. In some anti-MuSK
MG patients, hypersensitivity reactions have also been
reported. Anticholinesterase drugs offer symptomatic
rather than curative therapy, but are rapid-acting and
effective in most cases [56]. Anticholinesterase drugs are
therefore often administered before surgery.
Because controlled studies for anticholinesterase drugs
have not been performed, no formal evidence has been
accumulated. However, because their effectiveness is clear,
anticholinesterase drugs are used as the first-line treatment
after MG has been diagnosed [57].
Preoperative use
The half-life for the blood concentration of pyridostigmine
bromide (Mestinon) after a single 60-mg dose is about
200 min. Because of its muscarinic effects, such as vomiting, drool, bradycardia, and atrioventricular block, which
sometimes impair the general anesthesia, anticholinesterase
drugs are stopped before surgery [58, 59]. While anticholinesterase drugs are usually stopped in the morning on the
day of surgery, their continued administration can be tolerated in patients with concomitant use of steroids [58, 59].

Timing of surgery in severe MG

Postoperative use

Thymectomy can be indicated even in patients with

respiratory failure due to MG who are treated with
mechanical ventilation. Poor respiratory status alone is not
a contraindication for thymectomy. Even in MG patients
with inadequate preoperative control, the surgical mortality

The dosage of anticholinesterase drugs after surgery should

be determined from MG symptoms, their severity and
effects from cessation of anticholinesterase drugs [6063].
Munsat et al. [63] reported that, in patients with crisis,
temporary cessation of anticholinesterase drugs (drug

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holiday) may increase the sensitivity to these drugs.

Because such sensitivity may also increase during postoperative cessation, the initial dose after surgery should be
determined carefully. In general, it is recommended that
pyridostigmine bromide (Mestinon) be started at 1 tablet
(60 mg) per day or one-half of the preoperative dose; then,
the dose can be increased while monitoring symptoms or
based on an edrophonium test [6062]. Cholinergic crisis
can occur with an overdose.
In terms of resuming oral administration, some authors
recommend resumption after starting oral intake, whereas
others recommend resumption on day 2 after surgery [60,
62]. Since the severity of MG varies among patients, this
must be decided on an individual basis. Treatment is usually by oral administration, but if the patient has dysphagia,
the drug can be given through a nasogastric tube.
Steroid drugs
Steroid drugs are first-line drugs for immunomodulatory
therapy in MG patients [57, 64], and their effectiveness has
been clarified [6567]. Together with anticholinesterase
drugs, steroids are often administered before surgery. In the
European Federation of Neurological Societies (EFNS)
guideline the task force agreed that oral prednisolone
should be a first-choice drug when immunosuppressive
drugs are necessary in MG (good practice point) [57].
According to a questionnaire investigation by the Japanese Society of Neurology/Japanese Association for
Research on the Thymus (2010), over half of the 251
institutions use oral steroids as first-line drugs for treatment
before thymectomy, but about 40 % do not [48].
The significance of using steroids before surgery is
important for future treatments, so it should be investigated
from the perspectives of adverse events during the perioperative period and long-term prognosis [68, 69].
Improvement rates of 7080 % have been achieved with
oral steroid treatment, but no RCTs of steroids have been
conducted for MG treatment [57]. While a comparative
trial between steroids and thymectomy would be difficult,
an RCT of thymectomy for patients being treated with
steroids, namely, thymectomy combined with steroids vs.
steroids alone, by NIH is now ongoing [20], the results of
which should be able to indicate the significance of steroid
therapy for MG patients.
Thymectomy and timing of steroid initiation
After thymectomy, the onset of remission generally takes
6 months to a few years [18, 19]. Because the preoperative
use of steroid increases the perioperative risks, such as
infection and delayed wound healing, owing to increasing
the total dose and extending the duration of administration,

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patients with mild MG usually undergo thymectomy

