A review of myasthenia gravis: Pathogenesis, clinical features and treatment

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Current Anaesthesia & Critical Care (2007) 18, 1523 FOCUS ON: NEUROSCIENCE A review of myasthenia gravis: Pathogenesis, clinical features and treatment Chris Turner SpR in Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK KEYWORDS Myasthenia gravis; Immunosuppression; Autoimmunity; Neuromuscular junc- tion Summary Myasthenia gravis is an organ-specific autoimmune disease charac- terised by fatigable weakness of voluntary muscles. It is associated with antibodies to the post-synaptic nicotinic acetylcholine receptor in the neuromuscular junction. It peaks in the 20s especially in women and in the 50s in men. Patients may present with a wide range of neurological symptoms but usually develop ptosis and/or diplopia at some point in their illness. Some patients may present with neuromuscular respiratory failure from the onset. Management is aimed at firstly treating the symptoms with acetylcholine esterase inhibitors, such as pyridostig- mine, secondly treating the underlying disease process with immunosuppressants and thirdly considering thymectomy in patients with a thymoma and patients with generalised myasthenia. In this review, the important aspects of pathogenesis, diagnosis, investigation and management are discussed. & 2007 Published by Elsevier Ltd. Contents An introduction and brief history ................................................. 16 Epidemiology ............................................................. 16 Classification ............................................................. 16 Presence or absence of antibodies to the AChR .................................... 16 Seropositive ..................................................... 16 Seronegative .................................................... 17 Severity............................................................. 17 Aetiology ............................................................ 17 Anatomy and physiology of the normal neuromuscular junction ............................. 17 Immunopathogenesis .................................................... 17 Role of T cells and the thymus .............................................. 18 Clinical features of MG ....................................................... 18 Diagnosis of MG ............................................................ 19 Differential diagnosis of MG .................................................... 19 ARTICLE IN PRESS www.elsevier.com/locate/cacc 0953-7112/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.cacc.2007.01.006 E-mail address: [email protected].

Transcript of A review of myasthenia gravis: Pathogenesis, clinical features and treatment

Page 1: A review of myasthenia gravis: Pathogenesis, clinical features and treatment

ARTICLE IN PRESS

Current Anaesthesia & Critical Care (2007) 18, 15–23

0953-7112/$ - sdoi:10.1016/j.c

E-mail addr

www.elsevier.com/locate/cacc

FOCUS ON: NEUROSCIENCE

A review of myasthenia gravis: Pathogenesis,clinical features and treatment

Chris Turner

SpR in Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK

KEYWORDSMyasthenia gravis;Immunosuppression;Autoimmunity;Neuromuscular junc-tion

ee front matter & 2007acc.2007.01.006

ess: ctwork@btinternet

Summary Myasthenia gravis is an organ-specific autoimmune disease charac-terised by fatigable weakness of voluntary muscles. It is associated with antibodiesto the post-synaptic nicotinic acetylcholine receptor in the neuromuscular junction.It peaks in the 20s especially in women and in the 50s in men. Patients may presentwith a wide range of neurological symptoms but usually develop ptosis and/ordiplopia at some point in their illness. Some patients may present withneuromuscular respiratory failure from the onset. Management is aimed at firstlytreating the symptoms with acetylcholine esterase inhibitors, such as pyridostig-mine, secondly treating the underlying disease process with immunosuppressantsand thirdly considering thymectomy in patients with a thymoma and patients withgeneralised myasthenia. In this review, the important aspects of pathogenesis,diagnosis, investigation and management are discussed.& 2007 Published by Elsevier Ltd.

Contents

An introduction and brief history. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Presence or absence of antibodies to the AChR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Seropositive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Seronegative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Severity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Anatomy and physiology of the normal neuromuscular junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Immunopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Role of T cells and the thymus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Clinical features of MG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Diagnosis of MG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Differential diagnosis of MG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Published by Elsevier Ltd.

.com.

