Clinical Exp Neuroim - 2023 - Murai - The Japanese clinical guidelines 2022 for myasthenia gravis and Lambert Eaton

Received: 25 December 2022
Accepted: 25 December 2022
DOI: 10.1111/cen3.12739
INVITED REVIEW
The Japanese clinical guidelines 2022 for myasthenia gravis
and Lambert–Eaton myasthenic syndrome
Hiroyuki Murai 1
Tomihiro Imai
4
Kimiaki Utsugisawa 2
|
|
Akiyuki Uzawa
5
|
| Masakatsu Motomura 3
Shigeaki Suzuki
|
6
1
Department of Neurology, School of
Medicine, International University of Health
and Welfare, Narita, Japan
Abstract
The revised Japanese clinical guidelines for myasthenia gravis (MG) and Lambert–
2
Department of Neurology, Hanamaki General
Hospital, Hanamaki, Japan
Eaton myasthenic syndrome (LEMS) were published in 2022. The notable points in
3
these guidelines (GLs) are as follows: (i) these are the first Japanese GLs to include a
Faculty of Engineering, Department of
Engineering, Medical Engineering Course,
Nagasaki Institute of Applied Science,
Nagasaki, Japan
4
Department of Neurology, National Hospital
Organization Hakone National Hospital,
Odawara, Japan
5
Department of Neurology, Graduate School
of Medicine, Chiba University, Chiba, Japan
description of LEMS; (ii) diagnostic criteria of MG are revised to lessen the incidence
of false negative patients; (iii) MG is divided into six clinical subtypes; (iv) a high-dose
oral steroid regimen with escalation and de-escalation schedule is not recommended
by the GLs; (v) the GLs promote the early fast-acting treatment strategy initially proposed in the previous GLs; (vi) refractory MG is defined; (vii) the use of molecular targeted drugs is included; (viii) diagnostic criteria of LEMS are proposed; and
6
Department of Neurology, Keio University
School of Medicine, Tokyo, Japan
(ix) treatment algorithms for both MG and LEMS are presented. These new GLs are
expected to improve the patients' quality of life and will serve to bridge the present
Correspondence
Hiroyuki Murai, MD, PhD, Department of
Neurology, International University of Health
and Welfare, 852 Hatakeda, Narita 286-8520
Japan.
Email: [email protected]
era with the molecular targeted treatment eras.
KEYWORDS
guidelines, Lambert–Eaton myasthenic syndrome, molecular targeted treatment, myasthenia
gravis, refractory, steroids
Funding information
JSPS KAKENHI, Grant/Award Number:
17K09780; Ministry of Health, Labor and
Welfare, Grant/Award Number: 20FC1030
1
|
epidemiological survey,5 there are estimated to be approximately
I N T RO DU CT I O N
30 000 patients with MG in Japan, with an estimated prevalence rate
Myasthenia gravis (MG) is a common neurological autoimmune dis-
of 23.1 in 100 000, which has more than doubled from the previous
ease. Patients with MG produce autoantibodies targeting molecules in
survey held in 2006.6
the
receptor
The treatment of MG is currently undergoing drastic change.
(AChR),1 muscle-specific receptor tyrosine kinase (MuSK)2,3 and low-
neuromuscular
junctions,
including
acetylcholine
Since the 1970s, and the discovery that MG is an autoimmune dis-
density lipoprotein receptor-related protein 4.4 According to a 2018
ease, high doses of oral steroids have been widely used in its treatment. During this era, patients with generalized MG routinely
Japanese Committee of Clinical Guidelines for MG consists of the following members
present in Appendix.
received both thymectomy and high doses of oral steroids, in an escalating and de-escalating manner. Thanks to the use of corticosteroids
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2023 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society for Neuroimmunology.
Clin Exp Neuroimmunol. 2023;14:19–27.
wileyonlinelibrary.com/journal/cen3
19
MURAI ET AL.
