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Guidelines for treatment of autoimmune neuromusculartransmission disorders G. O. Skeiea, S. Apostolskib, A. Evolic, N. E. Gilhusd, I. Illae, L. Harmsf, D. Hilton-Jonesg,A. Melmsh, J. Verschuureni and H. W. HorgejaDepartment of Neurology, University of 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, Norway; eServei Neurologia, Hospital Sta. Creu i Sant Pau, Barcelona, Ciberned, Spain; 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; and jThe Norwegian Musculary Disorders Association, Norway Background: Important progress has been made in our understanding of the auto- immune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia (IsaacsÕ syn- Methods: 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.
Conclusions: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point).
Plasma exchange is recommended in severe cases to induce remission and in prepa-ration for surgery (recommendation level B). IvIg and plasma exchange are effectivefor the treatment of MG exacerbations (recommendation level A). For patients withnon-thymomatous MG, thymectomy is recommended as an option to increase theprobability of remission or improvement (recommendation level B). Once thymoma isdiagnosed, thymectomy is indicated irrespective of MG severity (recommendationlevel A). Oral corticosteroids are first choice drugs when immunosuppressive drugs arenecessary (good practice point). When long-term immunosuppression is necessary,azathioprine is recommended to allow tapering the steroids to the lowest possible dosewhilst maintaining azathioprine (recommendation level A). 3,4-Diaminopyridine isrecommended as symptomatic treatment and IvIG has a positive short-term effect inLEMS (good practice point). Neuromyotonia patients should be treated with an an-tiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point).
For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlyingtumour is essential (good practice point). Immunosuppressive treatment of LEMS andneuromyotonia should be similar to MG (good practice point).
caused by antibodies against the voltage-gated calcium Autoimmune neuromuscular transmission (NMT) dis- channels (VGCC) at the pre-synaptic side of the muscle orders are relatively rare, but often debilitating diseases.
endplate. The antibodies inhibit acetylcholine release Myasthenia gravis (MG) is caused by autoantibodies and cause NMT failure and muscle weakness. Neuro- against components of the post-synaptic neuromuscular myotonia (peripheral nerve hyperexcitability; IsaacsÕ junction. The autoimmune attack at the muscle end- syndrome) is caused by antibodies to nerve voltage- plate leads to NMT failure and muscle weakness.
gated potassium channels (VGKC) that produce nervehyperexcitability and spontaneous and continuousskeletal muscle overactivity presenting as twitching and Correspondence: Geir Olve Skeie (chair), Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway Our increased understanding of the basic mechanisms (tel.: +47 55 97 5000; fax: +55 97 51 65;e-mail: geir.olve.skeie@helse-bergen.no).
of neuromuscular transmission and autoimmunity has Ó 2010 The Author(s)Journal compilation Ó 2010 EFNS led to the development of novel treatment strategies.
NMT disorders are now amenable to treatment andtheir prognoses are good. Treatment developed for other MG is characterized by a fluctuating weakness of and more common antibody-mediated autoimmune skeletal muscle with remissions and exacerbations [2].
disorders with similar pathogenetic processes have In 85% of patients with MG, the disease is caused by been applied also for NMT disorders. Although present antibodies against the AChR at the post-synaptic side treatment strategies are increasingly underpinned by of the neuromuscular junction that cause transmission scientific evidence, they are still based partly on clinical failure and produce destruction of the endplate. Of the experience. In this article, we have evaluated the available 15% of generalized MG patients without AChR anti- literature and have given evidence-based treatment bodies, 20–50% have antibodies against another syn- aptic antigen, muscle-specific tyrosine kinase [MuSK][3]. The remaining patients probably have antibodiesagainst unknown antigens at the neuromuscular junc- tion or low level/affinity antibodies against AChR orMuSK that are not detectable by standard assays. MG is closely associated with thymic pathology. Fifteen per MEDLINE 1966–2009 and EMBASE 1966–2004 were cent of patients with MG have a thymoma and often examined with appropriate MESH and free subject have antibodies against additional striated muscle terms: 1. myasthenia, 2. myasthenia gravis, 3. Lambert– antigens such as titin [4] and ryanodine receptors [5].
These antibodies are more common in thymoma and LEMS, 5. neuromyotonia, 6. IsaacsÕ syndrome.
severe MG and are considered as useful markers [6,7].
1–6 was combined with the terms: 7. treatment, 8.
A hypertrophic thymus is found in 60% of patients with medication, 9. therapy, 10. controlled clinical trial, 11.
MG, typically young women, whilst most patients with randomized controlled trial, 12. clinical trial, 13. mul- debut after 50 years of age have a normal or atrophic ticenter study, 14. meta-analysis, 15. cross-over studies, 16. thymectomy and 17. immunosuppression.
MG often used to cause chronic, severe disability and The Cochrane Central Register of Controlled Trials had a high mortality. However, improved treatment allied with advances in critical care have transformed Articles in English that contained data which could the long-term prognosis and life expectancy is now near be rated according to the guidance statement for neurological management guidelines of EFNS wereincluded [1].
Information from patient and other voluntary orga- nizations and existing guidelines including those from Acetylcholine esterase inhibitors (of which pyridostig- the American Academy of Neurology was reviewed and mine is the most widely used) inhibit the breakdown of validated according to the above-mentioned criteria.
