Practical Therapeutics

Drugs 26: 174-184 (1983) 0012-6667/83/ 0800-0174/ $05.50/ 0 © ADiS Press Australasia Pty Ltd. All rights reserved.

Myasthenia Gravis

Pathogenesis and Current Concepts in Management C. W.H. Havard and Glenis K. Scadding Royal Free Hospital, London

Summary

Myasthenia gravis is a disorder of autoimmunity in which neuromuscular transmission is impaired by autoantibodies to the acetylcholine receptor (AChR). There is evidence for more than one form of the disorder with differing genetic susceptibilities. The aetiology is unknown. but thymic involvement is suggested by abnormal histology and by the beneficial response of the disorder to thymectomy in more than two-thirds of patients. Thymectomy is indicated in most patients unless the symptoms are minimal or are confined to the extraocular muscles alone. or the patient is elderly. Thymectomy alone results in remission in about one-third of patients. but. in addition. most patients require symptomatic anticholinesterase drugs to prolong the action of acetylcholine at the muscle end-plate. Overdosage of these drugs can also cause weakness. Immunosuppression with corticosteroids or azathioprine may also improve myasthenia; at present. these drugs are used mainly in patients who do not respond to thymectomy or in those patients considered unsuitable for operation. Plasma exchange can cause a rapid. though temporary. involvement in myasthenia. but it probably has no long term place in its treatment. Future therapy will probably involve specific immunotherapy. such as anti-idiotype antibodies.

Myasthenia gravis is an autoimmune disorder in which autoantibodies directed against the acetylcholine receptor (AChR) reduce the number of functioning acetylcholine receptors resulting in defective neuromuscular transmission. The symptoms are, therefore, those of muscular weakness which tends to be worse after effort and improved by rest. The weakness mainly affects proximal muscles, with the extraocular and bulbar muscles being the most commonly amicted.

1. Clinical Patterns There are several different varieties of myasthenia gravis.

1.1 Generalised Myasthenia Generalised myasthenia affects muscles other than the extraocular muscles and has a prevalence of about 1 in 30,000. It can be divided into 3 varieties according to clinical, immunological, therapeutic and HLA characteristics (table I): I. Firstly, it may be associated with a thymoma, when there is no clear HLA association. Only about one-third of patients with thymomas have myasthenia gravis, and 10 to 15% of myasthenic patients have a thymoma. They tend to be older individuals and usually have a severe form of the disease. The antireceptor antibody (anti-AChR) titre is usually high and striated muscle antibodies are present

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175

Table I. The various types of generalised myasthenia according to clinical, immunological and HLA characteristics (after Compston et aI., 1980)

Thymic histology

Age

Sex incidence

HLA association

Anti-AChR titre

Thymoma

Usually> 40y

M>F

In Japanese Gm 1,2,21 High

Response to thymectomy Poor

Anti-striated muscle positive Thymitis

< 40y

F> M

Ba/DRW3

Moderate Anti-striated muscle negative Other autoantibodies occur

Good

Thymitis

> 40y

M>F

A3 BdDRW2

Low

Poor

in most thymoma patients. 2. Secondly, it may be associated with thymitis in patients under the age of 40 years; in this group there is an association with HLA-B g or -DRW3, or both. Some patients often have other autoimmune diseases but do not usually possess antibodies to striated muscle. These patients usually respond well to thymectomy. 3. Thirdly, it may be associated with thymitis in patients over the age of 40. These patients have a high incidence ofHLA-A3 or -B7 or -DRW 2. They also have the lowest titres of antibodies to the AChR of patients with generalised myasthenia. Among Japanese myasthenics there is an association between a particular allotype, Gm 1.2.21 of the immunoglobulin heavy chain and severe generalised myasthenia, especially that associated with thymomas. However, this has not been shown for Caucasian myasthenics. Juvenile myasthenia is sometimes used to describe generalised myasthenia in prepubertal children. Opinions regarding treatment in this age group are divided. There is evidence to suggest that the response to thymectomy is not as good as in the adult and that symptomatic treatment with anticholinesterase drugs should be continued until the child reaches adolescence, when the disease often improves spontaneously. Associated disorders, such as thyroiditis and epilepsy are common.