TABLE 1
TABLE 2
Diagnostic criteria for myasthenia gravis
A. Symptoms
Clinical subtypes of MG (O/g-ELTMuN Classification)
Ocular
(1) Blepharoptosis
OMG
Generalized
AChR‐Ab positive
(2) Eye movement disorder
g‐EOMG
g‐LOMG
(3) Facial muscle weakness
g‐TAMG
(4) Dysarthria
AChR‐Ab negative
(5) Dysphagia
g‐MuSKMG
g‐SNMG
(6) Mastication disorder
(7) Cervical muscle weakness
(8) Limb muscle weakness
(9) Respiratory disorder
Note: These symptoms exhibit easy fatigability and diurnal
fluctuations
Abbreviations: Ab, antibody; AChR, acetylcholine receptor; g-EOMG,
generalized early-onset myasthenia gravis; g-LOMG, generalized lateonset myasthenia gravis; g-MuSKMG, generalized MuSK antibody-positive
myasthenia gravis; g-SNMG, generalized seronegative myasthenia gravis;
g-TAMG, generalized thymoma-associated MG; MG, myasthenia gravis;
OMG, ocular myasthenia gravis.
B. Pathogenic autoantibodies
(1) Anti-acetylcholine receptor antibody-positive
The new clinical GLs were published in May 2022, and include
(2) Anti-muscle-specific receptor tyrosine kinase antibody-positive
descriptions of clinical guidance for MG and Lambert–Eaton myasthenic syndrome (LEMS).11 These are the first clinical GLs for LEMS in
C. Neuromuscular junction disorders
(1) Positive on eyelid easy fatigability test
Japan. In the present review article, we introduce the essence of these
(2) Positive on ice pack test
revised GLs for MG/LEMS.
(3) Positive on edrophonium chloride (Tensilon) test
(4) Positive on repetitive stimulation test
(5) Jitter increase on single fiber electromyography test
D. Supportive diagnostic finding
2
|
D I A G N O S TI C C R I T E R I A O F M G
The diagnostic criteria of MG have been revised (Table 1). The previ-
History of improvement by plasmapheresis
ous criteria were set along with the previous 2014 clinical GLs, includ-
E. Determination
ing the description of MuSK antibodies and an eyelid fatigability
Definite: Diagnosis of MG made if either of the below is true:
test12 or ice pack test12–15 These were added to avoid reporting of
1. One or more items from A is true and any item of B is true.
false negative patients. However, even with these descriptions, some
2. One or more items from A is true and any item of C is true and
other diseases can be ruled out.
patients with MG are not being diagnosed properly. This is because
Probable: One or more items from A is true and D is true and other
diseases can be ruled out.
tests are negative, which can result in patients who are not diagnosed
Abbreviation: MG, myasthenia gravis.
diagnosing MG is often difficult if both the AChR and MuSK antibody
with MG not subsequently receiving correct treatment. Therefore,
implementation of plasmapheresis as a therapeutic diagnosis might be
considered when other diseases are well differentiated and clinical
symptoms strongly suggest MG. Consequently, we attempted to elim-
and other immunotherapy, the mortality rate markedly decreased
inate “false negative” patients using these new criteria.
between 1940 and 2000.7 In the first decade of the 21st century, calcineurin inhibitors, such as tacrolimus and cyclosporine, have been
approved as exclusive immunosuppressants in Japan. In addition,
3
|
CLINICAL SUBTYPES OF MG
intravenous immunoglobulins (IVIg) have been widely used since
2011. The clinical guidelines (GLs) for MG were published in 2014,
MG was classified into six clinical subtypes (O/g-ELTMuN Classifica-
and proposed new treatment targets and an early fast-acting treat-
tion; Table 2). These subtypes emerged from the data of JAMG-R using
ment strategy (EFT).8,9 The 2014 GLs largely changed the therapeutic
two-step cluster analysis and assessing treatment responses.16,17 This
approach to MG in Japan. According to the recent Japan MG Registry
classification agrees with the classification proposed by Gilhus
study (JAMG-R) 2021, increased EFT introduction resulted in a higher
et al.,18,19 with the only difference being that their classification con-
10
percentage of patients achieving their treatment target.
sists of seven subtypes, including LRP4-associated MG. LRP4 anti-
In 2017, the use of eculizumab was approved in Japan. This was
bodies are occasionally detected in other neurological diseases, such as
the first molecular-targeted treatment for MG, and it enabled a new
amyotrophic lateral sclerosis,20 and the positivity rate among double
treatment option for refractory generalized MG. Therefore, a revision
seronegative MG markedly differs in each report.21 We considered
of the clinical GLs for MG has been due that updates and organizes
these facts and concluded that the data are still too immature to regard
the treatment options.
