Guidelines for the treatment of autoimmune neuromuscular transmission disorders.

Abstract

Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short-term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non-thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long-term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti-epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point).

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EFNS TASK FORCE ARTICLE
Guidelines for the treatment of autoimmune neuromuscular transmission
disorders
G. O. Skeiea, S. Apostolskib, A. Evolic, N. E. Gilhusd, I. K. Harte, L. Harmsf, D. Hilton-Jonesg,
A. Melmsh, J. Verschuureniand H. W. Horgej
aDepartment of Neurology, University of Bergen, Bergen, Norway;bInstitute of Neurology, School of Medicine, University of Belgrade,
Serbia and Montenegro;cNeuroscience Department, Catholic University, Rome, Italy;dDepartment of Neurology, University of Bergen,
Bergen, Norway;eUniversity Department of Neurological Science, Walton Centre for Neurology and Neurosurgery, Liverpool, UK;
fUniversita ¨tsmedizin Berlin Charite´, Neurologische Klinik Berlin, Germany;gRadcliffe Infirmary, Oxford, UK;hNeurologische Klinik,
Universita ¨t Tu ¨bingen, Germany;iDepartment of Neurology, LUMC, Leiden, The Netherlands; andjPatient advocate, The Norwegian
Muscularly Disorders Association, Norway
Keywords:
Lambert–Eaton myasth-
enic syndrome, myasthe-
nia gravis, neuromuscular
transmission disorders,
neuromyotonia
Received 8 November 2005
Accepted 21 November 2005
Important progress has been made in our understanding of the cellular and molecular
processes underlying the autoimmune neuromuscular transmission (NMT) disorders;
myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuro-
myotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus
guidelines for the treatment of the autoimmune NMT disorders. References retrieved
from MEDLINE, EMBASE and the Cochrane Library were considered and state-
ments prepared and agreed on by disease experts and a patient representative. The
proposed practical treatment guidelines are agreed upon by the Task Force: (i)
Anticholinesterase drugs should be the first drug to be given in the management of
MG (good practice point). (ii) Plasma exchange is recommended as a short-term
treatment in MG, especially in severe cases to induce remission and in preparation for
surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and
plasma exchange are equally effective for the treatment of MG exacerbations (level A
Recommendation). (iv) For patients with non-thymomatous autoimmune MG,
thymectomy (TE) is recommended as an option to increase the probability of remis-
sion or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is
indicated irrespective of the severity of MG (level A recommendation). (vi) Oral
corticosteroids is a first choice drug when immunosuppressive drugs are necessary in
MG (good practice point). (vii) In patients where long-term immunosuppression is
necessary, azathioprine is recommended together with steroids to allow tapering the
steroids to the lowest possible dose whilst maintaining azathioprine (level A recom-
mendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and
IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuro-
myotonia patients should be treated symptomatically with an anti-epileptic drug that
reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive man-
agement of paraneoplastic neuromyotonia and LEMS is treatment of the underlying
tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and
NMT it is reasonable to adopt treatment procedures by analogy with MG (good
practice point).
Background and objectives
The autoimmune neuromuscular transmission (NMT)
disorders are relatively rare, but often debiliating dis-
eases. Myasthenia gravis (MG) is caused by autoanti-
bodies against the acetylcholine receptor (AChR) at the
neuromuscular junction. The autoimmune attack at the
muscle endplate leads to NMT failure and muscle
weakness. Lambert–Eaton
(LEMS) is caused by antibodies against the voltage-
gated calcium channels (VGCC) at the pre-synaptic side
of the muscle endplate. The antibodies inhibit acetyl-
choline (Ach) release and cause NMT failure and
muscle weakness. Neuromyotonia (peripheral nerve
hyperexcitability; Isaacs syndrome) is caused by anti-
bodies to nerve voltage-gated potassium channels
(VGKC) that produce nerve hyperexitability and
spontaneousandcontinuous
myasthenicsyndrome
skeletal muscle
Correspondence: Dr Geir Olve Skeie, Department of Neurology,
Haukeland University Hospital, 5021 Bergen, Norway
(tel.: +47 55 97 5000; fax: +47 55 97 5165; e-mail: geir.olve.skeie@
helse-bergen.no).
? 2006 EFNS
691
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overactivity presenting as twitching and painful cramps
and stiffness.