without preoperative steroid therapy. In practice, in
patients for whom perioperative management is difficult
with anticholinesterase drugs alone, the performance of
surgery is sometimes recommended after symptoms have
been stabilized using steroids or another MG treatment
modality, such as blood purification therapy [60, 7074].
However, no uniform consensus exists regarding the
association between the timing of steroid initiation and the
long-term outcomes of MG [7577].
The administration of large doses of steroids before
thymectomy may contribute to perioperative MG control,
but the effectiveness for long-term outcomes has not been
clarified [57, 70]. The grave concerns about massive preoperative administration of steroid are a delay in the timing
of the operation and the development of adverse effects of
steroid in the perioperative period, such as infection and
poor wound healing [57, 60, 70].
Preoperative use
Steroids are first-line drugs for immunomodulatory therapy, but caution is needed because of their possible initial
worsening of MG [78, 79]. The EFNS guidelines recommend starting steroids at low doses, with a gradual increase
or alternate-day doses [57]. Initial worsening of MG by
steroids has been reported to occur in 2575 % of patients
[8082]. While adverse effects vary with the steroid doses
and the duration of administration, they occur at a rate of
3867 %. These include susceptibility to infection, delayed
wound healing, peptic ulcer, impaired glucose tolerance,
psychiatric symptoms, and thrombogenesis [83]. Therefore,
when steroids are started preoperatively, the doses should
ideally be low. For patients undergoing thymectomy, some
researchers have described that the oral prednisolone dose
should be less than 25 mg/day [60, 84].
Preoperative steroid supplementation
Abrupt discontinuation of oral steroids at surgery may
worsen MG status. Therefore, if steroids are difficult to
administer orally (nasally) for any reason, intravenous
administration is used, which is called steroid cover. For
patients treated with steroids for a long period before surgery, the endogenous production of cortisol is usually
insufficient for surgical stress. Therefore, steroid cover
should be considered to prevent secondary adrenal insufficiency [85, 86]. While the effectiveness of steroid cover
with a dose larger than the maintenance one has not been
clarified, steroid doses are usually adjusted depending on
the degree of surgical damage [84, 8789]. In thymectomy
as well, steroid cover is usually conducted by intravenous
administration of methylprednisolone [60].

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Postoperative use
For patients who have been treated by steroids before
surgery, the steroids should be resumed soon after surgery
[60]. The route of administration is usually oral, but steroids can be administered through a nasogastric tube or
intravenously when oral intake is difficult.
Steroid pulse therapy
Steroid pulse therapy, that is, high intravenous doses of
methylprednisolone therapy, is frequently used for patients
with postoperative MG crisis [60]. In general, one course
comprising intravenous infusion of methylprednisolone at
1000 mg/day for 3 days is usually conducted for 13
courses [9092]. Although the long-term effects are
unknown [65], it has been reported that, even after thymectomy without MG crisis, steroid pulse therapy may be
able to reduce the doses of subsequent oral steroids [93]. A
placebo double-blind study demonstrated the efficacy of
steroid pulse therapy, with an efficacy rate of 80 % and a
mean duration of effect of 8 weeks (414 weeks) [91].
However, care should be taken about the initial worsening
of MG symptoms due to steroids [65].
Immunosuppressive drugs
In Japan, tacrolimus and cyclosporine are covered by the
National Health Insurance (NHI) as immunosuppressive
drugs for the treatment of MG. Both drugs are reported to
be effective and are generally used in refractory cases [94
98]. With administration of either drug, care should be
taken about adverse effects, while monitoring their blood
levels.

Gen Thorac Cardiovasc Surg (2015) 63:201215

period remains unclear. Tacrolimus for preoperative

administration has been covered by the Japanese National
Health Insurance since 2009, so such use for patients with
poorly controlled MG is expected to increase in the future.
Cyclosporine
Cyclosporine, a calcineurin inhibitor, is also a widely used
immunosuppressant. In Japan, cyclosporine (Neoral) for
the treatment of MG has been reimbursed by the National
Health Insurance since 2006. However, because of its side
effects, such as renal failure and hypertension, it should be
used with caution. The EFNS guidelines therefore recommend its use only for patients who do not respond to
azathioprine [57]. While the dose of tacrolimus for MG is
restricted to B3 mg/day under the Japanese National
Health Insurance, the dose of cyclosporine is not restricted.
However, the perioperative effectiveness of cyclosporine
has yet to be reported.
Other immunosuppressive drugs (drugs not covered
by the NHI in Japan)
Azathioprine is a drug used frequently outside of Japan. A
total of 412 months is required for its efficacy to start to
be exhibited. In a large-scale double-blind randomized
study, azathioprine was effective in reducing steroid doses
[103]. The EFNS guidelines recommend that, in patients
requiring long-term steroid therapy, an attempt should be
made to reduce steroid doses using a combination with
azathioprine [57], but the perioperative effectiveness of this
has not been demonstrated. As other drugs, while mycophenolate mofetil and cyclophosphamide have also been
reported to be effective for MG patients, both have
restricted indications.