LRP4-associated MG as an independent phenotype.
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20
The six subtypes are: (i) ocular MG (OMG); (ii) generalized early-
MG symptoms, it often led to long-term administration of mid-level or
onset MG (g-EOMG); (iii) generalized late-onset MG (g-LOMG);
higher doses of steroids in many patients, and steroid-related adverse
(iv) generalized thymoma-associated MG (g-TAMG); (v) generalized
reactions and impaired QOL became common.22–24 We hereby
MuSK antibody-positive MG (g-MuSKMG); and (vi) generalized
declare that a high-dose oral steroid regimen is not recommended any
seronegative MG (g-SNMG). OMG includes all forms of ocular MG
longer. Given the various treatment options available today, we no
regardless of auto-antibody status or thymus histology. g-EOMG is
longer must rely on this obsolete strategy.
AChR-positive generalized MG without thymoma, whose onset age is
Since 2010, the multicenter cross-sectional survey (JAMG-R) has
<50 years. g-LOMG is AChR-positive generalized MG without thy-
taken place, and has repeatedly obtained detailed clinical informa-
moma, whose onset age is ≥50 years. g-TAMG is thymoma-associated
tion of patients with MG throughout Japan.10 Notably, many
MG that includes all ages. g-MuSKMG is a generalized MG with posi-
patients suffer not only impaired QOL because of persistent symp-
tive MuSK antibodies. g-SNMG is a generalized MG without AChR or
toms or insufficiently reduced oral steroids, but also social disad-
MuSK antibodies; LRP4-positive generalized MG is classified in this
vantages. Approximately one-third of patients with MG have
final group.
experienced unemployment or a decrease in income.25 Physicians
are often unable to realize patient dissatisfaction with their symptoms and disease state,26 and as complete remission is difficult to
4 | FUNDAMENTAL PHILOSOPHY TO
TREAT MG
achieve, high QOL-related patient satisfaction should be attained
as rapidly as possible.
The treatment goal of MG was set to MM-5 mg.24,27 The interna-
4.1
|
Recommendations
tional consensus guidance defined the treatment goal as “Minimal Manifestation Status or better with no more than grade 1 Common
• Full remission is difficult in cases of adult-onset MG, so treatment
Terminology Criteria for Adverse Events (CTCAE) medication side
strategies should consider that treatment might be prolonged, and
effects”28 CTCAE grade 1 medication side-effects refer to asymptomatic
aim for maintaining health-related quality of life (QOL) and mental
or only mild symptoms, and intervention is not indicated. Considering
health.
that PSL of >5 mg might cause certain symptoms, this treatment goal of
• The first goal in MG treatment is minimal manifestations
the international consensus guidance is almost equivalent to MM-5 mg.
(MM) with oral prednisolone (PSL) of ≤5 mg/day (MM-5 mg), and
Refractory MG has been defined in the present GLs. According to
treatment strategies should strive to attain this level as rapidly as
the data of JAMG-R, refractory MG accounted for 21% of all patients
possible.
with MG.10 Mantegazza et al. described refractory MG as: (i) failure to
• The increase in the rate of patients who achieve the MM-5 mg goal
plateaus at 5 years, so rapid treatment is essential.
respond adequately to conventional therapies; (ii) inability to reduce
immunosuppressive therapy without clinical relapse or a need for
• Neither the maximum dose of PSL nor the duration of taking the
ongoing rescue therapy, such as IVIg or plasma exchange; (iii) severe
mid-level or higher dose of PSL predict the achievement of
or intolerable adverse effects from immunosuppressive therapy;
MM-5 mg.
(iv) comorbid conditions that restrict the use of conventional thera-
• Early fast-acting treatment is effective in early achievement of
MM-5 mg.
