PRACTICAL THERAPEUTICS

Clin. Immunother. 2 (6): 430-442 . 1994

1172·7039/94/0012-G430/S06.50/O © Adis International limited. All rights reserved.

Immunopathogenesis and Management of Myasthenia Gravis Aashit K. Shah Department of Neurology, Wayne State University, Detroit, Michigan, USA

Contents Summary . . . . . . . . . . .. .. ... . ... . 1. Pathogenesis . . . . . . . . . . .. . . . . . . . 1.1 Anatomy of the Neuromuscular Junction . 1.2 Structure of the Acetylcholine Receptor 1.3 Ultrastructural Abnormalities 1.4 Immunogenic Mechanisms 2. Presentation and Course 3. Diagnosis . . . . . . . . . . . . 3.1 Antibody Titres . . . . . . . 3.2 Electromyographic Studies 3.3 Pharmacological Testing 3.4 Other Tests . . . . . . . . . . 4. Treatment . . . . . . . . . . 4.1 Acetylcholinesterase Inhibitors 4.2 Corticosteroids . . . . . . . . . 4.3 Plasmapheresis . . . . 4.4 Intravenous Immunoglobulin G . 4.5 Other Immunomodulatory Agents 4.6 Thymectomy . . . . . . . . . 4.7 Future Therapies . . . . . . . 5. Myasthenia Gravis in Pregnancy . 6. Conclusions .. . . . . . . .

Summary

430 431 431 432 433 433 434 434 435 436 436 437 438 438 438 439 439 439 440 440 440 441

Myasthenia gravis is a well known and well understood autoimmune disorder. Weakness in patients with myasthenia gravis is caused by the autoimmune destruction of acetylcholine receptors at the neuromuscular junction. The autoimmune mechanisms are not simple, and involve T cells, B cells and their interactions. Tools for the diagnosis of myasthenia gravis include: (a) clinical evaluation; (b) determination of the serum anti-acetylcholine receptor antibody; and (c) electrodiagnostic methods such as single fibre electromyography and repetitive nerve stimulation. Treatment involves sy mptomatic treatment with acetylcholinesterase inhibitors and both conventional (corticosteroids and other immunosuppressants) and nonconventional (plasmapheresis, intravenous immunoglobulin and thymectomy) immunomodulating therapies.

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Vesicles Motor nerve terminal Acetylcholine receptor

...- Muscle fibre

Fig. 1. Structure of the normal neuromuscular junction. The motor nerve terminal enlargement contains multiple synaptic vesicles filled with acetylcholine. The postsynaptic membrane has many enfoldings, and most of the acetylcholine receptors are facing the presynaptic membrane.

Myasthenia gravis is an autoimmune disorder characterised clinically by weakness of skeletal muscles and easy fatiguability of strength. The idea of autoimmunity as a cause of myasthenia gravis was first entertained by Strauss et al. in 1960,[ I] who demonstrated antibodies to muscle striational proteins in the sera of patients suffering from the disease. In the last 3 decades our knowledge of the pathophysiological and pathogenic mechanisms of myasthenia has increased greatly. However, we do not yet fully understand the primary process responsible for the loss of immune tolerance to the acetylcholine receptor that results in production of antibodies against it. The presence of antibody to acetylcholine receptor is now a well established fact in patients with myasthenia gravis. Myasthenia gravis is one of the few autoimmune diseases with pathogenic © Adis International Limited. All rights reserved .

antibodies to a known target protein. Antibodies produced in myasthenia gravis are directed towards the acetylcholine receptor at the neuromuscular junction of skeletal muscles. Myasthenia gravis is not a common disease; various estimates have indicated prevalence rates of 0.5 to 5/100 000 and an incidence rate of OA/ 100000 per year,l2-4]

1. Pathogenesis 1.1 Anatomy of the Neuromuscular Junction

The terminal of the motor nerve enlarges at its end, and lies within a groove or indentation of a muscle fibre. The neuromuscular junction consists of a presynaptic membrane (nerve membrane), postsynaptic membrane (muscle membrane) and the synaptic cleft (the space between the 2 membranes). The presynaptic terminal contains many Clin. Immunother. 2 (6) 1994