ACh at the neuromuscular junction. This increases the Finished and ongoing Cochrane data based projects on availability of ACh to stimulate AChR and facilitates LEMS treatment, immunosuppressive MG treatment, muscle activation and contraction. These drugs are IvIg for MG, plasmapheresis for MG and corticoste- most helpful as initial therapy in newly diagnosed pa- roids for MG in addition to thymectomy for MG were tients with MG, and as sole long-term treatment of 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 Four members of the task force prepared parts of the both nicotinic and muscarinic synapses. The common manuscript and draft statements about the treatment of muscarinic effects are gut hypermotility (stomach MG, LEMS and neuromyotonia. Evidence was classi- fied as classes I to IV and recommendations as levels A respiratory and gastrointestinal secretions [12,13], and to C according to the scheme agreed for EFNS guide- bradycardia. The main nicotinic adverse effects are lines (1). When only class IV evidence was available but consensus could be reached, the task force has offered There are no placebo-controlled randomized studies advice as good practice points (1). The statements were of these drugs, but case reports, case series and daily revised and collated into a single document, which was clinical experience demonstrate an objective and then revised iteratively until consensus was reached.
marked clinical effect (class IV evidence). Although Journal compilation Ó 2010 EFNS European Journal of Neurology there is inadequate evidence for a formal recommen- pathologies that should be considered when designing dation, the task force agreed that an anticholinester- ase drug should be the first-line treatment for allforms of MG (class IV evidence, good practice point).
Although its use should be cautious in patients withanti-MuSK antibodies who often show Ach hyper- Antibodies are removed from patient sera by membrane filtration or centrifugation. The onset of improvement The optimal dose is determined by the balance is within the first week and the effect lasts for 1– between clinical improvement and adverse effects and 3 months. From unrandomized reports, semi-selective can vary over time and with concomitant treatment.
immunoadsorption to tryptophan-linked polyvinylal- There is one report of additional effect of intranasally cohol gels or protein-A columns appears to be as administered pyridostigmine, although this is not effective as plasmapheresis, with the advantage that commercially available [15] (class III evidence).
protein substitution is not required.
Short-term benefits of plasma exchange have been terminals. In a double-blind, placebo-controlled trial, reviewed by Gajdos et al. (Cochrane review) [21] who the drug seemed effective in congenital (hereditary and conclude: ÔThere are no adequate randomized con- non-immune) myasthenia patients. Juvenile patients trolled trials, but many case series report short-term with MG did not respond [16] (class III evidence).
benefit from plasma exchange in myasthenia gravis, The drug is not recommended in autoimmune MG, especially in myasthenic crisisÕ. The NIH consensus of although it may prove useful in some forms of con- 1986 states: Ôthe panel is persuaded that plasma genital myasthenia (level C recommendation).
exchange can be useful in strengthening patients with Ephedrine increases ACh release. It has probably less myasthenia gravis before thymectomy and during the effect and more severe side effects including sudden post-operative period. It can also be valuable in less- death and myocardial infarction, compared with pyri- ening symptoms during initiation of immunosuppres- dostigmine [17] (class III evidence). Terbutalin, a sive drug therapy and during an acute crisis.Õ (class IV B2-adrenergic agonist has also been tried and seems evidence). Plasma exchange is recommended as a short- promising as an adjunct for a subgroup of patients with term treatment in MG, especially in severe cases to MG [18]. Pyridostigmine should be preferred to induce remission and in preparation for surgery (level B ephedrine in the symptomatic treatment of MG (level C There is one report on the use of repeated plasma exchange over a long period in refractory MG. It failedto show any cumulative long-term benefit in combina- tion with immunosuppressive drugs [22] (class II evi- Definitive MG treatments target the autoimmune dence) [21] (class I evidence). Repeated plasma response by suppressing the production of pathogenic exchange is not recommended as a treatment to obtain antibodies or the damage induced by the antibodies.
a continuous and lasting immunosuppression in MG The aim of immunotherapy is to induce and then maintain remission. MG patients with a thymoma andother patients with anti-titin and anti-RyR antibodies usually have a severe disease [6,19] (class III evidence),thus suggesting more aggressive treatment strategies IvIg had a positive effect in several open studies espe- should be considered in these patients (level C recom- cially in the acute phase of MG [23,24] (class IV evi- dence). It has been used for the same indications as Most MG treatment studies are insufficient. There is plasma exchange; rapidly progressive disease, prepara- tion of weak patients for surgery including thymectomy thymectomy. In non-operated patients, it is unknown and as an adjuvant to minimize long-term side effects of how many of them had thymoma. In studies conducted oral immunosuppressive therapy [25]. A recent Coch- before 1980, the percentage of patients with and without rane review compared the efficacy of IvIg compared AChR antibodies is not known, and the MuSK anti- to plasma exchange, other treatments or placebo. It bodies were detected recently. There are no controlled concluded: Ôthe only randomized controlled trial and prospective trials of immunosuppressive treatment examining early treatment effects did not show a sig- in children and adolescents. Evidence suggests that each nificant difference between IvIg and plasma exchange immunological subtype of MG may be associated with a for the treatment of myasthenia gravis exacerbationsÕ.
different spectrum of clinical phenotypes and thymus Non-randomized evidence consistently favours the Ó 2010 The Author(s)Journal compilation Ó 2010 EFNS European Journal of Neurology interpretation that they are equally effective in this sit- written 1953–1998 describing outcomes in 21 MG uation [26,27] (class I evidence) (level A recommenda- cohorts with or without TE (class II evidence). Most tion). Two multicentre randomized controlled studies series used the trans-sternal approach, and the follow- suggest that although efficacy is equal, side effects of up ranged from 3 to 28 years. There are a number of IvIg may be fewer and less severe. Thus, IvIg may be methodological problems in the studies including the the preferred option [28] (class I evidence). However, definition of remission, the selection criteria, the medi- the controlled study by Gajdos et al. (1997) used a cal therapy applied in both groups and data on anti- lower volume of plasma exchange than usual for the body status. However, 18 of the 21 cohorts showed treatment of MG crisis, and the end-point was improvement in patients with MG who underwent TE.