Our increased understanding of the basic mecha-
nisms of NMT and autoimmunity has led to the
development of novel treatment strategies. NMT dis-
orders are now amenable to treatment and their prog-
noses are good. Treatment developed for other and
more common antibody-mediated autoimmune disor-
ders with similar pathogenetic processes have been
applied also for NMT disorders. However, although
present treatment strategies are increasingly under-
pinned by scientific evidence, they are still based partly
on clinical experience. In this paper we have reviewed
the available literature on treatment for the autoim-
mune NMT disorders and give evidence-based guide-
lines.
Materials and methods
Search strategy
MEDLINE 1966–2004 and EMBASE 1966–2004 were
examined with appropriate MESH and free subject
terms: 1. Myasthenia, 2. Myasthenia gravis, 3. Lam-
bert–Eaton, 4. Lambert–Eaton myasthenic syndrome/
LEMS, 5. Neuromyotonia, 6. Isaacs syndrome.
The terms 1–6 were combined with the terms: 7.
Treatment, 8. Medication, 9. Therapy, 10. Controlled
clinical trial, 11. Randomized controlled trial, 12.
Clinical trial, 13. Multicenter study, 14. Meta analysis,
15. Cross-over studies, 16. Thymectomy, 17. Immuno-
suppression.
The Cochrane Central Register of Controlled Trials
(CENTRAL) was also sought. Articles in English that
contained data which could be rated according to the
guidancestatement for
guidelines of EFNS were included [1].
Information from patient and other voluntary
organizations and existing guidelines including those
from the American Academy of Neurology was
reviewed and validated according to the above criteria.
Finished and ongoing Cochrane data based projects on
LEMS treatment, immunosuppressive MG treatment,
IvIg for MG, plasmapheresis for MG and corticoster-
oids for MG in addition to TE for MG were reviewed.
neurological management
Methods for reaching consensus
Four members of the task force prepared parts of the
manuscript and draft statements about the treatment of
MG, LEMS and neuromyotonia. Evidence was classi-
fied as class I to IV and recommendations as level A to
C according to the scheme agreed for EFNS guidelines
[1]. When only class IV evidence was available but
consensus could be reached the Task force has offered
advice as good practice points [1]. The statements were
revised and collated into a single document, which was
then revised iteratively until consensus was reached.
Conflicts of interest
None of the Task force members reported any conflicts
of interest.
Myasthenia gravis
Myasthenia gravis is characterized by a fluctuating
weakness of skeletal muscle with remissions and exac-
erbations [2]. In 85% of MG patients, the disease is
caused by antibodies against the AChR at the post-
synaptic side of the neuromuscular junction that cause
transmission failure and produce destruction of the
endplate. Of the 15% of generalized MG patients
without AChR antibodies, 20–50% have antibodies
against another synaptic antigen, muscle-specific tyro-
sine kinase (MuSK) [3]. The remaining patients prob-
ably have antibodies against unknown antigens at the
neuromuscular junction. MG is closely associated with
thymic pathology. Fifteen percent of MG patients have
a thymoma and often have antibodies against addi-
tional striated muscle antigens such as titin [4] and ry-
anodine receptors [5]. These antibodies are more
common in thymoma and severe MG and are consid-
ered as useful markers for these conditions [6,7]. A
hypertrophic thymus is found in 60% of MG patients,
typically young females, whilst most patients with debut
after 50 years of age, have a normal or atrophic
thymus.
Myasthenia gravis often used to cause chronic, severe
disability and had a high mortality. However, improved
treatment allied with advances in critical care have
transformed the long-term prognosis and life expect-
ancy is now near normal [8].
Symptomatic treatment
Acetylcholine esterase inhibitors (of which pyridostig-
mine is the most widely used) inhibit the breakdown of
ACh at the neuromuscular junction. This increases the
availability of ACh to stimulate AChR and facilitates
muscle activation and contraction. These drugs are
symptomatic treatments and most helpful when used as
initial therapy in newly diagnosed MG patients, and as
sole long-term treatment of milder, especially ocular,
disease.
These drugs are usually well tolerated at standard
doses of up to 60 mg five times per day. Adverse effects
are caused by the increased concentration of ACh at
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both nicotinic and muscarinic synapses. The common
muscarinic effects are gut hypermotility (stomach
cramps, diarrhoea), increased sweathing, excessive res-
piratory and gastrointestinal secretions [9,10] and bra-
dycardia. The main nicotinic adverse effects are muscle
fasciculations, and sometimes, cramps.