• A high-dose oral steroid regimen with an escalation and deescalation schedule is not recommended, because this often results
pies; and (v) frequent myasthenic crises even while on therapy.29 The
basic concept between these two is similar. Refractory MG should be
treated with molecular targeted therapies that are newly developed
or under development.
in various side-effects and lowered QOL, and does not relate to
complete remission or early MM-5 mg.
• Refractory MG is a state in which “treatment with multiple oral
immunotherapies” or a “combination of oral immunotherapies and
5 | EARLY FAST-ACTING TREATMENT
FO R M G
repeated fast-acting treatment” are carried out for a certain period
that “does not result in sufficient improvement” or in which “con-
5.1
|
Recommendations
tinuation of treatment is difficult because of side-effects or treatment burden.”
• Immunotherapy is always the primary method of treating generalized
MG, whereas cholinesterase inhibitors serve a supplementary role.
• In the EFT strategy, fast-acting treatment (FT) should be actively
carried out to attain both prompt improvement of the symptoms
and reduction of steroid dose.
• FT incorporates plasmapheresis, IVIg, intravenous methylpredniso-
In the 1980s, the main treatment method became administration
of high-dose oral steroids (1 mg/kg or 50–60 mg/day), which
lone (IVMP) or a combination of these. IVMP should be used
skillfully.
decreased the prevalence of fatalities as well as improved life expec-
• Compared with the conventional treatment depending on oral ste-
tancy.7,22 High-dose oral steroids were often administered in an esca-
roids, EFT has a higher achievement rate for MM-5 mg, the treat-
lating and de-escalating manner. Although this treatment did improve
ment goal.
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
21
MURAI ET AL.
MURAI ET AL.
• During EFT, the oral steroid dose should be kept low from the early
stage of the disease and in early combination with the calcineurin
treatment. In addition to these side-effects, steroid use itself relates
to decreased QOL in patients with MG.24
inhibitor.
Therefore, the present GLs do not recommended the use of high-
• The case in which frequent FT is required for a long time period
dose oral steroids, and the use of ≤5 mg is recommended in ocular
MG. In generalized MG, a recommended dose is ≤10 mg and 20 mg at
corresponds to refractory MG.
the most in severe cases. Non-steroidal immunosuppressants and
In generalized MG, FT should be used not only to avoid exacerbation of the symptoms, but also to reduce the medication (mainly oral
other immunological treatments are encouraged to suppress the dose
of steroids.
steroids) or as a maintenance therapy.23,30,31 Were it not for EFT,
doses of oral steroids tend to remain high and achievement of MM5 mg becomes difficult.
EFT is a treatment strategy whereby low-dose steroids (PSL
7 | NO N - S T E R O I D A L
IMMUNOSUPPRESSANTS FOR MG
≤10 mg/day) combined with calcineurin inhibitor are administered
from the beginning, and FT is used appropriately thereafter to
improve any residual symptoms.
23
7.1
|
Recommendations
FT incorporates plasmapheresis,
IVIg, IVMP or a combination of these. IVMP should be used with caution, because it might cause initial exacerbation. To avoid this condition, it is recommended to administer IVMP just after plasmapheresis
or IVIg with reduced dose and reduced days. Methylprednisolone at
500 mg/day for 1 or 2 days is suitable as an initial attempt.
Utsugisawa et al. compared the time to first achieve MM-5 mg
• The non-steroidal immunosuppressants available in Japan are two
kinds of calcineurin inhibitors: cyclosporine and tacrolimus.
• Calcineurin inhibitors combined with steroids are expected to
improve muscle power and lower steroid doses.
• Drug concentration should be checked and attention paid to sideeffects when using calcineurin inhibitors.
from 6 to 120 months after starting immunotherapy between EFT
and non-EFT patients, and found that achievement of MM-5 mg was
Cyclosporine and tacrolimus are the only non-steroidal immuno-
more frequent and earlier in the EFT group.30 The recent JAMG-R
suppressants available in Japan. Azathioprine was permitted for use in
data showed that approximately 40% of all patients with MG received
patients with generalized MG in 2022, but is still not commonly used
EFT, and those experiencing MM-5 mg increased from 53% in 2015
in Japan. The calcineurin inhibitors, cyclosporine and tacrolimus, have
10
to 65% in 2021.