improvement at a time-point set too late to allow Patients with MG undergoing TE were twice as likely proper assessment of whether one therapy worked to attain medication-free remission, 1.6 times as likely quicker than the other. There are published abstracts to become asymptomatic, and 1.7 times as likely to but no articles suggest that plasma exchange work improve. No study found a significant negative influ- ence of TE. Patients with purely ocular manifestations In mild or moderate MG, no significant difference in did not benefit from TE. The outcome for younger TE efficacy of IvIg and placebo was found after 6 weeks. In patients was not significantly different from the total moderate exacerbations of MG, no statistically signifi- MG group. Mild MG (Ossermann grade 1–2) did not cant difference in efficacy was found between IvIg and profit from surgery, whilst more severe cases (Osser- methylprednisolone. Randomized controlled trials have mann grade 2b-4) were 3.7 times as likely to achieve not shown evidence of improved functional outcome or steroid-sparing effect with the repeated use of IvIg in moderate or severe stable MG [26,27] (class I evidence).
Gronseth et al. asserted unequivocally that Ôfor pa- tients with non-thymomatous autoimmune MG, thy- showed a significant response in patients treated with mectomy is recommended as an option to increase the IvIg, the greatest improvement occurring in subjects probability of remission or improvementÕ. Their rec- ommendation is supported by this task force with thespecification that patients with generalized MG andAChR antibodies are the group most likely to benefit There are several surgical approaches to TE: full or The widespread opinion that an early TE in the partial sternotomy, transcervical and thoracoscopic.
course of MG improves the chance of a quick remission There are no randomized controlled studies for TE in is based on observations that lack detailed information and cannot be verified by meta-analysis. However, from It is difficult to compare the outcomes of the different pathogenic considerations it is tempting to assume operative techniques (confounding factors influenced that early TE should be preferred to TE after many both the controlled and the uncontrolled studies) but outcomes are probably similar [30] (Meyer et al., 2009) The indication for TE in AChR antibody-negative patients with MG is controversial. This group is het- Despite the absence of randomized, well-controlled erogenic. Some patients are false negative as they have studies, TE in MG patients with and without thymoma low affinity AChR antibodies not detected by standard is widely practised. Post-operative improvement can assays [34], whilst others have MuSK and possible other take months or years to appear, making it difficult to still undetected antibodies. A retrospective cohort study distinguish TE effects from those of immunosuppressive displayed a similar post-operative course in AChR drugs, which are often used concomitantly. In a con- trolled study, a 34% remission and a 32% improvement patients with a follow-up of at least 3 years [35].
rate were achieved after TE compared with 8% and Remission or improvement after TE occurred in 57% of 16% for matched patients without the operation [31] AChR antibody-negative patients and in 51% of AChR (class III evidence). The patient should be in a clinically antibody-positive patients. One study [36] could not stable condition before this elective intervention. The prove any effect of TE in 15 MuSK antibody-positive perioperative morbidity is very low and consists in patients, whilst MuSK antibodies predicted a poor wound healing disorders, bronchopneumonia, phrenic outcome of TE in another study [37]. Available evi- nerve damage and sternum instability.
dence suggests that TE should not be recommended in The Quality Standard Subcommittee of the American MuSK antibody-positive patients. Early onset general- Academy of Neurology [32,33] analysed 28 articles ized MG without AChR and MuSK antibodies should Journal compilation Ó 2010 EFNS European Journal of Neurology have TE in the same way as MG with AChR anti- occur in 10%, usually within the first few days of treatment. Some patients develop hepatitis with eleva- In MG patients with a thymoma, the main aim of TE tions of liver enzymes. Leucopenia, anaemia, throm- is to treat the tumour rather than for any effect on the bocytopenia or pancytopenia usually respond to drug MG. Once thymoma is diagnosed, TE is indicated withdrawal. Blood cell effects and hepatitis often do not irrespective of the severity of MG (good practice point).
recur after cautious reintroduction of the drug. Careful Thymoma is a slow-growing tumour, and TE should be monitoring of full blood cell count and liver enzymes is performed only after stabilization of the MG. After TE, mandatory and the dosage should be adjusted accord- the AChR antibody titre usually falls less in patients ing to the results. About 11% of the population are with thymoma than in those with thymic hyperplasia heterozygous and 0.3% homozygous for mutations of [38]. The prognosis depends on early and complete the thiopurine methyltransferase gene (which can be monitored in blood) and have an increased risk ofazathioprine-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 improvement is seen in 70–80% of patients with MG combination of azathioprine and steroids than in treated with oral corticosteroids, usually prednisolone patients treated with steroids alone [42] (class I evi- [40] (class IV evidence), but the efficacy has not been dence). It has an immunosupressive effect when used studied in double-blind, placebo-controlled trials. Ste- alone without steroids [43] (class III evidence). In a roids have side effects including weight gain, fluid small randomized study, prednisone was associated retention, hypertension, diabetes, anxiety/depression/ with better and more predictable early improvement in insomnia/psychosis, glaucoma, cataract, gastrointesti- muscle strength than azathioprine [44] (class III evi- dence). In patients where long-term immunosuppres- increased susceptibility to infections and avascular joint sion is necessary, we recommend starting azathioprine necrosis. The risk of osteoporosis is reduced by giving together with steroids to allow tapering the steroids to bisphosphonate [41] (class IV evidence), and antacids the lowest dose possible, whilst maintaining azathio- may prevent gastrointestinal complications. The task force agreed that oral prednisolone should be a firstchoice drug when immunosuppressive drugs are neces- sary in MG (good practice point). Some patients have atemporary worsening of MG if prednisolone is started Methotrexate should be used in selected patients with at high dose. This steroid dip occurs after 4–10 days MG who do not responde to first choice immunosup- and sometimes can precipitate a MG crisis. Thus, we pressive drugs (good practice point). It is well studied in recommend starting treatment at low dose, 10–25 mg other autoimmune disorders, but there is no evidence of on alternate days increasing the dose gradually (10 mg sufficient quality published for MG.