Tacrolimus
Tacrolimus, a calcineurin inhibitor, at a low dose (3 mg/
day) is reported to be effective in MG. In a retrospective
analysis, with a low dose of 0.1 mg/kg/day, muscle
strength was increased by 23 % at 1 month after treatment,
and anti-AChR antibodies decreased from 33.5 (mean
value) to 7.8 nmol/L [99]. Tacrolimus was developed in
Japan, and is now widely used in this country for the
treatment of MG, along with steroids [95, 99, 100].
The mechanism of action of tacrolimus, in addition to
the suppression of activated T cells, includes increasing
skeletal muscle contraction via the ryanodine receptor
(RyR), and increasing the intracellular concentration of
steroids [101, 102].
While it has been reported that tacrolimus can be used
early after thymectomy [99], its preoperative use has not
been reported, so its effectiveness during the perioperative

123

Other treatments used in the perioperative period

Other treatments reported to be used in the perioperative
period include blood purification therapy and high-dose
immunoglobulins.
Blood purification therapy
Blood purification therapy can be used in severe MG
patients who need short-term relief. Owing to the relatively
rapid onset of its effect, this may be indicated before thymectomy in severe MG [57]. Blood purification therapy
includes immunoadsorption (IA) and plasmapheresis,
which can remove anti-AChR antibody from the IgG
fraction of blood. Since first being reported by Antozzi
et al. in 1994, its effectiveness has frequently been

Gen Thorac Cardiovasc Surg (2015) 63:201215

described, with efficacy rates of 55100 % [104106].

Because blood purification therapy only removes the
autoimmune antibody, its effect is temporary [107, 108]. In
general, this treatment must be performed several times
(35 times or more) to achieve improvements in symptoms.
The onset of efficacy takes about 1 week and lasts for
about 13 months.
While blood purification therapy has not been evaluated
in RCT, a short-term improvement of the symptoms has
often been reported, so it may be useful as a treatment for
crisis [57]. Nagayasu et al. reported the following: in 51
patients with MG, the rate of postoperative crisis within
1 year after thymectomy was lower in 19 patients treated
with blood purification therapy before surgery than in 32
other patients without this [109]. Therefore, blood purification therapy could be useful in the perioperative period in
MG patients. In the EFNS guidelines, blood purification
therapy has recommendation level B for not only MG crisis
but also severe MG that requires short-term improvement
of symptoms at the time of thymectomy [57].
High-dose immunoglobulins
High-dose immunoglobulin therapy is reported to be
effective for severe MG, as for other autoimmune diseases
[110112]. It involves intravenous infusion of about 0.4 g/
kg/day of immunoglobulins for 5 days. High-dose immunoglobulin therapy, compared with immunoadsorption
(IA), does not require special equipment, but effectiveness
equal to that of IA may be expected [113, 114]. Huang
et al., in 12 MG patients with generalized MG (Osserman
type 2B) who were treated by the high-dose administration
of immunoglobulin, reported the following: (1) its effectiveness appeared at 3 days on average (range, 19 days)
after starting the treatment and reached its maximum at
7 days on average (range, 319 days); and (2) 6 of these
patients, who were also treated by thymectomy, recovered
after surgery without any complications [115].
The EFNS guidelines define high-dose immunoglobulin
therapy as being at recommendation level A for MG crisis
and severe MG patients who need prompt treatment [111].

209

surgery, if bulbar paralysis (dysphagia, dysarthria) and

severe respiratory symptoms occur, or if extubation
remains difficult even C24 h after general anesthesia, MG
crisis should be considered to have occurred [118], for
which treatment is necessary [60, 77].
Because there is no evidence-based treatment for postoperative MG crisis with respiratory failure, expert opinions and experience based on the literature are presented
below.
Incidence
The incidence of MG crisis in MG patients is reported to be
1020 % [119, 120]. While surgical treatment is known to
be one of the risk factors of MG crisis, its incidence after
thymectomy has been reported to be \10 % [121, 122].
Causes and risk factors
Other than surgical treatment, because perioperative
infections and psychological stress could be among the
causes of MG crisis, they should be prevented [123125].
Risk factors for the development of postoperative crisis
include preoperative worsening of MG symptoms, bulbar
symptoms, high blood levels of anti-AChR antibodies, a
prior history of crisis, age C50 years, and vital capacity
B2.0 L [122, 126]. Risk assessment with factor scoring has
also been reported [127].
Myasthenic crisis and cholinergic crisis
Crises include myasthenic crisis due to worsening MG
itself and cholinergic crisis due to an overdose of anticholinesterase drugs. The differential diagnosis may
require an edrophonium test [128]. Patients who cannot be
weaned off ventilator support even a few days after surgery
are usually in myasthenic crisis for the following reasons:
(1) the half-life of anticholinesterase drugs is only about
200 min; and (2) anticholinesterase drugs are usually
stopped during the perioperative period.
Respiratory management in postoperative MG crisis