Thus, EFT has been proved to be an exceedingly
powerful tool to achieve the treatment goal.
both been shown to be effective against MG.33,34 In the early 2000s,
calcineurin inhibitors were combined with oral steroid therapy several
months after treatment initiation if it was assessed that steroids had
been ineffective. It is now recommended that calcineurin inhibitors
6
ORAL STEROIDS FOR MG
|
should be started soon after the initiation of steroids or simultaneously with steroids.
6.1
|
Recommendations
• Oral steroids are widely accepted as a standard treatment for MG,
although no randomized controlled trial has been completed.
• Treatment with oral steroids is generally initiated early in the dis-
8 | INTRAVENOUS
METHYLPREDNISOLONE TREATMENT
FO R M G
ease course and continued over a long period.
• There is a responder and poor-responder status to oral steroids.
8.1
|
Recommendations
• Low-dose oral steroid therapy from the early stage facilitates the
achievement of the treatment goal.
• High-dose steroid therapy with an escalation and de-escalation
schedule requires a long time before taking effect, and adverse
reactions due to long-term therapy become a problematic issue.
• IVMP is efficacious against generalized MG; however, this must be
used with caution and ingenuity, because initial exacerbation might
occur.
• Intermittent treatment with IVMP improves MG symptoms, while
reducing the dose of oral steroids and steroid-related adverse
The efficacy of prednisone on MG was first reported in 1970.32
reactions.
From then onward, the use of high-dose oral steroids had been a
• Initial exacerbation of symptoms caused by IVMP might be miti-
mainstream of MG treatment. However, steroids caused various
gated by performing the treatment immediately after IVIg or
adverse reactions or side-effects, such as susceptibility to infection,
plasmapheresis.
peptic ulcer, diabetes mellitus, hypertension, dyslipidemia, femur head
necrosis, osteoporosis, psychosis, insomnia, thrombogenesis, cataract,
IVMP shows an early reaction and is highly efficacious in treating
glaucoma, cushingoid appearance, acne, skin atrophy, erythema and
MG, with only mild long-term side-effects.35,36 One drawback is an
myopathy. Occasionally, the disadvantages exceed the benefits of the
initial exacerbation, but this usually lasts for only 2–5 days. If this
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
22
initial exacerbation is manageable, IVMP is a very simple and effective
exacerbation (especially in crises), before thymectomy or when other
measure to treat MG, and is frequently used to treat ocular MG.37
treatments are insufficiently effective. One proposed approach to
treating generalized MG is an EFT of combined plasmapheresis and
IVMP to rapidly improve symptoms.23,30
9 | I N T RA V E N O U S I M M U N O G L O B U LI N
TREATMENT FOR MG
9.1
Recommendations
|
• IVIg is effective for treating moderate-to-serious cases of
11 | M O L E C U L A R T A R G E T E D D R U G
(ECULIZUMAB) FOR MG
11.1
|
Recommendations
MG. Efficacy in mild cases or ocular MG is unclear.
• IVIg treatment improves exacerbated MG symptoms at approxi-
• Eculizumab is effective against AChR antibody-positive MG and
mately the same level of efficacy as plasmapheresis. There is no
should be used only when MG symptoms are uncontrollable with
evidence of long-term effects.
IVIg or plasmapheresis treatment.
• The standard therapy regimen is 0.4 g/kg/day for five continuous
• Vaccination against Neisseria meningitidis should be carried out
days. The speed of infusion should comply with package insert
>2 weeks before the initiation of eculizumab, because immunoge-
instructions.
nicity against this bacteria weakens during eculizumab treatment.
• IVIg treatment increases blood viscosity, so dosage quantities and
infusion speed should be adjusted appropriately based on the over-
Eculizumab is a humanized monoclonal antibody that binds to
all condition of the patient if concomitant cardiovascular or cere-
human terminal complement protein C5. This inhibits cleavage of C5
brovascular conditions are present.
to C5a and C5b, and prevents formation of the membrane attack
• IVIg treatment is more useful than plasmapheresis for elderly
patients or patients with unstable circulatory dynamics.
• IVIg can be administered in outpatient clinics.
complex. Eculizumab was first approved for treating paroxysmal nocturnal hemoglobinuria and then for treating atypical hemolytic uremic
syndrome. Eculizumab is now approved for generalized MG and neuromyelitis optica therapy.