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Acetylcholine receptor

Ion channel Fig. 2. Three-dimensional view of acetylcholine receptors embedded in the cell membrane. The cross-sectioned receptor on extreme left shows a central opening that works as an ion channel.

vesicles filled with acetylcholine, the contents of which are released into the synaptic cleft in a Ca 2 +dependent manner on arrival of a nerve action potential. The acetylcholine molecules diffuse across the synapse and bind to the acetylcholine receptor on the postsynaptic membrane. The acetylcholine receptor is a ligand-gated Na+ channel that opens briefly on binding of acetylcholine to its binding site, causing partial depolarisation of the postsynaptic membrane and generation of the excitatory postsynaptic potential. This may generate a self-propagating action potential in the postsynaptic membrane (muscle action potential) if sufficient numbers of the channels open simultaneously. The acetylcholine is hydrolysed by the enzyme acetylcholinesterase, which is present abundantly at the neuromuscular junction. The acetylcholine receptors are heavily concentrated on the postsynaptic membrane at the neuromuscular junction. The surface area of the postsynaptic membrane at this site is increased by multiple enfolding of the membrane just underneath the nerve terminal (fig. 1). © Adis International Limited. All rights reserve d .

1.2 Structure of the Acetylcholine Receptor

The acetylcholine receptor consists of 5 subunits, each of which is a membrane-spanning protein molecule. At the mature neuromuscular junction, the acetylcholine receptor is composed of 2 a subunits and 1 each of the ~, £ and 0 subunits. In the thymus or at extrajunctional sites, and in the receptor on immature or denervated muscle, the £ subunit is replaced by a y subunit. The acetylcholine receptor subunits show homologies between different species and between the subunits themselves, suggesting that the genes coding for the different subunits have evolved from a common ancestral gene.l 5 ) The subunits are arranged in a circular fashion, making a central opening that functions as an ion channel (fig. 2). The acetylcholine molecule binds to the a chain. Binding of an acetylcholine molecule to the acetylcholine receptor causes a conformational change of the 3-dimensional structure of the receptor, resulting in increased conductance of Na+ ion or opening of the channel. Clin. Immunother. 2 (6) 1994

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Table I. Experimental observations supporting the autoimmune aetiology 01 myasthenia gravis Occurrence of myasthenia-like syndrome in mice after injection of IgG from patients with myasthenia gravis (passive transfer experiments)161 Demonstration of IgG and complement at the postsynaptic membrane in patients with myasthenia gravis l71 Induction of myasthenia-like syndrome in experimental animals immunised against acetylcholine receptor by injection of acetylcholine receptor isolated from electric fish{81

1.3 Ultrastructural Abnormalities

There are 3 ultrastructural abnormalities at the neuromuscular junction in patients with myasthenia gravis, namely: • reduced numbers of acetylcholine receptors on the postsynaptic membrane, resulting in inability to achieve the desired number of bound acetylcholine molecules to initiate the muscle action potential • oversimplification of the postsynaptic membrane secondary to loss of folds • widening of the synaptic cleft. 1.4 Immunogenic Mechanisms

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and acetylcholine receptor-presenting (interdigitating) cells. 19 ] Myoid cells present in the thymus possess the acetylcholine receptor on their surface and, like muscle cells, are capable of contraction. In patients with myasthenia gravis, the presence of this acetylcholine receptor could lead to the formation of acetylcholine receptor-specific T helper cells, capable of enhancing the production of antiacetylcholine receptor autoantibodies by B lymphocytes. 191 T cells and B cells are MHC compatible in the same individual, and are present in high concentration in the thymus of patients with myasthenia gravis. 1.4.2 Molecular Mimicry

Another suggested hypothesis is molecular mimicry between the acetylcholine receptor and some viral or environmental antigen . Sequence homologies between the acetylcholine receptor and certain exposed or hydrophilic residues of herpes simplex virus type I (HSV-l) have been demonstrated. 1101 However, a high percentage of the general population has experienced HSV-I infection in their childhood or early adulthood, and the incidence of myasthenia gravis is very 10w.l 10 ] 1.4.3 Features of the Autoantibody Response