per dose) to 60–80 mg on alternate days. If the patientis critically ill, one should start on a high dose every day and use additional short-time treatments to overcomethe temporary worsening. When remission occurs, Cyclophosphamide is an alkylating agent with immu- usually after 4–16 weeks, the dose should be slowly nosuppressive properties. It is a strong suppressor of reduced to the minimum effective dose given on alter- B-lymphocyte activity and antibody synthesis and at high doses it also affects T-cells. In a randomized,double-blind, placebo-controlled study including 23patients with MG, those on treatment had significantly improved muscle strength and a lower steroid dose Azathioprine is in extensive use as an immunosup- compared with the placebo group. Intravenous pulses pressant. It is metabolized to 6-mercaptopurine, which of cyclophosphamide allowed reduction of systemic inhibits DNA and RNA synthesis and interferes with steroids without deterioration of muscle strength or T-cell function. The onset of therapeutic response may serious side effects [45] (class II evidence). However, the be delayed for 4–12 months, and maximal effect is relative high risk of toxicity including bone marrow obtained after 6–24 months. Azathioprine is usually suppression, opportunistic infections, bladder toxicity, well tolerated but idiosyncratic flu-like symptoms or sterility and neoplasms, limits the use of this medication to patients with MG intolerant or unresponsive to Ó 2010 The Author(s)Journal compilation Ó 2010 EFNS European Journal of Neurology steroids plus azathioprine, methotrexate, cyclosporin or the immunosuppression (53). FK506 should be tried in mycophenolate mofetil (level B recommendation).
MG patients with poorly controlled disease, especiallyin RyR antibody-positive patients (level C recommen-dation).
Cyclosporin has an immunosuppressive effect in both organ transplantation and autoimmune disorders. It isan inhibitor of T-cell function through inhibition of There are case reports of improvement of refractory calcineurin signalling [46]. Tindall et al. [47] conducted MG with monoclonal antibodies against different a placebo-controlled double-blind randomized study in lymphocyte subsets such as anti-CD20 (rituximab) 20 patients for 6 months with an open extension (class (B-cell inhibitor) [67–70] (class IV evidence) and anti- II evidence) [48,49] (class III evidence). The cyclosporin CD4 (T-cell inhibitor) [71](class IV evidence), both group had significantly improved strength and reduc- reporting good clinical outcome. These treatment tion in AChR antibody titre compared with the placebo strategies are promising, but more evidence is needed group. Two open trials of 1 and 2 years treatment and before any recommendations can be given.
one retrospective study all support the beneficial effectof cyclosporin [10,50–52] (class III evidence). Cyclo- Training, weight control and lifestyle modifications sporin is effective in MG, has significant side effects ofnephrotoxicity and hypertension and should be con- The importance of reducing weight and modification of sidered only in patients intolerant or unresponsive to activities of daily living has been suggested, but there is azathioprine (level B recommendation).
no hard scientific evidence to this. There are reportsthat show some benefit of respiratory muscle training inMG [72,73] (class III evidence) and strength training in mild MG [74] (class III evidence). Physical training can Mycophenolate mofetilÕs active metabolite, mycophen- be carried out safely in mild MG and produces some olic acid, is an inhibitor of purine nucleotide synthesis improvement in muscle force (level C recommenda- and impairs lymphocyte proliferation selectively. A few tion). Seasonal flu vaccination should be recommended studies including a small double-blind, placebo-con- in patients with MG (good practice point).
trolled study of 14 patients have shown that myco- MG is associated with a slightly increased rate of phenolate mofetil is effective in patients with poorly complications during birth and more frequent need of controlled MG and as a steroid-sparing medication [53– operative interventions [75,76] (class II evidence).
59] (class III, class IV evidence). These findings could Transient neonatal MG occurs in 10–20% of children not be reproduced in a recent placebo-controlled born to MG mothers. Maternal MG is also a rare cause study over 9 months [60] (class II evidence). Therefore, of arthrogryphosis congenita and of recurrent miscar- the effect of mycophenolate mofetil in MG is not riages [77]. Acetylcholine esterase inhibitors and unequivocally documented, but it may be tried in immunosuppressive drugs should be continued during patients intolerant or unresponsive to azathioprine pregnancy when necessary for the MG, except for methotrexate which is damaging to ova and sperm andshould be stopped at least 3 months before attemptingconception. Mycophenolate mofetil and other new drugs where no safety data are available should also be Tacrolimus (FK506) is a macrolide molecule of the stopped 3 months before conception [78] (good practice same immunosuppressant class as cyclosporin. It point). Effective immunosuppression can improve se- inhibits the proliferation of activated T-cells via vere foetal MG-related conditions (class III evidence).