Perioperative respiratory management and treatment

of MG acute exacerbation (MG crisis)
Postoperative MG crisis
Clinical condition
Because surgical stress is one of the factors of MG crisis,
MG symptoms could worsen in the early postoperative
period after thymectomy [116, 117]. For a few days after

Ventilatory support
The respiratory insufficiency associated with MG is caused
by decreased respiratory muscle strength and increased
bulbar symptoms. Because the respiratory insufficiency
with MG sometimes progresses rapidly and cannot be
expected to recover promptly, the need for the use of
mechanical ventilation should be assumed during the perioperative period. When a crisis develops, the edrophonium
test is performed to distinguish between myasthenic and

123

210

cholinergic crisis. However, the differential diagnosis is

frequently difficult. Therefore, Okumura et al. [60] recommended prompt endotracheal intubation and mechanical
ventilation for MG patients with postoperative respiratory
failure.
If a crisis develops despite respiratory management, the
treatment for MG should also be started. One of the goals
of mechanical ventilation in patients with crisis is to rest
the respiratory muscles. If control of the disease is difficult,
steroid pulse or blood purification therapy is used to obtain
a short-term therapeutic effect [57, 60, 129].
Indications for mechanical ventilation
One criterion for mechanical ventilation in MG exacerbation is a vital capacity of less than 1520 ml/kg of body
weight [118]. However, in practice, the changes of respiratory condition or bulbar symptom should be assessed for
determining the indication of mechanical ventilation [61,
118]. For patients with possible airway obstruction due to
difficulty in expectoration, early tracheal intubation is
particularly important.
To rest the respiratory muscles, ventilatory support is
usually continued for a certain period.
For mechanical ventilation, positive pressure ventilation
is recommended to prevent the collapse of pulmonary
alveoli and the development of atelectasis [61]. Anticholinesterase drugs are not necessary during mechanical
ventilation and are usually discontinued. With this drug
holiday, sensitivity to anticholinesterase drugs can be
expected to increase [61, 63]. Recoveries of the respiratory
muscles are necessary for weaning from ventilatory
supports.
Elimination of triggers
Any possible triggers should be eliminated. Common
triggers for MG crisis include changes in medications,
infections, and surgical stress [123, 129]. In the perioperative period, drug changes and infections are particularly
important triggers. Because postoperative infections are
frequently caused by airway infection, care should be taken
to prevent aspiration pneumonia, especially in patients with
bulbar symptoms [118].
Predicting the need for postoperative mechanical
ventilation
Several factors have been reported to predict the need for
postoperative mechanical ventilation. These include disease duration, bulbar symptoms, history of MG crisis,
preoperative doses of anticholinesterase drug, coexisting
respiratory disease, vital capacity, and blood antibody

123

Gen Thorac Cardiovasc Surg (2015) 63:201215

levels. The scoring of these factors has been attempted to

predict the need for mechanical ventilation [127, 130132].
Weaning and extubation from mechanical ventilation
While stepwise weaning from mechanical ventilation is
usually conducted in patients with general respiratory
failure for respiratory muscle training, it is not recommended for MG patients because it could cause muscle
fatigue, resulting in failure of the weaning [6062]. In
general, if the tidal volume is 300-500 ml, weaning and
extubation from mechanical ventilation can be attempted
[61]. After general anesthesia is completed in MG patients,
Gorback et al. recommended the following criteria for
transfer from mechanical ventilation to a T-piece or continuous positive airway pressure (CPAP; 5 cm H2O): PaO2
C90 mmHg under FiO2 B0.4; pH[7.3; and respiratory rate
B30 breaths/min [133]. They also described vital capacity
C10 ml/kg to be a criterion for extubation [133135].
Rabinstein et al. and Mori et al. have reported the criteria of re-intubation after extubation to be atelectasis,
tachypnea ([40 breaths/min), and progression of acidosis
[135, 136].
In acute exacerbation of MG associated with respiratory
insufficiency, resting of the respiratory muscles and elimination of triggers are often insufficient to achieve recovery. To prevent prolongation of mechanical ventilation, it is
necessary to reduce autoimmune antibody, such as by
steroid pulse therapy and blood purification therapy [57,
60, 129]. Okumura et al. advocated temporal cessation of
anticholinesterase drugs during mechanical ventilation, and
then resuming the administration on the way to weaning
[60]. In addition, if the improvement with anticholinesterase drugs alone is insufficient, steroid pulse therapy is
recommended [60, 61]. However, care should be taken for
temporary worsening of MG on days 34 after starting
steroid pulse therapy [60, 61].
Tracheostomy in postoperative crisis
Tracheostomy is sometimes required for patients with
long-term mechanical ventilation [136138]. In patients
with MG crisis, when extubation is not possible for
C1 week, tracheostomy should be considered [60, 61].
However, because the tracheostomy is usually near the
wound of median sternotomy, care should be taken about
mediastinitis caused by tracheostomy. In addition, in
patients undergoing immunomodulatory therapy, such as
steroids, tracheostomy should ideally not be performed
until the surgical wound heals [139].
Tracheostomy after a median sternotomy is often performed after open-heart surgery. Generally, a tracheostomy
should be avoided within 2 weeks after open-heart surgery