1.2 Ocular Myasthenia In this condition, the weakness is clinically confined to the extraocular muscles. It is more common in males and in the older age groups. It responds poorly to anticholinesterase drugs and to thymectomy, although corticosteroids are usually very effective. These patients have the lowest antiAChR titres, and in one-quarter of cases the values are within the normal range; however, if ocular muscle is employed as the antigen, a greater proportion is positive. 1.3 Neonatal Myasthenia This occurs in 1 in every 8 babies born to myasthenic mothers and is due to the transplacental passage of anti-AChR. The disorder may be fatal unless treated with anticholinesterase drugs. It tends to persist for I to 6 weeks. As the anti-AChR level falls, the muscle strength improves. 1.4 D-Penicillamine-induced Myasthenia This is similar to myasthenia gravis in that there is muscular fatiguability associated with antiAChRs. The disorder occurs after several months of treatment with D-penicillamine, and like other D-penicillamine-induced autoimmune disorders,

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affects susceptible people. Thus, it is usually seen in patients with rheumatoid arthritis treated with D-penicillamine, rather than in those with Wilson's disease. Possession of the DRW 3 haplotype increases the risks of most side effects from the drug; however, D-penicillamine-induced myasthenia gravis is associated with the DR, haplotype (Garlep et aI., 1983). Although the disorder usually remits after stopping D-penicillamine and anti-AChR titres fall with a half-life of 2 to 3 months, in some patients the myasthenia continues and is indistinguishable from the spontaneous form of the disease. 1.5 Congenital Myasthenia

This comprises a group of rare disorders, some of which are genetic. In some patients the defect is presynaptic. An absence of anticholinesterase at the end-plate has been described. Anti-AChRs are not present and no effective treatment is available. Anticholinesterase drugs are unhelpful and 4-aminopyridine is too toxic. The remainder of this review will be confined to generalised myasthenia gravis.

2. Natural History of Generalised Myasthenia Knowledge of the natural course of a disease is a prerequisite to evaluating therapeutic procedures. Two-thirds of myasthenic patients are women, with a peak age of onset in the twenties. Men tend to develop the disease later in life and the majority of patients presenting after the age of 50 are male. Spontaneous remissions occur in about one-quarter of patients but these rarely last more than 2 years and are not often repeated. The death rate in series reported before 1965 (e.g. Kennedy and Moersch, 1937; Rowland et aI., 1956) was about 30% and death usually occurred during the first 3 years of the disease. However, with the advances in intensive care and anaesthesia, the death rate in a recent series was 7% in non-thymectomised patients (Oosterhuis. 1981).

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The myasthenia in patients who do not undergo thymectomy tends to be worst in the first 5 years, with fluctuations due to infections, pregnancy, emotions and stress, but some spontaneous fluctuations also occur. After 5 years, there is usually a slow improvement with fewer fluctuations. However, exceptions do occur: some patients may have myasthenic crises several years after the onset of the disease; others remain severely disabled without improvement and others have isolated episodes of mild disease. The prognosis is less favourable in patients with thymomas. About 50% of these patients have respiratory problems. They are threatened also by the invasive growth of the tumour and by other immunological effects of thymoma, such as red cell aplasia and pancytopenia. In a recent series, the death rate was 36% in a group of patients undergoing thymectomy, and 48% in a group of thymoma patients on whom thymectomy was not performed (Oosterhuis, 1981).

3. Pathogenesis Myasthenia has long been postulated as an autoimmune disease. In 1959, Smithers noted that the myasthenic thymus was histologically similar to the thyroid in Hashimoto's disease. In 1960, Simpson formulated his hypothesis that the disease was due to autoantibodies to the motor end-plate, having noted the occurrence of myasthenia in young females with other autoimmune conditions, such as systemic lupus erythematosus, rheumatoid arthritis and thyroiditis. Simultaneously, fluctuations of complement levels with disease activity were reported. Antibodies to the motor end-plate were sought but not found. However, circulating antibodies to striated muscle, which cross-react with thymic myoid cells were reported in some myasthenic patients in 1960. Only about one-third of myasthenic patients have such antibodies and these are usually patients with thymomas. Such antibodies also occur in association with thymoma without myasthenia and do not play any part in the pathogenesis of muscular weakness.