Immunogenic mechanisms seem to play an important role in the pathogenesis of the structural changes described in section 1.3. This hypothesis is supported by many experimental (table I) and clinical (table II) observations. The exact mechanism of loss of immunological tolerance to acetylcholine receptor as a self antigen in patients with myasthenia gravis has yet to be clarified. There are various hypotheses to explain this loss of tolerance. 1.4. 1 Role of the Thymus

One hypothesis suggests that the thymus plays a primary role in initiating the autoimmune response against the acetylcholine receptor. This has been supported by the demonstration in the thymus gland of patients with myasthenia gravis ofT cells specific for the acetylcholine receptor, together with acetylcholine receptor-producing (myoid) © Adis International Limited. All rights reserved.

The anti-acetylcholine receptor antibody is ultimately responsible for the structural changes at the neuromuscular junction outlined in section 1.3. The antibody response in myasthenia gravis is polyclonal and, in an individual patient, antibodies are composed of different subclasses of IgG. In

Table II. Clinical observations supporting the autoimmune aetiology of myasthenia gravis Presence of associated autoimmune disorders (e.g. autoimmune thyroiditis, systemic lupus erythematosus, rheumatoid arthritiS) in patients suffering from myasthenia graviS and in their family members Infants born to myasthenic mothers sometimes develop transient myasthenia graviS (neonatal myasthenia gravis) Therapeutic response to various immunomodulating therapies including plasmapheresis, corticosteroids, intravenous IgG, immunosuppressants and thymectomy Anti-acetylcholine receptor antibody found in the serum of approximately 80 to 90% of patients with myasthenia graviS

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Table III. Possible mechanisms for damage to the neuromuscular junction by anti-acetylcholine receptor antibody Crosslinking of 2 adjacent acetylcholine receptors by antibody accelerates the internalisation and degradation of acetylcholine receptor rnolecules Complement·mediated destruction of the junctional folds of the postsynaptic membrane Antibody blocks the binding of acetylcholine to acetylcholine receptor

most instances, 1 of the antibodies is directed against the main immunogenic region on the a subunit of the acetylcholine receptor. The a subunit is also the site of acetylcholine binding, although the binding site for acetylcholine is not the same as the main immunogenic region. The binding of acetylcholine receptor antibodies to the acetylcholine receptor results in impairment of neuromuscular transmission in several ways (table III). Blocking antibodies have been detected in sera from some patients with myasthenia gravis, but in most instances they are only a minor fraction of all the acetylcholine receptor antibodies and are probably not responsible for weakness in the majority of the patients. The disruption of the folds on the postsynaptic membrane decreases the available surface area for insertion of newly synthesised acetylcholine receptor, and may cause a decrease in the total number of acetylcholine receptors at the neuromuscular junction (fig. 3).

2. Presentation and Course Myasthenia gravis can present with various symptoms, ranging from a droopy eyelid to difficulty in swallowing or walking, and may even present with respiratory failure. In a series described by Oosterhuis,f II] the most common presenting signs were ocular, which occurred in over 50% of patients. Bulbar weakness was the next most common presentation, followed by limb weakness. In onethird of patients with ocular myasthenia this remained the only feature, and the other two-thirds progressed to develop the generalised disease. Spontaneous remission occurred in 22% of patients during the first year, but they relapsed after 3 © Adis International Limited. All rights reserved.

months to 6 years and half did so within 12 months) I I] Osserman[2] proposed a classification of myasthenia gravis on the basis of clinical criteria that is still useful. The classification is as follows: • category I represents only ocular myasthenia, with lid weakness and problems with ocular motility • category II includes generalised myasthenia, subdivided into categories IIA (mild generalised) and lIB (severe generalised) • category III represents acute fulminating disease • category IV represents chronic severe myasthenia • category V consists of myasthenic patients with early muscle atrophy. Over the years the prognosis of myasthenia gravis has improved significantly, from 33% mortality in patients with generalised disease between 1940 and 1960 to 12% between 1960 and 1980,f12] and a more recent report has indicated an even lower mortality rate of 5.2%)13] The mortality rate of myasthenic crises at the same institution changed from 42% between 1960 and 1964 to 6% between 1975 and 1979)14] Myasthenia gravis is most active in the early years, and reaches its maximum severity in 65% of patients within the first year and in 83% by 3 years. Patients who survive the first 1 to 3 years usually improve in subsequent years or maintain a steady state)12]