IVIg treatment is widely used for autoimmune neuromuscular dis-
The REGAIN study showed the efficacy of eculizumab treatment
eases. Many details of the mechanism of action of IVIg against MG
on generalized MG.39 The MG activities of daily living score reduced
remain unknown, but it is hypothesized to be caused by inhibition
by 4.7 points in the eculizumab group and 2.8 points in the placebo
of the complement cascade and competition with autoantibodies
group. Long-term efficacy and safety were shown in REGAIN and its
in the postsynaptic membrane of the neuromuscular junction. 38
open label extension study.40 Improvements in clinical symptoms
Compared with plasmapheresis, IVIg therapy requires less special
were maintained through 3 year-treatment and there were no cases
expertise and experience on the part of the practitioner and offers
of meningococcal infection. Eculizumab is ineffective for patients with
greater safety, as this does not entail transient post-therapy
rare C5 mutations, which accounts for 3.5% of the Japanese
exacerbation.
population.41
10
12 | T H YM E C TOM Y F O R
NON-THYMOMATOUS MG
PLASMAPHERESIS FOR MG
|
10.1
|
Recommendations
12.1
|
Recommendations
• Plasmapheresis is effective for treating MG.
• As long-term efficacy of plasmapheresis treatment is not proven, it
should be combined with immunotherapy, such as IVMP.
• Simple plasma exchange, double filtration plasmapheresis and
immunoadsorption plasmapheresis can all be carried out against
MG, and all have equivalent effects.
• Plasma exchange is recommended for treating anti-MuSK
• Thymectomies might be effective and could be considered for
non-thymomatous
patients
with
early
onset
MG
(onset
<50 years years) in cases that show positive AChR antibodies and
thymic hyperplasia in the early stages of the disease.
• Thymectomy is not considered first-line treatment for nonthymomatous LOMG.
antibody-positive MG.
Until publication of the MGTX study in 2016 and 2019,42,43 there
Plasmapheresis is carried out to temporarily improve clinical
had been no precise analysis of thymectomy outcomes for non-
symptoms by removing causative substances, such as AChR and
thymomatous MG. The MGTX study reported that the Quantitative
MuSK antibodies, from the circulating plasma. Plasmapheresis is indi-
MG score was lower in the thymectomy + steroid group than that in
cated for MG when symptoms become worse, during acute
the steroid-only group (6.15 vs 8.99, respectively, over the 3-year
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
23
MURAI ET AL.
MURAI ET AL.
F I G U R E 1 Treatment algorithm for myasthenia gravis. AChEI, acetylcholinesterase inhibitor; CNI, calcineurin inhibitor; EFT, early fast-acting
treatment; FT, fast-acting treatment; g-EOMG, generalized early-onset myasthenia gravis; g-LOMG, generalized late-onset myasthenia gravis; gMuSKMG, generalized MuSK antibody-positive myasthenia gravis; g-SNMG, generalized seronegative myasthenia gravis; g-TAMG, generalized
thymoma-associated myasthenia gravis; IAPP, immunoadsorption plasmapheresis; IVIg, intravenous immunoglobulin; IVMP, intravenous
methylprednisolone; OMG, ocular myasthenia gravis; PLEX, plasma exchange; PSL, prednisolone
observation period).42 The Quantitative MG score reduction was
2.84 points.
The MGTX study was the first ever evidence-rich research cover-
TABLE 3
syndrome
Diagnostic criteria for Lambert–Eaton myasthenic
A. Symptoms
ing thymectomy for non-thymomatous MG, and it proved the efficacy
(1) Weakness of proximal extremities
of thymectomy on patients with EOMG. However, it also proved that
(2) Decreased tendon reflexes
the effect is modest and that the surgery could not bring patients to
remission. Given the various treatment options available recently, this
level of reduction might be achieved with EFTs and several of the
(3) Autonomic symptoms
B. Abnormalities on repetitive stimulation test
drugs that target newly identified mechanisms. Therefore, thymec-
(1) Decreased amplitude of initial compound muscle action
potential
tomy should be considered as one of the options for patients with
(2) Decrement ≥10% at low frequency (2 5 Hz)
non-thymomatous MG.