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Treatment of MG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Acetylcholinesterase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Other immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Plasmapheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Intravenous immunoglobulin (IVIg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Thymectomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

MG and pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Myasthenic crisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Prognosis of MG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Recent advances in MG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

An introduction and brief history

Myasthenia gravis (MG) is a treatable organ-specificautoimmune disease characterised by fatigablemuscle weakness. It is associated with autoantibo-dies to the nicotinic acetylcholine receptor (AChR)on the postsynaptic membrane at the neuromus-cular junction (see Fig. 1). In 1672, Thomas Willisdescribed a patient with limb and bulbar weaknesswhich worsened during the day. Jolly in 1895described fatigable weakness that improved withrest and gave the name ‘‘myasthenia gravispseudoparalytica’’. It was not until 1935 thatneostigmine, an orally administered anticholines-terase, was used in MG.1 In 1976, Lindstorm andcolleagues described antibodies against the AChR inup to 87% of patients with MG.2

Epidemiology

MG is the commonest disorder affecting theneuromuscular junction (NMJ). Its prevalence in

Fig. 1 The neuromu

the UK has been reported at 2–7/10,000.3 It canpresent at any age but there is a bimodal peak ofincidence with the first peak in the third decadeaffecting mostly women and a second peak in thesixth and seventh decade affecting mostly men.

Classification

MG can be classified by the presence or absence ofantibodies to the AChR, by the severity of thedisease and by the aetiology.

Presence or absence of antibodies to theAChR

SeropositiveThis is the commonest type of acquired autoim-mune MG. Approximately 85% of patients withgeneralised MG and 50% of patients with isolatedocular MG are seropositive using a radioimmunoas-say to detect the AChR antibodies.

scular junction.

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SeronegativeBetween 10% and 20% of patients with acquired MGdo not have AChR antibodies. Recently, antibodiesto muscle specific kinase (MuSK) have been re-ported in some of these patients. MuSK is a proteinon the post-synaptic membrane which is closelyassociated with the AChR.4 These patients pre-dominantly have bulbar weakness, a reducedresponse to immunosuppressant agents and musclewasting.

Severity

Osserman’s original classification divides adult MGinto four groups based on the severity of thedisease5:

(1)

ocular myasthenia; (2) generalised myasthenia of mild or moderate

severity;

(3) severe generalised myasthenia; and (4) myasthenic crisis with respiratory failure.

This has now been expanded upon and is mainlyused for research purposes.

Aetiology

(1)

Acquired autoimmune MG is the commonestform in adults.

(2)

Transient neonatal MG is caused by passivetransfer of maternal anti-AChR antibodies.

(3)

Drug-induced MG6 e.g. D-penicillamine. Presen-tation may be identical to acquired autoim-mune MG with positive AChR antibodies. Otherdrugs that can exacerbate MG or cause amyasthenia-like weakness include curare, ami-noglycosides, quinine, procainamide, and cal-cium channel blockers.

(4)

Congenital myasthenic syndromes are causedby mutations in proteins involved in postsynap-tic neuromuscular transmission.

Anatomy and physiology of the normalneuromuscular junction

The normal anatomy and physiology of the neuro-muscular junction is outlined in Fig. 1. An actionpotential passes down motor neurons towardsskeletal muscle. Each motor axon divides up intoa number of terminal branches just before itreaches the muscle. Each one of these branchesends at a pre-synaptic nerve terminal whichcontains vesicles of acetylcholine. The action

potential causes calcium to flood into the terminalwhich triggers the acetylcholine-containing vesiclesto fuse with the pre-synaptic membrane. Thisreleases acetylcholine into the synaptic cleft. Theacetylcholine crosses the synaptic cleft andbinds to ACRs on the post-synaptic muscle end-plate membrane. This results in depolarisationof the muscle fibre and subsequent contraction ofthe muscle. The acetylcholine is then brokendown by acetylcholinesterase, which is boundto the basement membrane in the synapticfolds. Acetylcholinesterase inhibitors are used inthe treatment of MG and cause an increasedavailability of acetylcholine to react with theAChRs.7–9

Immunopathogenesis

There are several lines of evidence that autoanti-bodies to the AChR cause MG10:

(1)

AChR antibodies are found in 80–90% of patientswith generalised autoimmune MG.