3. Diagnosis Management of any disease first requires a firm diagnosis and if possible determination of prognosis, followed by an appropriate treatment plan. The diagnosis of myasthenia gravis usually rests on the characteristic clinical history and physical findings. It is not difficult to diagnose myasthenia gravis in patients with full blown generalised myasthenia, but it may sometimes be difficult if disease is mild and no physical signs are present at the time of examination. Other conditions that may Clin . Immunother. 2 (6) 1994

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mimic myasthenia gravis include: neurasthenia, oculopharyngeal muscular dystrophy, progressive external ophthalmoplegia with or without myopathy, botulism, myopathy from various causes, LambortEaton myasthenic syndrome, congenital myasthenic syndromes and, rarely, multiple sclerosis if only ocular signs are present. Investigations or tests to help make the diagnosis of myasthenia gravis include: • determination of acetylcholine receptor antibody titre in serum • electromyographic studies • pharmacological tests • in vitro microelectrode studies of neuromuscular transmission • immunocytochemical and ultrastructural studies of the neuromuscular junction • imaging, if necessary, to rule out eNS, orbital or retroorbital pathology. 115] 3.1 Antibody Titres 3. 1. 1 Acetylcholine Receptor Antibodies

The acetylcholine receptor antibody test is a fairly reliable test for making the diagnosis of autoimmune myasthenia gravis. It is positive in 80 to 100% of patients with generalised myasthenia and is highly specific. 'False positive' anti-acetylcholine receptor antibody values in patients without myasthenia gravis have been reported in cases of thymoma without myasthenia gravis, and in patients with rheumatoid arthritis treated with penicillamine.!16] However, penicillamine can induce myasthenia gravis that is clinically and immunologically similar to the acquired immune-mediated myasthenia gravis.! 17] Occasionally, antibody tests may be negative, especially in patients suffering from ocular myasthenia or in remission ('false negatives'). Results and mean antibody titres from a series of patients are shown in table Iv. 118 ] There is a trend suggesting higher antibody titre in more severe disease, although in an individual patient titre is not predictive of the severity of the disease. Serial measurements of antibody titres may be helpful in an individual patient, and reduction in © Adis International limited. All rights reseNed.

Fig. 3. Ultrastructural changes at the neuromuscular junction in patients with myasthenia gravis. Top: antibodies against acetylcholine receptor crosslink adjacent receptors, resulting in internalisation and degradation of the receptors and damage to the postsynaptic membrane. Bottom: the ultimate effect is simplification of the junctional folds and reduced numbers of acetylcholine receptors. A normal neuromuscular junction is shown in figure 1 for comparison .

antibody titre of more than 50% sustained for more than 12 months is associated with sustained clinical improvement. IIS ] A strong correlation has been observed between change in acetylcholine receptor Clin. lmmunother. 2 (6) 1994

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Table IV. Prevalence and titre of anti-acetylcholine receptor antibody in patients with myasthenia gravis (after Tindall. Psl with permission) Osserman class'

Mean antibody titre (nmoIlL)

Antibody-positive patients (%)

R

0.79 2.17 49.8 57.9 78.5 205.3

24 55 80 100 100 89

IIA liB III IV a

= =

=

=

Classification: R remission; I ocular only; IIA mild generalised; liB moderate generalised; III acute severe; IV = chronic severe.12.1S1

=

antibody concentration and change in clinical condition in patients treated with immunomodulatory therapies such as prednisone, thymectomy or immunosuppressants'! 191 3.1.2 Other Autoantibodies