(3) Increment ≥60% after maximum voluntary contraction for 10 s
or at high frequency (20 50 Hz)
C. Pathogenic autoantibodies
13
|
T RE A T M E N T A L G O R I T H M F O R M G
In the present GLs, a treatment algorithm was proposed according to
the six clinical subtypes (Figure 1). In OMG, cholinesterase inhibitor
and topical naphazoline eye drops are initially used, and can be followed by a low dose of PSL if necessary. PSL should be administered
at a dose of ≤5 mg/day. Thymectomy should be carried out if thymoma exists. If these treatments are insufficient, IVMP should be carried out and repeated as required. Calcineurin inhibitors could be
added to the treatment.
P/Q-type voltage-gated calcium channel (P/Q-type VGCC)
antibody
D. Determination
Diagnosis of LEMS made if either of the below is true:
1. Two or more items including (1) from A are true and all three
items of B are true.
2. Two or more items including (1) from A are true and two or
more items including (3) from B are true and C is positive
Abbreviations: LEMS, Lambert–Eaton myasthenic syndrome; P/Q-type
VGCC, P/Q-type voltage-gated calcium channel.
In generalized MG, the treatment should be started with a low
dose of PSL with calcineurin inhibitor and cholinesterase inhibitor.
Generally, the PSL dose should be kept to <10 mg/day and should not
produce insufficient results, EFT should be introduced. FT is repeated
exceed 20 mg/day. Thymectomy is mandatory for g-TAMG, but
until MM-5 mg is achieved. If FT is required frequently, such as three
optional for g-EOMG. There is no indication of thymectomy for
times or more per year, the case is certified as refractory and the use
g-LOMG, g-MuSKMG or g-SNMG. If the aforementioned treatments
of molecular targeted drugs is taken into consideration.
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
24
F I G U R E 2 Treatment
algorithm for Lambert–Eaton
myasthenic syndrome (LEMS).
3,4-DAP, 3,4-diaminopyridine;
AZA, azathioprine; IVIg,
intravenous immunoglobulin;
PLEX, plasma exchange; PSL,
prednisolone; SCLC, small cell
lung cancer
14
|
DIAGNOSTIC CRITERIA OF LEMS
completed to detect small cell lung cancer. Even if the result is negative, these examinations should be repeated every 3–6 months for at
These are the first GLs for LEMS, and the diagnostic criteria of LEMS
least 2 years.46
are proposed herein (Table 3). The measurement of P/Q-type voltage-
If muscle weakness is severe, immunotherapy should be carried
gated calcium channel antibody levels is now commercially available
out based on treating MG. IVIg and plasmapheresis are selected in the
in Japan. However, measuring these antibody levels is not mandatory
acute phase, and steroids and immunosuppressants are used for long-
in diagnosing LEMS, and electrophysiology surpasses immunological
term treatment. However, as these treatments are not approved in
findings in LEMS diagnosis.
Japan, they remain off label.
LEMS is a paraneoplastic neurological syndrome in which a malignant tumor, mostly small-cell lung cancer, is present in >50% of cases.
In >90% of LEMS patients, antibodies against P/Q-type voltage-gated
16
|
C O N CL U S I O N S
calcium channel, which are located at nerve terminals, are detected.
The prevalence of LEMS in Japan was estimated to be 0.27 per
Eight years have passed since the previous clinical GLs were pub-
100 000.44 Core symptoms of LEMS are weakness of proximal extremi-
lished. The 2014 GLs set the patient QOL as a central issue and
ties, decreased tendon reflexes and autonomic symptoms. Cases
sought to ensure this was nourished as much as possible. This spirit
accompanied by small cell lung cancer have more severe muscle weak-
has been maintained with the 2022 GLs. The treatment scene of MG
ness. Differential diagnosis of LEMS should be given even in patients
is drastically changing, with many novel molecular targeted drugs on
with mild weakness or cerebellar ataxia because of a condition called
trial. It is expected that the new GLs will value the QOL of patients
“paraneoplastic cerebellar degeneration with LEMS.” Recently, along
and will connect the present treatment regimens to the developing
with the increased use of immune checkpoint inhibitors, LEMS cases
molecular targeted treatment era.
have been drawing attention as immune-related adverse events.