(2)

Circulating maternal anti-AChR antibodies arefound in the serum of babies with neonatal MGand the titre of the antibodies decreases as thebaby improves.

(3)

Passive transfer experiments of IgG frommyasthenic patients to experimental miceproduces disease similar to MG.

(4)

Plasmapheresis lowers levels of AChR resultingin improvement of MG.

(5)

Antibodies bind to the AChR at the neuromus-cular junction.

(6)

An experimental model of MG can be made byimmunising animals with purified AChR.

The major abnormalities at the NMJ in MG include areduced number of AChRs, shortening of thesynaptic folds due to destruction of the terminalfolds and widening of the synaptic cleft caused byshortening of the junctional folds. These changesoccur due to immune attack of the post-synapticmembrane. The mechanisms behind the destruc-tion of AChR include antibodies that cross-linkAChRs leading to an accelerated endocytosis anddegradation of the receptors by muscle cells. Theseantibodies may also act by blocking the bindingsites of the AChRs and there may be complement-mediated destruction of the junctional folds of thepost-synaptic membrane.

The titre of antibody does not correlate with thelevel of weakness in a patient but within a patientthe titre does reflect the severity of the weakness.

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Between 10% and 20% of patients with MGdo not have anti-AChR antibodies and are called‘‘seronegative’’.4 A proportion of these patientshave circulating antibodies to the MuSK protein inthe post-synaptic membrane. MuSK is one of theproteins involved in anchoring the AChR intoclusters in the postsynaptic membrane. Other casesof seronegative MG are associated with antibodiesthat can destroy AChRs in culture systems andproduce a myasthenic-like illness when passivelytransferred to mice.

Role of T cells and the thymus

MG is predominantly caused by circulating anti-bodies to the AChR but Tcells also have a role in thepathogenesis of the disease.11 Specific subsets of Tcells respond to antigenic stimulation and activateAChR-specific B cells. The mechanism of breakdownof immune tolerance is unknown but may involvethe thymus. Thymic abnormalities are found in over75% of patients. Germinal hyperplasia is found in85% and thymic tumours in 15%.12 Over 90% ofpatients with thymomas and MG have anti-striatedmuscle antibodies. Myoid (muscle-like) cells thatexpress AChRs are found in the thymus and it issuggested that these receptors are the source ofthe autoantigen which produces MG.

Clinical features of MG

Patients characteristically present with weaknessand fatigability that is worse on repeated orsustained activity and improves after rest. Thesymptoms can vary from hour to hour and day today and it usually gets worse towards the end of theday. Factors that worsen weakness include, ex-ercise, emotional stress, hot temperatures, infec-tions, certain drugs (aminoglycosides, phenytoin,local anaesthetics), surgery, menses and pregnancy.The most commonly affected muscles are thelevator palpebrae superioris, extraocular muscles,proximal limb muscles, facial muscles and neckextensors. The extraocular muscles are affected in50% of patients at presentation and 90% at sometime in the illness. Ptosis is a common presentingfeature and may be unilateral, partial and fluctu-ating leading to confusion in making the initialdiagnosis.