Myasthenia gravis may be associated with other autoimmune disorders, and a number of other autoantibodies may be found in patients with myasthenia gravis, including antibodies against[20] • striated muscle (50% of patients) • thyroglobulin (40%) • thymocytes (80%) • double-stranded DNA (10%) • single-stranded DNA (25%) • nuclei (i.e. antinuclear antibody) [20%]. Evaluation of thyroid function is very important in patients with myasthenia gravis, because thyroid dysfunction may coexist. Hyper- or hypo-thyroidism coexisting with myasthenia gravis may worsen the muscle weakness. Anti-striated muscle antibody was the first antibody described in patients with myasthenia gravis, and its presence suggested an autoimmune pathogenesis of the disease.! II Anti-striated muscle antibody has been associated with thymoma in patients with myasthenia gravis. Anti-striated muscle antibodies are present in the majority of young patients «40 years) with thymoma, and their prevalence is low in patients without thymoma. In older patients (>40 years), anti-striated muscle antibodies are more prevalent even without thymoma.! 15] © Adis International limited. All rights reserved.

3.2 Electromyographic Studies

Electromyographic studies, especially single fibre electromyography, are a very sensitive tool for the diagnosis of myasthenia gravis. Compared with more conventional methods of electromyographic studies of neuromuscular junction diseases, such as repetitive nerve stimulation, single fibre electromyography is much more sensitive but less specific. Electrodiagnostic findings in patients with myasthenia gravis are shown in table V. Single fibre electromyography shows abnormalities in 77 to 100% of patients with myasthenia gravis, whereas repetitive nerve stimulation shows abnormalities in only 44 to 65%.[21 I Treatment with acetylcholinesterase inhibitors does not normalise single fibre electromyography. In generalised myasthenia gravis, examination of the extensor digiti communis muscle is abnormal in 87% of patients, but if a second muscle is examined the sensitivity increases to 99%.!22] In ocular myasthenia gravis, examination of the frontalis muscle is more useful because it shows abnormality in 54 to 100% of patients, compared with 26 to 66% of patients if only the extensor digiti communis is examined.!21 I Repetitive nerve stimulation is also a useful test in the diagnosis of myasthenia gravis, and classically shows a decrease in response with a tendency towards recovery on continued stimulation (fig. 4). 3.3 Pharmacological Testing

The primary defect in myasthenia gravis is acetylcholine receptor deficiency at the neuromuscular junction, resulting in an inadequate number of interactions between the acetylcholine receptor Table V. Electromyographic characteristics in myasthenia gravis Findings on single fibre electromyography Definitely increased jitter with or without neuromuscular blocking Increasing jitter abnormality with higher discharge rate Normal fibre densityl211 Findings on repetitive nerve stimulation Decrease in the amplitude of the compound muscle action potential with stimulation of the nerve at 3Hz

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Normal

Ismv

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1 sec

Fig. 4. Repetitive stimulation of a motor nerve at 3Hz with response (compound muscle action potential) recorded from the muscle. Top: normal response, showing no significant change in the amplitude of the action potential with repetitive stimulation. Bottom: response from a patient with myasthenia gravis, showing a decrease in the amplitude of the action potential with successive stimulation . The decrease is maximal at the fifth stimulation, and the action potential shows improvement with continued stimulation.

and acetylcholine released from the motor nerve terminal. Acetylcholine released from the motor nerve terminal is metabolised by acetylcholinesterase. Inhibition of acetylcholinesterase increases the concentration of acetylcholine at the synapse, improving the chance of interaction between acetylcholine and its receptor. Edrophonium is a short-acting acetylcholinesterase inhibitor that acts within seconds; its effects last for a few minutes. Evaluation of weakness (ptosis, diplopia, partial or complete ophthalmoplegia, or forced hand grip) before and after administration of edrophonium can be used as one of the diagnostic tools for myasthenia gravis. Blinding of the examiner as well as of the patient in© Adis International Limited. All rights reserved.