the calcium–calcineurin pathway. FK506 also acts on Women with MG should not be discouraged from ryanodine receptor-mediated calcium release from conceiving, and pregnancy does not worsen the long- sarcoplasmic reticulum to potentiate excitation–con- term outcome of MG [79] (class II evidence).
traction coupling in skeletal muscle [61]. Case reportsand a small open trial all showed a useful improvement of MG with minor side effects [9,62–66] (class III evi-dence). Interestingly, patients with anti-RyR antibodies After the diagnosis of MG is established, an acetyl- (and potential excitation–contraction coupling dys- choline esterase inhibitor should be introduced. Thy- function) had a rapid response to treatment indicating a moma patients should have thymectomy. AChR symptomatic effect on muscle strength in addition to antibody-positive early-onset patients with generalized Journal compilation Ó 2010 EFNS European Journal of Neurology MG and insufficient response to pyridostigmine therapy should be considered for thymectomy, ideally within 1 year of disease onset. Immunosuppressive medicationshould be considered in all patients with progressive This commonest acquired form of generalized periph- MG symptoms. We recommend starting with prednis- eral nerve hyperexcitability is autoimmune and caused olone covered by bisphosphonate and antacid and by antibodies to nerve voltage-gated potassium chan- azathioprine. Non-responders or patients intolerant to nels (VGKC). [87], although the only generally avail- this regime should be considered for treatment with one able assay detects these antibodies in only 30–50% of of the other recommended immunosupressive drugs.
all patients [87]. Neuromyotonia is paraneoplastic in up Recommendation levels are B, C or good practice to 25% of patients and can predate the detection of neoplasia, usually thymus or lung, by up to 4 years [88].
The clinical hallmark is spontaneous and continuousskeletal muscle overactivity presenting as twitching and painful cramps and often accompanied by stiffness, Antibodies to peripheral nerve P/Q-type VGCC anti- pseudomyotonia, pseudotetany and weakness [89]. One bodies are present in the serum of at least 85% of third of patients also have sensory features and up to LEMS patients [80]. The disease is characterized by ascending muscle weakness that usually starts in the involvement. Central nervous system features can occur proximal lower limb muscles and is associated with autonomic dysfunction. Ptosis and ophthalmoplegiatend to be milder than in MG [81]. LEMS rarely causes Symptomatic and immune-directed treatment respiratory failure [81]. In half of the patients, LEMS isa paraneoplastic disease and a small cell lung carcinoma Neuromyotonia usually improves with symptomatic treatment [89], although evidence is case reports andcase series (class IV evidence). Carbamazepine, phe-nytoin, lamotrigine and sodium valproate can be used, Symptomatic and immune-directed treatment Evidence from small, randomized, controlled trials Neuromyotonia often improves and can remit after showed that both 3,4-diaminopyridine and IvIg im- treatment of an underlying cancer [89]. In patients whose proved muscle strength scores and compound muscle symptoms are debilitating or refractory to symptomatic action potential amplitudes in LEMS patients [83] therapy, immunomodulatory therapies should be tried (Cochrane review) (class I evidence).
[89,91]. Plasma exchange often produces useful clinical First-line treatment is 3,4-diaminopyridine [84]. An improvement lasting about 6 weeks accompanied by a additional therapeutic effect may be obtained if com- reduction in electromyography activity [89] and a fall in bined with pyridostigmine. If symptomatic treatment is VGKC antibody titres [92]. Single case studies suggest insufficient, immunosuppressive therapy should be that IvIg can also help [93]. There are no good trials of started, usually with a combination of prednisone and long-term oral immunosuppression. However, prednis- azathioprine. Other drugs like cyclosporin or myco- olone, with or without azathioprine or methotrexate, phenolate can be used, although evidence of benefit is has been useful in selected patients 86 [94] (class IV limited to case series reports (class IV evidence) (level C For patients with a paraneoplastic LEMS, it is essential to treat the tumour. Chemotherapy is the firstchoice in SCLC, and this will have an additional 1. Brainin M, Barnes M, Baron JC, et al. Guidance for the immunosuppressive effect. In LEMS patients with a preparation of neurological management guidelines byEFNS scientific task forces – revised recommendations possible underlying SCLC corticosteroids, when re- 2004. Eur J Neurol 2004; 11: 577–581.
quired for the disease treatment, can be used; immu- 2. Vincent A. Unravelling the pathogenesis of myasthenia nosuppressants should be avoided before the tumour is gravis. Nat Rev Immunol 2002; 2: 797–804.
ruled out. This does not apply to thymoma that has a 3. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptortyrosine kinase MuSK in patients with myasthenia gravis The presence of LEMS in a patient with SCLC without acetylcholine receptor antibodies. Nat Med 2001; improves tumour survival [85]. For a more detailed description of LEMS, consult the Guidelines for the 4. Aarli JA, Stefansson K, Marton LS, Wollmann RL.
management of paraneoplastic disorders [86].
Patients with myasthenia gravis and thymoma have in Ó 2010 The Author(s)Journal compilation Ó 2010 EFNS European Journal of Neurology their sera IgG autoantibodies against titin. Clin Exp 24. Elovaara I, Apostolski S, van Doorn P, et al. EFNS guidelines for the use of intravenous immunoglobulin in 5. Mygland A, Tysnes OB, Matre R, Volpe P, Aarli JA, treatment of neurological diseases: EFNS task force on Gilhus NE. Ryanodine receptor autoantibodies in myas- the use of intravenous immunoglobulin in treatment of thenia gravis patients with a thymoma. Ann Neurol 1992; neurological diseases. Eur J Neurol 2008; 15: 893–908.