There are no placebo controlled randomized studies
of these drugs, but case reports, case series and daily
clinicalexperience demonstrate an
marked clinical effect (class IV evidence). Although
there is inadequate evidence for a formal recommen-
dation, the Task force agreed that an anticholinesterase
drug should be the first-line treatment for all forms of
MG (class IV evidence, good practice point).
The optimal dose is determined by the balance
between clinical improvement and adverse effects, and
can vary over time and with concomitant treatment.
There is one report of additional effect of intranasally
administered pyridostigmine, although this is not
commercially available [11] (class III evidence).
Another symptomatic agent, ephedrine, increases
ACh release. It has probably both less effect and more
severe side-effects than pyridostigmine [12] (class III
evidence). Pyridostigmine should be preferred to eph-
edrine in the symptomatic treatment of MG (level C
recommendation).
3,4-diaminopyridine releases ACh from nerve termi-
nals and is used as a treatment for LEMS. In a double-
blind, placebo-controlled trial the drug seemed effective
in congenital (hereditary and non-immune) myasthenia
patients. Juvenile MG patients did not respond [13]
(class III evidence). The drug is not recommended in
autoimmune MG although it may prove useful in some
forms of congenital myasthenia (level C recommenda-
tion).
objective and
Immune-directed treatment
Definitive MG treatments target the autoimmune
response by suppressing the production of pathogenic
antibodies or the damage induced by the antibodies.
The aim of immunotheraphy is to induce and then
maintain remission. MG patients with a thymoma and
other patients with anti-titin and anti-RyR antibodies
usually have a severe disease [6,14] (class III evidence),
thus, suggesting that more aggressive treatment strat-
egies should be considered in these patients (level C
recommendation).
Most MG treatment studies are insufficient. There is
no consideration of whether patients have had TE and
it is not possible to extract from the data how many
patients of a treatment arm have had TE and how many
have not. In non-operated patients, it is unknown how
many of them had thymoma. In studies conducted
before 1980, the percentage of patients with and with-
out AChR antibodies is not known, and the MuSK
antibodies were detected very recently. There are no
controlled or prospective trials of immunosuppressive
treatment in children and adolescents. Evidence sug-
gests that each immunological subtype of MG may be
associated with a different spectrum of clinical pheno-
types and thymus pathologies that should be considered
when designing optimum treatment strategies.
Plasma exchange
Antibodies are removed from patient sera by membrane
filtration or centrifugation. The onset of improvement
is within the first week and the effect lasts for 1–
3 months. Short-term benefits of plasma exchange have
been reviewed by Gajdos et al. (Cochrane review) [15]
who conclude: ?There are no adequate randomized
controlled trials, but many case series report short-term
benefit from plasma exchange in MG, especially in
myasthenic crisis?. Numerous reports have shown this
[16–18] (all class IV). The NIH consensus of 1986 states:
?the panel is persuaded that plasma exchange can be
useful in strengthening patients with MG before TE
and during the postoperative period. It can also be
valuable in lessening symptoms during initiation of
immunosuppressive drug therapy and during an acute
crisis? (class IV evidence). Therefore, sham controlled
trials would be unethical. Plasma exchange is recom-
mended as a short-term treatment in MG, especially in
severe cases to induce remission and in preparation for
surgery (level B recommendation).
There is one report on the use of repeated plasma
exchange over a long period in refractory MG. It failed
to show any cumulative long-term benefit of plasma
exchange in combination with immunosuppressive
drugs over immunosuppressive treatment alone [19]
(class II evidence). A Cochrane review concludes that:
?There are no adequate randomized controlled trials to
determine whether plasma exchange improves the long-
term outcome from MG? [15] (class I evidence).
Repeated plasma exchange is, thus, not recommended
as a treatment to obtain a continuous and lasting
immunosuppression in MG (level B recommendation).
Intravenous immunoglobulin
Intravenous immunoglobulin had a positive effect in
several open studies especially in the acute phase of MG
[20] (class IV evidence). It has been used for the same
indications as plasma exchange; rapidly progressive
disease, preparation of weak patients for surgery
including TE, and as an adjuvant to minimize long-term
side-effects of oral immunosuppressive therapy [21]. A
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recent Cochrane review compared the efficacy of IvIg
compared with plasma exchange, other treatments, or
placebo. It concluded the only randomized controlled
trial examining early treatment effects did not show a
significant difference between IvIg and plasma exchange
for the treatment of MG exacerbations. Non-random-
ized evidence consistently favours the interpretation
that they are equally effective in this situation [22] (class
I evidence) (level A recommendation). Two multicentre
randomized controlled studies suggest that, although
efficacy is equal, side-effects of IvIg may be fewer and
less severe. Thus, IvIg may be the preferred option [23]
(class I evidence). However, the controlled study by
Gajdos et al. [23] used a lower volume of plasma
exchange than usual for the treatment of MG crisis, and
the end-point was improvement at a time-point set too
late to allow proper assessment of whether one therapy
worked quicker than the other. There are published
abstracts but no papers suggesting that plasma
exchange work faster in MG crisis.