creases the validity of the test, especially where the degree of the weakness is mild. The response to the drug can be tested by intravenous injection of O.2ml of a lOmg/ml solution of the drug. If there is no response and no adverse effects, a second injection of O.8ml should be administered. Sinus bradycardia due to excessive cholinergic stimulation of the heart is a serious complication, and atropine should be immediately available while performing the test. Edrophonium may be used to differentiate between weakness caused by myasthenia gravis (myasthenic crisis) and weakness caused by overdosage with acetylcholinesterase inhibitors (cholinergic crisis). In cholinergic crisis, administration of the drug may cause fasciculation, flushing or cramps, without significant change in weakness. This result should be interpreted cautiously, as some muscle groups may be overmedicated (cholinergic excess) and at the same time other groups may be undermedicated and will show improvement in strength. While interpreting the results of tests with acetylcholinesterase inhibitors, one should not forget that these drugs can improve weakness in diseases other than myasthenia gravis, e.g. in amyotrophic lateral sclerosis, poliomyelitis and peripheral neuropathies. However, in these diseases the improvement is seldom as striking as in myasthenia gravis. 3.4 Other Tests

In vitro tests of neuromuscular junction structure and function, such as microelectrode studies of transmission, electron microscope ultrastructural examination and immunocytochemical studies of a-bungarotoxin and IgG binding, are useful research techniques but are not routinely utilised in clinical practice. Imaging of brain, orbit and retroorbital structures may be useful to evaluate symptoms such as diplopia that could be caused by myasthenia gravis or by diseases involving these structures. Clin. Immunother. 2 (6) 1994

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4. Treatment Acetylcholinesterase inhibitors and immunomodulating therapies are the 2 major forms oftreatment for patients with myasthenia gravis. Acetylcholinesterase inhibitors are useful initially in the mild form of the disease, but most patients with generalised myasthenia additionally require some type of immunomodulating therapy. There is no consensus on timing, sequence of introduction or continuation of the different immunomodulating therapies. 4.1 Acetylcholinesterase Inhibitors

A number of acetylcholinesterase inhibitors are available, but only a few are used routinely. The mechanism of the action of these drugs has already been outlined in section 3.3. Pyridostigmine, an intermediate-acting agent, is preferred in clinical use to the short-acting neostigmine or the longer-acting ambenonium chloride. In the US, pyridostigmine is available as 60mg tablets, 60mg/Sml syrup and 180mg slow release tablets. The drug starts to act in 30 to 60 minutes and its effect lasts for 3 to 6 hours. The slow release tablet has immediate effects similar to those of the 60mg tablets , but the duration of action is 2.S times longer. The difference in bioavailability between individual patients is far greater with the slow release tablets; they should not be used as the only mode of treatment, but are useful for control of myasthenic symptoms at night. The required dosage of pyridostigmine varies tremendously between patients. The dosage has to be individualised, and all symptoms may not be controlled without producing adverse effects. Myasthenia gravis does not affect all skeletal muscles with the same severity, and the dosage required for control of myasthenic symptoms of I muscle group may cause excessive cholinergic stimulation of other groups. Adverse effects of the acetylcholinesterase inhibitors include dosage-related and idiosyncratic effects. Excessive stimulation of muscarinic receptors for acetylcholine results in excessive sal© Adis International Limited. All rights reseNed.

Shah

ivation, abdominal cramps, diarrhoea, blurring of vision and flushing . Gastrointestinal adverse effects are common and can be controlled by anticholinergic drugs that preferentially affect muscarinic acetylcholine receptors, such as diphenoxylate plus atropine, atropine patches or propantheline. As mentioned in section 3.3, it is difficult to diagnose clearly a cholinergic crisis in a patient with myasthenia gravis treated with acetylcholinesterase inhibitors. If there is exacerbation of weakness in a patient with myasthenia receiving such medication, cholinergic crisis has to be considered. When in doubt, a decrease in the dosage or discontinuation of the drug is helpful. Close monitoring of respiratory status is mandatory in this situation. When the exacerbation of weakness is severe enough to warrant respiratory support with assisted ventilation, it is prudent to discontinue acetylcholinesterase inhibitors, because they are of limited help and may create more problems by their adverse effect of increasing pulmonary secretions. 4.2 Corticosteroids