25. Dalakas MC. Intravenous immunoglobulin in the treat- 6. Skeie GO, Mygland A, Aarli JA, Gilhus NE. Titin anti- ment of autoimmune neuromuscular diseases: present bodies in patients with late onset myasthenia gravis: status and practical therapeutic guidelines. Muscle Nerve clinical correlations. Autoimmunity 1995; 20: 99–104.
7. Somnier FE, Skeie GO, Aarli JA, Trojaborg W. EMG 26. Gajdos P, Chevret S, Toyka K. Intravenous immuno- evidence of myopathy and the occurrence of titin auto- globulin for myasthenia gravis. Cochrane Database Syst antibodies in patients with myasthenia gravis. Eur J 27. Gajdos P, Chevret S, Toyka K. Intravenous immuno- 8. Gerber NL, Steinberg AD. Clinical use of immunosup- globulin for myasthenia gravis. Cochrane Database Syst pressive drugs: part II. Drugs 1976; 11: 90–112.
9. Evoli A, Di Schino C, Marsili F, Punzi C. Successful 28. Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C.
treatment of myasthenia gravis with tacrolimus. Muscle Clinical trial of plasma exchange and high-dose intrave- nous immunoglobulin in myasthenia gravis. Myasthenia 10. Goulon M, Elkharrat D, Gajdos P. Treatment of severe Gravis Clinical Study Group. Ann Neurol 1997; 41: myasthenia gravis with cyclosporin. A 12-month open trial. Presse Med 1989; 18: 341–346.
29. Zinman L, Ng E, Bril V. IV immunoglobulin in patients 11. Owe JF, Daltveit AK, Gilhus NE. Causes of death among with myasthenia gravis: a randomized controlled trial.
patients with myasthenia gravis in Norway between 1951 and 2001. J Neurol Neurosurg Psychiatry 2006; 77: 203–207.
30. Meyer DM, Herbert MA, Sobhani NC, et al. Compara- 12. Szathmary I, Magyar P, Szobor A. Air-flow limitation tive clinical outcomes of thymectomy for myasthenia in myasthenia gravis. The effect of acetylcholinesterase gravis performed by extended transsternal and minimally inhibitor therapy on air-flow limitation. Am Rev Respir invasive approaches. Ann Thorac Surg 2009; 87: 385–390.
31. Buckingham JM, Howard FM Jr, Bernatz PE, et al. The 13. Shale DJ, Lane DJ, Davis CJ. Air-flow limitation in value of thymectomy in myasthenia gravis: a computer- myasthenia gravis. The effect of acetylcholinesterase assisted matched study. Ann Surg 1976; 184: 453–458.
inhibitor therapy on air-flow limitation. Am Rev Respir 32. Gronseth GS, Barohn RJ. Thymectomy for Myasthenia Gravis. Curr Treat Options Neurol 2002; 4: 203–209.
14. Punga AR, Flink R, Askmark H, Stalberg EV. Cholin- ergic neuromuscular hyperactivity in patients with myas- thymectomy for autoimmune myasthenia gravis (an thenia gravis seropositive for MuSK antibody. Muscle evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
15. Sghirlanzoni A, Pareyson D, Benvenuti C, et al. Efficacy of intranasal administration of neostigmine in myasthenic 34. Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to patients. J Neurol 1992; 239: 165–169.
acetylcholine receptors in ÔseronegativeÕ myasthenia gra- 16. Anlar B, Varli K, Ozdirim E, Ertan M. 3,4-diaminopyri- dine in childhood myasthenia: double-blind, placebo- 35. Guillermo GR, Tellez-Zenteno JF, Weder-Cisneros N, controlled trial. J Child Neurol 1996; 11: 458–461.
et al. Response of thymectomy: clinical and pathological 17. Sieb JP, Engel AG. Ephedrine: effects on neuromuscular transmission. Brain Res 1993; 623: 167–171.
myasthenia gravis patients. Acta Neurol Scand 2004; 109: 18. Soliven B, Rezania K, Gundogdu B, Harding-Clay B, Oger J, Arnason BG. Terbutaline in myasthenia gravis: a 36. Evoli A, Tonali PA, Padua L, et al. Clinical correlates pilot study. J Neurol Sci 2009; 277: 150–154.
with anti-MuSK antibodies in generalized seronegative 19. Romi F, Skeie GO, Aarli JA, Gilhus NE. The severity of myasthenia gravis. Brain 2003; 126: 2304–2311.
myasthenia gravis correlates with the serum concentration 37. Pompeo E, Tacconi F, Massa R, Mineo D, Nahmias S, of titin and ryanodine receptor antibodies. Arch Neurol extended thymectomy for nonthymomatous myasthenia 20. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis. Eur J Cardiothorac Surg 2009; 36: 164–169.
gravis: emerging clinical and biological heterogeneity.
38. Reinhardt C, Melms A. Normalization of elevated CD4)/ CD8) (double-negative) T cells after thymectomy paral- 21. Gajdos P, Chevret S, Toyka K. Plasma exchange for lels clinical remission in myasthenia gravis associated with myasthenia gravis. Cochrane Database Syst Rev 2002; 4: thymic hyperplasia but not thymoma. Ann Neurol 2000; 22. Gajdos P, Simon N, de Rohan-Chabot P, Raphael JC, 39. Chen G, Marx A, Wen-Hu C, et al. New WHO histologic Goulon M. Long-term effects of plasma exchange in classification predicts prognosis of thymic epithelial myasthenia. Results of a randomized study. Presse Med tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002; 95: 420–429.