In mild or moderate MG, no significant difference in
efficacy of IvIg and placebo was found after 6 weeks. In
moderate exacerbations of MG no statistically signifi-
cant difference in efficacy was found between IvIg and
methylprednisolone. Randomized controlled trials have
not shown evidence of improved functional outcome or
steroid-sparing effect with the repeated use of IvIg in
moderate or severe stable MG [22] (class I evidence).
Clinical experience does, however, suggest that IvIg
can be helpful in patients with severe MG who fail to
respond to maximal tolerated doses of corticosteroids
and/or immunosuppressive agents.
Thymectomy
There are several surgical approaches to TE: full or
partial sternotomy, transcervical and thoracoscopic.
There are no randomized controlled studies for TE in
MG. It is difficult to compare the outcomes of the
different operative techniques (confounding factors
influenced both the controlled and the uncontrolled
studies). Despite the absence of randomized, well-con-
trolled studies, TE in MG patients with and without
thymoma is widely practised. Postoperative improve-
ment can take months or years to appear, making it
difficult to distinguish TE effects from those of immu-
nosuppressive drugs, which are often used concomit-
antly. In a controlled study, a 34% remission and a
32% improvement rate were achieved after TE com-
pared with 8% and 16% for matched patients without
the operation [24] (class III evidence). As TE is an
elective intervention, the patient should be in a clinic-
ally stable condition. The perioperative morbidity is
very low and consists in wound healing disorders,
bronchopneumonia, phrenic nerve damage and, ster-
num instability with transsternal procedures.
The Quality Standard Subcommittee of the American
Academy of Neurology [25,26] analysed 28 articles
written 1953–1998 describing outcomes in 21 MG
cohorts with or without TE (class II evidence). Most
series used the transsternal approach and the follow-up
ranged from 3 to 28 years. There are a number of
methodological problems in the studies including the
definition of remission, the selection criteria, the med-
ical therapy applied in both groups, and data on anti-
body status. However, 18 of the 21 cohorts showed
improvement in MG patients who underwent TE
compared with those who did not. The authors used
median relative outcome rates and found that MG
patients undergoing TE were twice as probably to
attain medication-free remission, 1.6 times as probably
to become asymptomatic, and 1.7 times as probably to
improve. No study found a significant negative influ-
ence of TE on the outcome. A sub-group analysis after
controlling for different single confounding variables
yielded additional results: Patients with purely ocular
manifestations did not benefit from TE. The outcome
for younger TE patients was not significantly different
from the total MG group. Mild MG (Ossermann grade
1–2) did not profit from surgery, whilst more severe
cases (Ossermann grade 2b-4) were 3.7 times as prob-
ably to achieve remission after TE than those without
surgery (P < 0.0077).
The widespread opinion that an early TE in the
course of MG improves the chance of a quick remission
is based on observations that lack detailed information
and cannot be verified by meta-analysis. However, from
pathogenic considerations it is tempting to assume that
early TE should be preferred to TE after many years.
Gronseth et al. asserted unequivocally that ?for
patients with non-thymomatous autoimmune MG, TE
is recommended as an option to increase the probability
of remission or improvement?. Their recommendation is
supported by this Task force with the specification that
patients with generalized MG and AChR antibodies are
the group most probably to benefit (level B recom-
mendation).
A future randomized trial to assess the efficacy of TE
in the different clinical and immunological subgroups of
MG patients is needed. The indication for TE in AChR
antibody negative MG patients is controversial. A ret-
rospective cohort study displayed a similar postopera-
tive course in AChR antibody negative and AChR
antibody positive patients with a follow-up of at least
3 years [27]. Remission or improvement after TE
occurred in 57% of AChR antibody negative patients
and in 51% of AChR antibody positive patients.
Another study [28] could not prove any effect of TE in
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15 MuSK antibody positive patients, but the data do
not permit any recommendations at present regarding
TE in MG without AChR antibodies.