Gen Thorac Cardiovasc Surg (2015) 63:201215

because of the high risk of mediastinitis [140148]. On the

other hand, high tracheostomy or percutaneous tracheostomy through the cricothyroid membrane is reported to
reduce the risk of mediastinitis. Hubner et al. performed
percutaneous tracheostomy through the cricothyroid
membrane in 45 patients soon after open-heart surgery
(median, day 6), resulting in no wound infection or mediastinitis occurring in any patients [145]. However, many
researchers reported that the indications of tracheostomy
should be carefully considered after open-heart surgery by
median sternotomy, particularly in cases with poor preoperative status or high surgical damage [140, 141, 143, 146].

211

Analgesia
Pain control is also basically the same as in other types of
thoracic surgery. Non-steroidal anti-inflammatory drugs
(NSAIDs) are not contraindicated, but they sometimes
worsen the MG symptoms [152]. Okumura et al. advised
caution when administering NSAIDs as analgesics, and
recommended acetaminophen or pentazocine instead of
NSAIDs [6062]. Epidural anesthesia is useful for pain
relief without worsening MG symptoms in the perioperative period [6062, 152, 154].
Sedation

Non-invasive positive pressure ventilation (NIPPV)

Recently, in patients with respiratory failure caused by
neuromuscular diseases, NIPPV has been used to assist
ventilation. Because the symptoms of respiratory failure
due to MG are often reversible, the usefulness of NIPPV
has been evaluated in MG patients [149, 150]. However,
reports on the usefulness of NIPPV in postoperative MG
crisis are limited.
Seneviratne et al. used NIPPV in 24 MG patients with
respiratory failure (not including post-thymectomy crisis),
resulting in tracheal intubation being avoided in 14
patients, while the remaining 10 required this intubation.
Most of these latter 10 patients had difficulty in expectorating or a past history of crisis [150]. NIPPV has also been
reported to enable the avoidance of re-intubation after
weaning off mechanical ventilation [135, 151]. Although
NIPPV cannot be used upon mechanical ventilation via a
tracheal tube, it may be useful in selected cases [135, 150].

Perioperative infection control, analgesia, and sedation

Infection control
Infection control after thymectomy is basically the same as in
other types of thoracic surgery, but the risk of infection is
higher than usual in patients using steroids or immunosuppressive drugs. In addition, aspiration due to bulbar symptoms or atelectasis associated with decreased respiratory
muscle strength increases the risk of pneumonia. A reduction
in preoperative steroid doses may be attempted to decrease
the risk of infection. However, there has been no evidence to
confirm a causal relationship between the administration of
immunosuppressive drugs, including steroids, and the
development of infection after thymectomy [152].
With regard to the use of antibiotics, aminoglycoside
antibiotics and polypeptide antibiotics are known to worsen
MG symptoms. Caution is therefore required when using
these drugs [152, 153].

Because sleeping drugs and anxiolytic drugs, including

benzodiazepines, have muscle-relaxing activity to some
extent, they are contraindicated in MG patients [152]. In
addition, it has also been reported that premedication with
sedative agents before general anesthesia is not required in
MG patients [60]. In general, hydroxyzine HCl (atarax-P)
can be used with expectation of its hypnotic effect due to
antihistamine activity, but extra caution is required in
patients with worsening of MG symptoms [60, 62].
In actual clinical practice, because MG symptoms can
also worsen due to psychological stress, these sleeping
drugs and anxiolytic drugs are sometimes used before
surgery in patients with good MG control who only have
mild symptoms. However, because surgical damage is also
a factor that worsens MG, there are many restrictions on
sleeping drugs and anxiolytic drugs during the perioperative period [116, 117]. Consultation with a neurologist is
necessary before perioperative administration of these
drugs.
Acknowledgments The authors thank the former guidelines committees of Japanese Association for Chest Surgery: Drs. Hiroaki
Nomori and Masazumi Watanabe for their contribution to this work.
Conflict of interest
interest exists.

The authors have declared that no Conflict of

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