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177

3.1 Evidence Suggesting Involvement of Acetylcholine Receptor Antibodies in Pathogenesis In 1962, Chang and Lee discovered a-bungarotoxin (a-BT), a snake venom protein which binds specifically and irreversibly to AChRs. Purification of AChRs from the electric organ of electric eels was achieved by affinity chromatography, using similar, less irreversible toxins. Immunisation of rabbits with purified AChRs emulsified in Freund's complete adjuvant resulted in their developing muscular weakness and dying of respiratory paralysis. These animals were suffering from experimental autoimmune myasthenia gravis, having developed antibodies to the eel AChR which crossreacted with their own AChR. The similarities between this condition and myasthenia gravis prompted a renewed search for anti-AChRs in the human disease. In 1974, it was noted that a factor present in the globulin fraction of the sera of myasthenic patients blocked a-BT binding to solubilised rat AChRs (Almon et aI., 1974). Since then, several other methods have shown humoral interference with AChRs. The most widely used method of measuring antibodies to AChRs is the radioimmunoassay of Lindstrom et ai. (1976) [fig. 1],

using as antigen crude detergent extracts of human muscle in which the AChRs are labelled with radio-iodinated a-BT. This is incubated with the test serum and then any immune complexes can be precipitated by anti-IgG. About 90% of patients with myasthenia gravis have serum anti-AChRs detected by this method, titres ranging from 0 to 840 nmol of a-BT binding sites precipitated per litre of serum. Control sera from normal individuals or from patients with other neurological or autoimmune diseases give results close to zero. The test is therefore useful in the diagnosis of myasthenia gravis. Although the anti-AChR titre between individuals does not correlate with disease severity, thymoma patients tend to have high titres and those with purely ocular myasthenia have the lowest mean titres. However, in an individual patient, there is usually an increase in disease severity with a rise in titre and vice versa. Several lines of evidence suggest that antiAChRs are the cause of muscular weakness. Injection of a-BT into animals has shown that a decrease in functioning AChRs gives rise to myasthenic symptoms. Mice injected repeatedly with immunoglobulin prepared from myasthenic sera become weak, with a decreased number of AChRs as shown by a-BT binding. The third component of complement (C 3), is necessary for this phen-

AChR antibodies ,', -' ' r::.,(

~~tF'

+

---+

(;!i~~~: .~
\"-:~~

// '('l/?

.,

''\( Myasthenic serum

AChRs from human muscle labelled with 125 1 a-bungarotoxin

Fig. 1. Radioimmunoassay for anti-AChRs.

Human anti-lgG added

Immune complex preCipitated and radioactivity counted

Myasthenia Gravis

omen on to occur, whereas the fifth component of complement (C 5) is not. Removal of anti-AChRs by plasma exchange increases muscular strength in most of the myasthenic patients so treated. The return of weakness correlates with the reappearance of serum anti-AChRs rather than with total IgG or C3• Furthermore, neonatal myasthenia is associated with the presence of anti-AChRs transferred transplacentally to the baby, and the weakness has been found to decrease as the antibody levels fall. Recently, an affected baby improved rapidly after an exchange transfusion which was needed for a coincident condition (Donat et aI., 1981). Thoracic duct drainage is beneficial in myasthenia gravis. Reinfusion of cell-free lymph causes deterioration. One of our patients with myasthenia gravis developed a nephrotic syndrome and was losing anti-AChRs in his urine; his weakness diminished as his serum anti-AChR titre fell. 3.2 How Do Anti-AChRs Cause Muscular Weakness? There are probably 3 main mechanisms by which anti-AChRs interfere with neuromuscular transmission: I. Complement-mediated lysis 2. Modulation of AChRs 3. Direct block. 3.2.1 Complement-mediated Lysis IgG has been demonstrated on the postsynaptic membrane, where its distribution corresponds to that of AChRs. C3 together with a little C9 , the lytic component of complement, are also present on the postsynaptic membrane; C9 is found mainly on debris in the synaptic space. This is consistent with complement-mediated lysis of the postsynaptic membrane, leading both to loss of AChRs and the characteristic morphological changes of elongation and simplification ofthe membrane with widening of the synaptic cleft. AChRs are constantly being degraded and synthesised. The average AChR in a normal individual has a life of about 7 days while in a myasthenic individual it has a life of about 1 day.