In MG patients with a thymoma the main aim of TE
is to treat the tumour rather than for any effect on the
MG. Once thymoma is diagnosed, TE is indicated
irrespective of the severity of MG (good practice point).
Thymoma is a slow-growing tumour and TE should be
performed only after stabilization of the MG. After TE,
the AChR-antibody titre usually falls less in patients
with thymoma than in those with thymic hyperplasia
[29]. The prognosis depends on early and complete tu-
mour resection [30].
Corticosteroids
In
improvement is seen in 70–80% of MG patients treated
with oral corticosteroids, usually prednisolone [31]
(class IV evidence), but the efficacy has not been studied
in double-blind, placebo-controlled trials. Steroids have
side-effects including weight gain, fluid retention,
hypertension, diabetes, anxiety/depression/insomnia/
psychosis, glaucoma, cataract, gastrointestinal hae-
morrhage and perforations, myopathy, increased sus-
ceptibility to infections and avascular joint necrosis.
The risk of osteoporosis is reduced by giving bisphos-
phonate [32] (class IV evidence), and antacids may
prevent gastrointestinal complications. The Task force
agreed that oral prednosolone should be a first choice
drug when immunosuppressive drugs are necessary in
MG (good practice point). Some patients have a tem-
porary worsening of MG if prednisolone is started at
high dose. This steroid dip occurs after 4–10 days and
sometimes can precipitate a MG crisis. Thus, we
recommend starting treatment at low dose, 10–25 mg
on alternate days increasing the dose gradually (10 mg
per dose) to 60–80 mg on alternate days. If the patient
is critically ill one should start on a high dose every day
and use additional short-time treatments to overcome
the temporary worsening. When remission occurs,
usually after 4–16 weeks, the dose should be slowly
reduced to the minimum effective dose given on alter-
nate days (good practice point).
observationalstudies,remission or marked
Azathioprine
Azathioprine is in extensive use as an immunosup-
pressant. It ismetabolized
which inhibits DNA and RNA synthesis and interferes
with T-cell function. The onset of therapeutic response
may be delayed for 4–12 months, and maximal effect is
obtained after 6–24 months. Azathioprine is usually
well tolerated but idiosyncratic flu-like symptoms or
to 6-mercaptopurine,
gastrointestinal
occur in 10%, usually within the first few days of
treatment. Some patients develop hepatitis with eleva-
tions of liver enzymes. Leucopenia, anaemia, thromb-
ocytopenia or pancytopenia usually respond to drug
withdrawal. Blood cell effects and hepatitis often do not
recur after cautious reintroduction of the drug. Careful
monitoring of full blood cell count and liver enzymes is
mandatory and the dosage should be adjusted accord-
ing to the results. About 11% of the population are
heterozygous and 0.3% homozygous for mutations of
the thiopurine methyltransferase gene and have an in-
creased risk of azathioprine-induced myelosuppression.
One large double-blind randomized study has dem-
onstrated the efficacy of azathioprine as a steroid
sparing agent with a better outcome in patients on a
combination of azathioprine and steroids than in
patients treated with steroids alone [33] (class I evi-
dence). It has an immunosupressive effect when used
alone without steroids [34] (class III evidence). In a
small randomized study, prednisone was associated
with better and more predictable early improvement in
muscle strength than azathioprine [35] (class III evi-
dence). In patients where long-term immunosuppres-
sion is necessary, we recommend starting azathioprine
together with steroids to allow tapering the steroids to
the lowest dose possible, whilst maintaining azathiop-
rine (level A recommendation).
disturbancesincludingpancreatitis
Methotrexate
Methotrexate should be used in selected MG patients
who do not respond to first choice immunosuppressive
drugs (good practice point). It is well studied in other
autoimmune disorders, but there is no evidence of
sufficient quality published for MG.
Cyclophosphamide
Cyclophosphamide is an alkylating agent with immu-
nosuppressive properties. It is a strong suppressor of B-
lymphocyte activity and antibody synthesis and at high
doses it also affects T-cells. In a randomized, double-
blind, placebo-controlled study including 23 MG pa-
tients, those on treatment had significantly improved
muscle strength and a lower steroid dose compared with
the placebo group. Intravenous pulses of cyclo-
phosphamide allowed reduction of systemic steroids
without deterioration of muscle strength or serious side-
effects [36] (class II evidence). However, the relative
high risk of toxicity including bone marrow suppres-
sion, opportunistic infections, bladder toxicity, sterility
and neoplasms, limits the use of this medication to MG
patients intolerant or unresponsive to steroids plus
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