23. Fateh-Moghadam A, Wick M, Besinger U, Geursen RG.
40. Pascuzzi RM, Coslett HB, Johns TR. Long-term corti- High-dose intravenous gammaglobulin for myasthenia costeroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984; 15: 291–298.
Journal compilation Ó 2010 EFNS European Journal of Neurology 41. Saag KG. Prevention of glucocorticoid-induced osteopo- mofetil in myasthenia gravis. Neurology 2008; 71: 400– rosis. South Med J 2004; 97: 555–558.
42. Palace J, Newsom-Davis J, Lecky B. A randomized 61. Timerman AP, Ogunbumni E, Freund E, Wiederrecht G, double-blind trial of prednisolone alone or with azathio- Marks AR, Fleischer S. The calcium release channel of prine in myasthenia gravis. Myasthenia Gravis Study sarcoplasmic reticulum is modulated by FK-506-binding Group. Neurology 1998; 50: 1778–1783.
protein. Dissociation and reconstitution of FKBP-12 to 43. Witte AS, Cornblath DR, Parry GJ, Lisak RP, Schatz NJ.
the calcium release channel of skeletal muscle sarcoplas- Azathioprine in the treatment of myasthenia gravis. Ann mic reticulum. J Biol Chem 1993; 268: 22992–22999.
62. Takamori M, Motomura M, Kawaguchi N, et al. Anti- 44. Bromberg MB, Wald JJ, Forshew DA, Feldman EL, ryanodine receptor antibodies and FK506 in myasthenia Albers JW. Randomized trial of azathioprine or predni- gravis. Neurology 2004; 62: 1894–1896.
sone for initial immunosuppressive treatment of myas- 63. Konishi T, Yoshiyama Y, Takamori M, Yagi K, Mukai thenia gravis. J Neurol Sci 1997; 150: 59–62.
E, Saida T. Clinical study of FK506 in patients with 45. De Feo LG, Schottlender J, Martelli NA, Molfino NA. Use myasthenia gravis. Muscle Nerve 2003; 28: 570–574.
of intravenous pulsed cyclophosphamide in severe, gener- 64. Yoshikawa H, Mabuchi K, Yasukawa Y, Takamori M, alized myasthenia gravis. Muscle Nerve 2002; 26: 31–36.
Yamada M. Low-dose tacrolimus for intractable myas- 46. Matsuda S, Koyasu S. Mechanisms of action of cyclo- thenia gravis. J Clin Neurosci 2002; 9: 627–628.
sporine. Immunopharmacology 2000; 47: 119–125.
65. Tada M, Shimohata T, Oyake M, et al. Long-term thera- 47. Tindall RS, Rollins JA, Phillips JT, Greenlee RG, Wells peutic efficacy and safety of low-dose tacrolimus (FK506) L, Belendiuk G. Preliminary results of a double-blind, for myasthenia gravis. J Neurol Sci 2006; 247: 17–20.
randomized, placebo-controlled trial of cyclosporine in 66. Nagaishi A, Yukitake M, Kuroda Y. Long-term treat- myasthenia gravis. N Engl J Med 1987; 316: 719–724.
ment of steroid-dependent myasthenia gravis patients with 48. Tindall RS. Immunointervention with cyclosporin A in low-dose tacrolimus. Intern Med 2008; 47: 731–736.
autoimmune neurological disorders. J Autoimmun 1992; 67. Wylam ME, Anderson PM, Kuntz NL, Rodriguez V.
Successful treatment of refractory myasthenia gravis using 49. Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K. A rituximab: a pediatric case report. J Pediatr 2003; 143: clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci 1993; 681: 539–551.
68. Illa I, Diaz-Manera J, Rojas-Garcia R, et al. Sustained 50. Goulon M, Elkharrat D, Lokiec F, Gajdos P. Results of a response to Rituximab in anti-AChR and anti-MuSK one-year open trial of cyclosporine in ten patients with positive Myasthenia Gravis patients. J Neuroimmunol severe myasthenia gravis. Transplant Proc 1988; 20: 69. Lebrun C, Bourg V, Tieulie N, Thomas P. Successful 51. Bonifati DM, Angelini C. Long-term cyclosporine treat- treatment of refractory generalized myasthenia gravis with ment in a group of severe myasthenia gravis patients.
rituximab. Eur J Neurol 2009; 16: 246–250.
70. Stieglbauer K, Topakian R, Schaffer V, Aichner FT.
52. Ciafaloni E, Nikhar NK, Massey JM, Sanders DB. Ret- Rituximab for myasthenia gravis: three case reports and rospective analysis of the use of cyclosporine in myas- review of the literature. J Neurol Sci 2009; 280: 120–122.
thenia gravis. Neurology 2000; 55: 448–450.
71. Ahlberg R, Yi Q, Pirskanen R, et al. Treatment of 53. Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders myasthenia gravis with anti-CD4 antibody: improvement DB. Mycophenolate mofetil for myasthenia gravis: an correlates to decreased T-cell autoreactivity. Neurology open-label pilot study. Neurology 2001; 56: 97–99.
54. Chaudhry V, Cornblath DR, Griffin JW, OÕBrien R, 72. Weiner P, Gross D, Meiner Z, et al. Respiratory muscle Drachman DB. Mycophenolate mofetil: a safe and training in patients with moderate to severe myasthenia promising immunosuppressant in neuromuscular diseases.
gravis. Can J Neurol Sci 1998; 25: 236–241.