Corticosteroids are one of the most effective and relatively safe forms of immunomodulating therapy for the treatment of myasthenia gravis. Corticosteroids are indicated in moderate or severe disease not adequately responding to acetylcholinesterase inhibitors and thymectomy. They can be used effectively to improve the condition of a seriously disabled patient before thymectomy. However, the use of corticosteroids should be avoided when symptoms can be managed by simpler means, e.g. an eye patch for diplopia in otherwise asymptomatic patients, and where corticosteroid use can be deleterious, e.g. in severe diabetes or osteoporosis. Initiation of treatment with high dosage corticosteroids (prednisone 60 to 80 mg/day) may improve weakness rapidly, but may cause severe initial deterioration in weakness before improvement is evident. This may be secondary to a direct effect of corticosteroids on the muscle membrane, although the exact mechanism is not known. This C lin. lmmunother. 2 (6) 1994

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serious complication means that high dosage corticosteroid treatment should be initiated in a supervised setting. Initial low dosage therapy with prednisone 25mg on alternate days, with a gradual increase in dosage, has been suggested as an alternati ve.l 23 ) Long term treatment with corticosteroids is very effective, and will induce remission, or cause marked to moderate improvement, in the majority of patients.l 24 ,25) It may take a few months (usually I to 4 months on average) for significant improvement to occur, and improvement may be associated with decreased antibody titre.l l5 ) An alternate day corticosteroid regimen may minimise adverse effects. A trial of withdrawal of corticosteroid may be attempted, although most patients receiving long term corticosteroid therapy relapse after withdrawal and therapy may have to be reinstituted. Long term corticosteroid use is associated with significant morbidity. The common adverse effects include weight gain, cushingoid appearance, cataracts, diabetes mellitus, hypertension, osteoporosis and aseptic necrosis of the hip. Infrequently, long term corticosteroids can also predispose the patient to gastrointestinal bleeding and opportunistic infections.

achieve rapid postoperative recovery and to shorten the period of assisted ventilation. The complications of plasmapheresis are primarily limited to those of the procedures for intravenous access, such as central line placement. Occasional serious complications have been reported, including cardiac or respiratory arrest.[26) Transient exacerbation of weakness also has been reported when the replacement fluid contains a high concentration of citrate and a low concentration of Ca 2 +.[27)

4.4 Intravenous Immunoglobulin G

Several nonrandomised trials have reported that intravenous administration of pooled human IgG is helpful in the treatment of myasthenia gravis. The improvement is usually apparent within a few days, and may last up to 2 months,l28.29) Initial worsening of weakness before improvement has been reported,128) although not in all studies.[29) Adverse effects of intravenous IgG include headaches, 'flu-like' illness, aseptic meningitis, and possibly stroke.l 30 ) There is a small but real risk of transmission of infectious agents , e.g. nonA non-B hepatitis. f3l )

4.3 Plasmapheresis 4.5 Other Immunomodulatory Agents

Plasmapheresis is an effective treatment modality for patients with myasthenia gravis. It is very effective as a short term measure in management of a crisis. It improves weakness within days, but the beneficial effects do not last for a prolonged period. It is a relatively safe but expensive treatment. It is usually used as an adjunct to other immunomodulatory therapies and as a tool for crisis management. Long term infrequent use of plasmapheresis on a weekly or monthly basis can be used if other treatments are inadequate to control the disease. A short course of preoperative plasmapheresis in severely weak patients undergoing thymectomy is often very beneficial, as is postoperative plasmapheresis. The improvement in strength may help to © Ad is International limited . All rights reserved.

Other immunomodulatory agents used in the treatment of myasthenia gravis include azathioprine,l32-34] cyclophosphamide[35J and cyclosporin.136-39) Azathioprine is the immunomodulatory drug most widely used in myasthenia gravis after corticosteroids. The improvement in the patient's clinical condition may not be apparent for 6 months after starting the therapy, and may not be maximal until 12 to 14 months. These drugs are used primarily for patients with severe disease not responding to corticosteroid therapy, or those who cannot tolerate corticosteroids. The adverse effects of these drugs vary, and are often responsible for limiting their routine use. C lin. Immunother. 2 (6) 1994