The presence of an eyelid twitch response(Cogan’s lid twitch sign) is characteristic of MG.When the patient’s eyes are looking down for20–30 s and a rapid vertical movement back to theprimary position is made, the eyes either droop

back down or twitch several times before settling.Ptosis improves after sleep and following applica-tion of ice to the eyelid. The ocular palsies areoften asymmetrical, fluctuating and can mimicseveral ophthalmoplegias. The pupils are spared.The face may appear expressionless and the patientmay tilt their head backwards so that they can seebeneath their ptosis. The jaw and neck may be heldup with a finger. When the patient attempts tosmile there may be a snarl due to the corners of themouth not being drawn up as the centre of the lipsare elevated. The voice may have a nasal characterand nasal regurgitation may occur if the soft palateis involved. Dysphonia results from laryngealweakness. Dysphagia is also common and maynecessitate nasogastric feeding during a crisis.

Weakness may remain limited to the ocularmuscles as ‘‘ocular myasthenia’’ but is generalisedin most patients. Weakness often progresses in acranio-caudal direction involving ocular then fa-cial, lower bulbar, truncal and finally proximal limbmusculature. Weakness of the intercostals musclesand diaphragm can cause dyspnoea on exertion, onlying flat and eventually at rest. Orthopnoea withrapid resolution on sitting up as well as paradoxicalbreathing are important clinical signs of neuromus-cular respiratory failure. Severe dyspnoea candevelop over hours and careful monitoring offorced vital capacity (FVC) should be performedtogether with arterial blood gas monitoring if thereis doubt about patient technique in measuring theFVC. In severe cases, intubation and mechanicalventilation may be required. A tired patient with anFVC of less than 1 L and a rising pCO2 are signs thatshould prompt consideration of non-invasive venti-lation or intubation.13,14

On beside examination, fatigability can be testedby assessing muscle power and then asking thepatient to repeat a movement with the muscle andretesting power. Sustained up gaze for greater than30 s can often cause ptosis and extraocular eyemovement abnormalities. Deep tendon reflexes areoften normal or exaggerated (in contrast toLambert-Eaton Myasthenic syndrome) and sensoryexamination is normal.

Thymomas are present in approximately 5% ofpatients. Thymic tissue should not be visualisedafter the age of 40 on CT or MRI and should promptfurther investigation. Thyroid abnormalities areseen in 13% of patients and include hyperthyroid-ism, hypothyroidism and non-functioning goitre.Other autoimmune diseases are associated with MGand include rheumatoid arthritis, pernicious anae-mia, systemic lupus erythematosus, sarcoidosis,Sjorgen’s disease, polymyositis, ulcerative colitis,and pemphigus.

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Diagnosis of MG

A typical history and examination of MG canestablish the diagnosis. The following tests areused as an adjunct to confirm the diagnosis and, toa lesser extent, monitor treatment.

(1) Tensilon (Edrophonium) test: Edrophonium isa short-acting intravenous acetylcholinesterase(AChE) inhibitor that works within 30 s and lastsapproximately 5min. It is usually performedblinded with two investigators and compared to asimilar injection of normal saline to optimise theobjectivity of the effect. There is little value indoing the test if there is no fatigable weakness asthere will be no objective sign to assess. A test doseof 2mg is first given, and followed by 8mg after 30 sif there is no response to the initial 2mg. There is alow but serious risk of bradycardia and hypotensionin patients and full facilities for resuscitationshould be available. Patients should have a pre-test 12 lead ECG and if there is evidence ofconduction block or acute cardiac disease thenthe test should not be performed. The patientshould undergo ECG monitoring during the test andatropine should be available to counteract anybradyarrythmias. The test can also be positive inother conditions such as motor neuron diseasepoliomyelitis, peripheral neuropathies, brainstemlesions mitochondrial myopathies and normal in-dividuals. Any result needs to be interpreted in thecontext of the patients symptoms, signs and otherinvestigations.15

(2) Anti-AChR antibody test: These antibodiesare found in 80–85% of generalised and 50–60% ofocular MG. The test is highly specific for MG.Although the antibody titres do not correlate withdisease severity across a population, they do withinan individual.16,17

(3) Anti-MuSK antibodies: These are not foundconcurrently with AChR antibodies and should betested if there is a high clinical suspicion e.g.muscle wasting with bulbar involvement or theAChR antibody test is negative.