ACKNOWLEDG MENTS
This review includes a study supported (in part) by a Health and
15
|
TREATMENT ALGORITHM FOR LEMS
Labor Sciences Research Grant on Rare and Intractable Diseases
(Validation of Evidence-based Diagnosis and Guidelines, and
Figure 2 shows the treatment algorithm for LEMS.45 Although the
Impact on Quality of Life in Patients with Neuroimmunological
algorithm indicates that treating commences with 3,4-diaminopyridine
Diseases) from the Ministry of Health, Labor and Welfare of Japan
(3,4-DAP), it is not yet available in Japan. A clinical trial is now in pro-
(Grant number: 20FC1030), and by JSPS KAKENHI (Grant number:
gress. Once LEMS diagnosis has been made, vigorous examinations,
17K09780). We thank Mike Herbert, PhD, from Edanz Group
such as computed tomography, magnetic resonance imaging, tumor
(https://en-author-services.edanz.com/ac) for editing a draft of
marker expression, and positron emission tomography, should be
this manuscript.
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
25
MURAI ET AL.
MURAI ET AL.
CONF LICT OF IN TE RE ST
H. Murai has served as a consultant for Alexion, argenx, UCB and
Roche, and has received speaker honoraria from the Japan Blood
Products Organization and Chugai Pharmaceutical, and research support from the Ministry of Health, Labor and Welfare, Japan. H. Murai
is Editor-in-Chief of Clinical and Experimental Neuroimmunology.
K. Utsugisawa has served as a paid consultant for UCB Pharma,
argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma
and Mitsubishi Tanabe Pharma, and has received speaker honoraria
from argenx, Alexion Pharmaceuticals and the Japan Blood Products
Organization. M. Motomura has served as a consultant for Alexion,
argenx, UCB and Dydo, and received research support from the Ministry of Health, Labor and Welfare, Japan. A. Uzawa has received honoraria from Alexion Pharmaceuticals and argenx. S. Suzuki received
personal fees from Alexion Pharmaceuticals, the Japan Blood Products
Organization and Asahi Kasei Medical. T. Imai has no conflict of interest to declare.
DIS CLOSUR ES OF E THICAL STATEMENTS
Approval of the research protocol: N/A.
Informed Consent: N/A.
Registry and the Registration No. of the study/trial: N/A.
Animal Studies: N/A.
ORCID
Hiroyuki Murai
https://orcid.org/0000-0003-1612-1440
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How to cite this article: Murai H, Utsugisawa K, Motomura M,
Imai T, Uzawa A, Suzuki S. The Japanese clinical guidelines
2022 for myasthenia gravis and Lambert–Eaton myasthenic
syndrome. Clin Exp Neuroimmunol. 2023;14(1):19–27.
https://doi.org/10.1111/cen3.12739
APPENDIX A
Japanese Committee of Clinical Guidelines for MG consists of the following members. Chairperson: Hiroyuki Murai; Co-chairperson: Kimiaki
Utsugisawa, Masakatsu Motomura; Committee members: Keiko Ishigaki, Tomihiro Imai, Akiyuki Uzawa, Meinoshin Okumura, Naoki Kawaguchi, Shingo Konno, Shigeaki Suzuki, Yasushi Suzuki, Masanori
Takahashi, Shunya Nakane, Yoshiko Nomura, Naoya Minami, Hiroaki
Yoshikawa; Collaborators: Takashi Irioka, Kazuo Iwasa, Makoto Samukawa, Hirokazu Shiraishi, Yuriko Nagane, Ichiro Yabe, Daisuke Yamamoto; Systematic reviewers: Tetsuya Kanai, Takashi Kanzaki, Tomoya
Kubota, Takatoshi Sato, Keiko Toyooka; Member from outside the committee: Takeo Nakayama; Advisors: Akio Suzumura, Masaharu Takamori. The authors wrote this review on behalf of all the members.
17591961, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cen3.12739 by Cochrane Mexico, Wiley Online Library on [20/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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MURAI ET AL.