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4.6 Thymectomy

Thymectomy is a very important mode of treatment, not only in patients with myasthenia gravis and thymoma but in any patient with acquired autoimmune myasthenia gravis. The beneficial effect of thymectomy was reported as early as the 1930s and 1940s)40.41] Thymectomy may induce remission. The percentage of patients achieving remission continues to increase with time after thymectomy, and reaches about 40 to 60% in patients without thymoma. Remission is more likely to occur in young females with thymic hyperplasia and high antibody titre.[15] In a series of patients, excellent or good responses were reported in 75% of patients with myasthenia gravis without thymoma)42J Thymectomy is indicated in all patients with thymoma with or without myasthenia gravis to prevent the spread of the tumour. 4.7 Future Therapies

Recently, successful treatment of myasthenia gravis with anti-CD4 monoclonal antibody has been reported.l 43 ] In this case report, the patient's clinical and electrophysiological improvement correlated well with diminished autoreactivity of T cells to human acetylcholine receptor, but not to the peripheral blood CD4+ lymphocyte count. In the future there may be more specific treatment options available to target the immune cells or antibodies responsible for myasthenia gravis, and the current approach of generalised immunosuppression will no longer be required. The various strategies may include targeting of: • B cells (,hot antigen suicide') • antigen-specific T cells (T cell vaccination) • activated T cells (immunotoxins).[44]

5. Myasthenia Gravis in Pregnancy Women of child-bearing age are affected by myasthenia gravis more often than any other age or gender group. Pregnancy in a myasthenic woman needs special considerations for management of the disease. Exacerbation of existing myasthenia © Adis International Limited. All rights reserved.

gravis during pregnancy occurs in 41 % of women, and during the puerperium in 30% of women.l 45 ] Postpartum exacerbation may be sudden and severe. It has been postulated that this is due to the sudden decrease in serum a-fetoprotein level. First trimester nausea and vomiting with erratic gastrointestinal absorption warrants frequent adjustment of the dosage of acetylcholinesterase inhibitors. Corticosteroids and plasmapheresis are 2 relatively safe treatment modalities in severe myasthenia gravis, but the use of corticosteroids may increase the chance of certain congenital malformations such as cleft lip and palate. The children of myasthenic mothers are more likely to be delivered prematurely. They acquire anti-acetylcholine receptor antibodies via placental transfer of IgG, and may therefore have congenital malformations caused by antenatal myasthenia. Such malformations include arthrogryposis multiplex and defective development of the lungs because of weakness of the respiratory muscles. However, these malformations are quite rare. Labour in myasthenic women should be monitored very closely, and maternal fatigue or respiratory failure resulting in hypo-oxygenation should be identified early. If anaesthesia is necessary, careful choice of anaesthetic is required and regional anaesthesia is preferable. Nondepolarising muscle relaxants should be avoided if possible, because myasthenia gravis patients are very sensitive to their effects. Some children of myasthenic mothers may have transient neonatal myasthenia due to the effects of maternal antibodies, and these children should be observed very carefully for a few days after birth. Although most children born to myasthenic mothers posses anti-acetylcholine receptor antibodies at birth, only a few acquire neonatal myasthenia gravis. This may be due to the protective effects of a-fetoprotein, which inhibits binding of antiacetylcholine receptor antibody to the acetylcholine receptor.l 46 ] A very high maternal serum level of acetylcholine receptor antibody may increase the chance of neonatal myasthenia gravis, and deClin. Immunother. 2 (6) 1994

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creasing the maternal serum titre antenatally by plasmapheresis may be useful.

6. Conclusions It is quite obvious from the discussion above that myasthenia gravis is a complex but fascinating disease. The management of patients with myasthenia gravis is challenging but gratifying, as is the science behind it. We have learned tremendously by studying the disease. The future holds more promise: a day will certainly arrive when we will be able to alter the immune response in such a way that only aberrant responses will be controlled, without impairing the healthy immune system.

Acknowledgements I am indebted to Dr R.P. Lisak for his help and guidance in preparing this manuscript.

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Correspondence and reprints: Dr Aashit K. Shah, Department of Neurology, Wayne State UniverSity, 6E University Health Center, 4201 St Antoine, Detroit, MI 48201, USA.

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