(4) Electrophysiological tests: Repetitive nervestimulation and single fibre EMG are the two maintests of NMJ function. Repetitive nerve stimulationinvolves applying repetitive supramaximal electri-cal stimulations at a frequency 3Hz to a nerve andmeasuring the response in the distal muscle. In MG,the test demonstrates progressive reduction in theamplitude of the compound muscle action potentialfrom the fourth stimulation. In normal individualsthe fourth response should be less than 7% smaller.If the reduction is greater than 10% then the test ispositive and shows a ‘‘decremental response’’. Thetest is more likely to be positive when several

muscles are tested or the tested muscle is weak.The test is nearly always positive in generalised MGbut can be negative in 50% of cases of ocularmyasthenia.

Single fibre EMG is the most sensitive (95% ofcases) test for MG. The action potentials of closelyadjacent muscle fibres are recorded by a very fineelectrode. Action potentials within a motor unit donot reach their respective muscle fibres at thesame time. This difference in time can be mea-sured as ‘‘jitter’’ and is less than 55 ms. In MG, thejitter is usually greater than 100 ms.18

(5) MRI/CT chest: Patients with MG may have athymic tumour especially over the age of 40. Thepersistence of thymic tissue after the age of 40 oran increase in thymic size should prompt suspicionof a thymic tumour.

Differential diagnosis of MG

(1) Other disorders of NMJ:

(i)

Lambert-Eaton myasthenic syndrome: This isan autoimmune disorder caused by an antibodyto the pre-synaptic voltage-gated calciumchannel and is associated with limb weakness.Exercise improves weakness temporarily andreflexes may be absent or reduced initially andthen return on exercise. Repetitive nervestimulation demonstrates an incremental re-sponse compared to MG which is decremental.It is often associated with an underlying smallcell carcinoma of the lung and the syndromecan precede the development of the cancer byseveral years. Table 1 lists features used todistinguish between Lambert-Eaton syndromeand MG.

(ii)

Drug-induced MG: Penicillamine-induced MG isan autoimmune disorder that resembles MGand which resolves several weeks after stop-ping the drug. Other drugs such as, aminogly-cosides, procainamide, calcium channelblockers and quinine can make normal peopleweak and exacerbate MG.

(iii)

Botulism: Botulinum toxin inhibits the fusion ofthe pre-synaptic acetylcholine-containing vesiclewith the pre-synaptic membrane. Botulismcauses a generalised weakness, ophthalmople-gia and respiratory muscle weakness. It isdistinguished from MG by pupillary involve-ment and an incremental response on repeti-tive stimulation.

(iv)

Congenital myasthenia: This consists of severaldisorders characterised by mutations in genescoding for proteins involved in neuromusculartransmission.
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Table 1 Differentiation of myasthenia gravis and Lambert-Eaton syndrome.

Myasthenia gravis Lambert-Eaton syndrome

Location of ion channel Post-synaptic AChR Pre-synaptic voltage-gated calcium channelEpidemiology Young women/older men Middle-aged and older men and womenClinical presentation Ocular weakness Proximal limb weaknessProgression Craniocaudal Less commonly affects respiration and eyesExercise Worsens weakness Improves weakness initiallyTumour-association Thymoma Small cell lung cancerReflexes Preserved or brisk Absent or reduced but improve with exerciseAutonomic involvement Absent PresentAuto-antibody Anti AChR antibody or MUSK Voltage-gated calcium channelElectrophysiology Decremental response Incremental response

C. Turner20

(2) Myopathies: Ocular myasthenia can mimicchronic progressive ophthalmoplegia (a mitochon-drial cytopathy) and Grave’s eye disease.

(3) Brainstem processes: The combination ofocular and bulbar symptoms and signs can be seenin brainstem conditions e.g. ischaemic, infective,inflammatory and neoplastic.