73. Rassler B, Hallebach G, Kalischewski P, Baumann I, 55. Schneider C, Gold R, Reiners K, Toyka KV. Myco- Schauer J, Spengler CM. The effect of respiratory muscle phenolate mofetil in the therapy of severe myasthenia endurance training in patients with myasthenia gravis.
gravis. Eur Neurol 2001; 46: 79–82.
Neuromuscul Disord 2007; 17: 385–391.
56. Hauser RA, Malek AR, Rosen R. Successful treatment of 74. Lohi EL, Lindberg C, Andersen O. Physical training a patient with severe refractory myasthenia gravis using effects in myasthenia gravis. Arch Phys Med Rehabil 1993; mycophenolate mofetil. Neurology 1998; 51: 912–913.
57. Meriggioli MN, Rowin J. Single fiber EMG as an out- 75. Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis: come measure in myasthenia gravis: results from a double- consequences for pregnancy, delivery, and the newborn.
blind, placebo-controlled trial. J Clin Neurophysiol 2003; 76. Wen JC, Liu TC, Chen YH, Chen SF, Lin HC, Tsai WC.
58. Meriggioli MN, Rowin J. Treatment of myasthenia gravis No increased risk of adverse pregnancy outcomes for with mycophenolate mofetil: a case report. Muscle Nerve women with myasthenia gravis: a nationwide population- based study. Eur J Neurol 2009; 16: 889–894.
59. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Myco- 77. Vincent A, Newland C, Brueton L, et al. Arthrogryposis phenolate mofetil for myasthenia gravis: an analysis of multiplex congenita with maternal autoantibodies specific efficacy, safety, and tolerability. Neurology 2003; 61: for a fetal antigen. Lancet 1995; 346: 24–25.
78. Ferrero S, Pretta S, Nicoletti A, Petrera P, Ragni N.
60. Sanders DB, Hart IK, Mantegazza R, et al. An interna- Myasthenia gravis: management issues during pregnancy.
tional, phase III, randomized trial of mycophenolate Eur J Obstet Gynecol Reprod Biol 2005; 121: 129–138.
Ó 2010 The Author(s)Journal compilation Ó 2010 EFNS European Journal of Neurology 79. Batocchi AP, Majolini L, Evoli A, Lino MM, Minisci C, 87. Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills Tonali P. Course and treatment of myasthenia gravis KR. Phenotypic variants of autoimmune peripheral nerve during pregnancy. Neurology 1999; 52: 447–452.
hyperexcitability. Brain 2002; 125: 1887–1895.
80. Motomura M, Johnston I, Lang B, Vincent A, New- 88. Hart IK, Waters C, Vincent A, et al. Autoantibodies som-Davis J. An improved diagnostic assay for Lam- detected to expressed K+ channels are implicated in bert-Eaton myasthenic syndrome. J Neurol Neurosurg neuromyotonia. Ann Neurol 1997; 41: 238–246.
89. Newsom-Davis J, Mills KR. Immunological associations 81. Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in of acquired neuromyotonia (IsaacsÕ syndrome). Report of distribution of muscle weakness between myasthenia five cases and literature review. Brain 1993; 2: 453–469.
gravis and the Lambert-Eaton myasthenic syndrome.
90. Liguori R, Vincent A, Clover L, et al. MorvanÕs syn- J Neurol Neurosurg Psychiatry 2002; 73: 766–768.
drome: peripheral and central nervous system and cardiac 82. Wirtz PW, Willcox N, van der Slik AR, et al. HLA and involvement with antibodies to voltage-gated potassium smoking in prediction and prognosis of small cell lung channels. Brain 2001; 124: 2417–2426.
cancer in autoimmune Lambert-Eaton myasthenic syn- 91. Hayat GR, Kulkantrakorn K, Campbell WW, Giuliani drome. J Neuroimmunol 2005; 159: 230–237.
MJ. Neuromyotonia: autoimmune pathogenesis and 83. Maddison P, Newsom-Davis J. Treatment for Lambert- response to immune modulating therapy. J Neurol Sci Eaton myasthenic syndrome. Cochrane Database Syst Rev 92. Shillito P, Molenaar PC, Vincent A, et al. Acquired neu- 84. McEvoy KM, Windebank AJ, Daube JR, Low PA 3. 3,4- romyotonia: evidence for autoantibodies directed against Diaminopyridine in the treatment of Lambert-Eaton K+ channels of peripheral nerves. Ann Neurol 1995; 38: myasthenic syndrome. N Engl J Med 1989; 321: 1567–1571.
85. Maddison P, Newsom-Davis J, Mills KR, Souhami RL.
93. Alessi G, De Reuck J, De Bleecker J, Vancayzeele S.
Favourable prognosis in Lambert-Eaton myasthenic Successful immunoglobulin treatment in a patient with syndrome and small-cell lung carcinoma. Lancet 1999; neuromyotonia. Clin Neurol Neurosurg 2000; 102: 173– 86. Vedeler CA, Antoine JC, Giometto B, et al. Management 94. Nakatsuji Y, Kaido M, Sugai F, et al. IsaacsÕ syndrome of paraneoplastic neurological syndromes: report of an successfully treated by immunoadsorption plasmaphere- EFNS Task Force. Eur J Neurol 2006; 13: 682–690.
sis. Acta Neurol Scand 2000; 102: 271–273.
Journal compilation Ó 2010 EFNS European Journal of Neurology

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