Treatment of MG

Acetylcholinesterase inhibitors

These drugs act by inhibiting the synaptic enzyme,acetylcholinesterase, which leads to an increase ofacetylcholine at the post-synaptic membrane. Theydo not treat the underlying disease process and arepurely symptomatic. In very mild disease, they maybe the only treatment required. Pyridostigmine(‘‘Mestinon’’) is the most common drug to be usedin this class and is started at small doses such as30mg tds, and slowly increased up to 90mg fivetimes per day, titrated to the patient’s symptoms.It has a rapid onset of action within 15–30min, andlasts for 4 h. Its main side-effects include diar-rhoea, abdominal pain and excessive salivation.These muscarinic side-effects can be treated withanticholinergic drugs such as propantheline ordiphenoxylate without affecting the nicotinic re-ceptors at the NMJ.

A cholinergic crisis is caused by too muchacetylcholine at the NMJ and presents withworsening weakness. It can be distinguished froma myasthenic crisis by prominent muscarinic side-effects (abdominal pain, diarrhoea and hypersali-vation) but a Tensilon test at the peak-dose mayneed to be performed in order to clarify thesituation. If the patient deteriorates with theTensilon test then a cholinergic crisis is likely tobe the cause for the deterioration whereas if the

patient improves it is likely to be due to amyasthenic crisis.

Other anticholinesterase inhibitors are some-times also used, such as neostigmine, and theshort-acting edrophonium or ‘‘Tensilon’’ is used inthe Tensilon test as described previously.

Corticosteroids

Patients with refractory mild disease or moderate/severe MG require steroids to treat the underlyingdisease process in conjunction with symptomatictreatment with acetylcholinesterase inhibitors.19,20

They are usually started at a low dose, such as10mg/day, and increased slowly up to 60mg/day.Patients may initially deteriorate if high dosesteroids are started from the onset, but if a patientis rapidly deteriorating, as long as the patient is in aclosely monitored in-patient environment, thenhigh doses can be used. Improvement usually beginsafter 2–4 weeks and continues for 6–12 months.Once the patient is in clinical remission, then thesteroids can be tapered over several months to analternate day regimen in order to reduce side-effects.

Other immunosuppressants

Most patients require a small dose of steroids tomaintain disease remission. The long-term sideeffects of steroids have necessitated the introduc-tion of other immunosuppressive ‘‘steroid-sparing’’agents. Azathioprine, cyclophosphamide, cyclos-porin, methotrexate and mycophenalate have allbeen used in this capacity. It takes weeks if notmonths for these agents to work so they are oftenstarted concurrently with steroids. Azathioprinehas the advantages of having been used for a longtime and it has a relatively safe side-effect profile.The thiomethyl purine transferase (TMPT) levels

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should be measured before it is started as a methodof assessing patients who may potentially developsevere bone marrow suppression and hepatotoxi-city. Its effectiveness has been demonstrated inrandomised control trials. The dose can be startedat 1mg/kg/day and slowly increased usually up to2.5mg/kg/day maximum titrated to the clinicalresponse. It usually takes 3–6 months to take effectand should therefore be commenced when steroidsare commenced.21 Cyclosporin has also beendemonstrated to be effective in treating MG,although there is a high rate of drop-out due toside-effects including nephrotoxicity and hyperten-sion.22

Low dose tacrolimus and steroids have been usedin intractable disease when other drugs have notbeen tolerated or have been ineffective.23

Plasmapheresis

Plasmapheresis has been used in the treatment ofMG for over 30 years. It produces a rapid buttemporary improvement by reducing the circulat-ing anti-AChR antibodies.24 It is currently used toachieve rapid control when a patient has severe MGor enters a myasthenic crisis. It is also used in thepreparation of a patient prior to thymectomy, inthe early post-operative period or during the periodwhen immunosuppressants have not started to beeffective. The improvement rarely lasts more then4–10 weeks. It is being used less because of the costof staff and equipment, acute complications(related to central access, hypotension and clottingdisorders) as well as the increasing availability ofimmunoglobulin.

Intravenous immunoglobulin (IVIg)

IVIg has been demonstrated to be effective intreating MG and has similar indications to plasma-pheresis. The mechanism of action is not knownalthough it may be involved in removal of AChRantibodies or the T-cells involved in their produc-tion. A course is usually 400mg/kg/day for 5days.25

Plasmapheresis works more rapidly than IVIg buta direct comparison of the two treatments hasfound them to be equally as effective in the long-term.26

Thymectomy

There are two indications for thymectomy in MG.The first is for the 10% of patients who have anassociated thymoma which are potentially locally

invasive. The second is in younger patients withgeneralised myasthenia where thymectomy is per-formed to treat the underlying disease process. Arecent study has suggested that, contrary toprevious belief, age is not an important factor inpredicting favourable outcome of MG post-thy-mectomy. Approximately 80% of patients experi-ence an improvement in their MG afterthymectomy. Patients need to be medically opti-mised prior to surgery and muscle relaxants shouldbe avoided. The benefits take months or even yearsto become apparent. In centres with experience inthe management of perioperative patients withmyasthenia gravis, thymectomy is a relatively safeprocedure.27,28

MG and pregnancy

One third of patients improve, one third do notchange and one third deteriorate during pregnancy.Worsening of symptoms usually occurs in the firsttrimester and improves in the third. Anticholines-terase inhibitors and steroids have not been foundto be associated with a significant risk of congenitaldefects. MG does not affect the uterine smoothmuscle and therefore the early stages of pregnancyare usually not problematic. During the secondstage, when abdominal striated muscles are re-quired, problems with fatigue can occur.29,30

Myasthenic crisis

Crises may occur on the background of infections inthe context of immunosuppression, initial high dosesteroid treatment or due to inadequate treatment.The crisis consists of weakening of respiratorymuscles leading to respiratory failure and thesubsequent need for non-invasive/invasive ventila-tion in an HDU/ITU. All patients with worsening MGshould have their FVC monitored several timesthroughout the day, preferably in the lying andstanding positions. Plasmapheresis and IVIg areoften effective in gaining control of the diseaseinitially, with a background escalation of immuno-suppression and optimisation of the acetylcholineesterase inhibitors.

Prognosis of MG

Untreated MG has a 10 year mortality of 20–30%.Modern management has reduced this to virtuallyzero. Most patients can live normal lives but elderly

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C. Turner22

patients with thymoma tend to carry a worseprognosis. In most patients, 10 years after theonset, the disease enters a relatively quiescentplateau phase although ongoing steroid depen-dence and crises can still occur.

Recent advances in MG

Mycophenolate mofetil has the advantage of beingrelatively less toxic compared to other immuno-suppressant drugs and does improve treatment-resistant MG patients.31 Rituximab is a human/mouse chimeric anti-CD20 monoclonal antibodythat has been used to treat B cell malignanciessuch as non-Hodgkin’s lymphoma as well as auto-immune diseases such as systemic lupus erythema-tosus. There are case reports of it being effective intreatment-resistant MG.32 Etanercept is a recom-binant human tumour necrosis factor-a receptor.TNF has been implicated in the pathogenesis of MG.It may be effective in treatment resistant-MGassociated with low levels of interleukin-6 andinterferon-g.33 CT-guided injection of ethanol inthe thymus has been demonstrated to be effective,minimally invasive, and safe in the treatment ofMG.34 Fab fragments to the main immunogenicregion of the AChR have been shown to be effectivein preventing passively transferred experimentalautoimmune MG which may represent a target forfurther drug development.35

Conclusions

MG is a rare but treatable disorder of the NMJ. Theimprovement in our understanding of the under-lying molecular mechanisms has enabled thedevelopment of several therapeutic options. Pa-tients can be severely ill, especially during crises,although with correct intensive medical support,most patients have an excellent prognosis.

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