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3.2.2 Modulation of AChRs The rate of degradation of AChRs is increased after they have been cross-linked by antibody. Resynthesis may also increase, and the balance between these 2 processes will determine the number of AChRs remaining. 3.2.3 Direct Block Antibodies directed against the ACh binding site could directly inhibit AChR function. Such antibodies do exist in myasthenic patients as shown by the reduction of a-BT binding to human AChRs by myasthenic sera, but they usually form only a small proportion of the total anti-AChR present. Few reports exist of the direct effect of myasthenic serum upon a neuromuscular preparation. In contrast, complement-depleted sera from animals with experimental autoimmune myasthenia gravis do have a direct effect upon neuromuscular preparations with a time course and lack of temperature dependence suggesting direct block rather than modulation.

3.3 Reasons for Poor Correlation Between Anti-AChR Level and Disease Severity The poor correlation between anti-AChR level and disease severity probably has several explanations. About 5% of patients with generalised myasthenia gravis have no detectable anti-AChRs. Conversely, some other patients in clinical remission have high circulating anti-AChR titres. Antibody heterogeneity is partly responsible for this. In an individual patient, there are probably several types of anti-AChRs, some of which are more effective at blocking or destroying the AChR than others. Avidity of the anti-AChRs appears to be low at the onset of the disease but increases with increasing duration of the disease. Antibodies directed against the acetylcholine binding site of the AChR would, in theory, cause a profound decrease in neuromuscular transmission, yet these are not detected by the routine radioimmunoassay since this site is blocked by a-BT. Alternatively, detergent extraction of AChRs may hide or destroy antigenic sites recognised in vivo. The rate of re-syn-

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179

Table II. Anticholinesterase drugs used in myasthenia gravis Drug

Mode of administration and dose

Onset and duration of action

Uses

Edrophonium

IV [5-10mg]

Very rapid; lasts minutes only

Diagnosis Assessment of therapeutic status

Neostigmine

Oral Parenteral [15-30mg]

15 min; 2h

On awakening

Pyridostigmine

Oral (symptomatically) Parenteral [30-180mg]

30 min; 4h

Regular therapy (given in doses up to 180mg 3-hourly)

Ambenonium

Oral [5-25mg]

30 min; 4-Sh

Given 3-4 times daily

thesis of AChRs after their destruction also varies between individuals and this could also determine the severity of muscular weakness. In a few patients, possibly in the older age groups, AChR damage may be cell-mediated rather than humoral, although there is little morphological evidence in support of this.

4. Management There is still debate about the correct management of patients with myasthenia gravis. A recent review from the USA entitled 'Controversies about the treatment of myasthenia gravis' (Rowland, 1980) emphasises this. There is a choice between cholinergic drugs, corticosteroids, immunosuppressive drugs, plasma exchange and thymectomy, and controversy concerning the sequence and combinations of these therapies. Each form of treatment has been endorsed enthusiastically without controlled trials. In his review, Rowland comments that since myasthenia is not the serious disease it was 20 years ago, we must be doing something right. As space does not permit detailed discussion of these problems, our policy, which is similar to that of most other British centres, is described.

4.1 Medical Treatment

4.1.1 Symptomatic Treatment (A nticholi nesterase Drugs) Symptomatic treatment is by anticholinesterase drugs (table II) which prolong the action of acetylcholine at the postsynaptic membrane by inhibiting the enzyme which normally hydrolyses it. Pyridostigmine is the drug most commonly used, given orally as tablets or suspension. If bulbar paresis makes swallowing difficult or if absorption from the intestine is poor, it can be given parenterally in about 1/30th of the oral dose as a 5 mgfml solution. The usual starting dose is 60mg qid by mouth and this is slowly increased every few days until the maximum response is obtained. Neostigmine has a shorter duration of action but a quicker onset and can therefore offer an advantage at the beginning of the day. The dose is 15 to 30mg orally, or it may be given by subcutaneous injection or via an infusion pump subcutaneously. Establishing the Optimum Dosage It is important to establish the dose of anticholinesterase which gives the maximum therapeutic response. This may not restore muscle strength to normal, and some patients often have

Myasthenia Gravis

180

to live with some degree of disability. If the dose is increased above the maximum response level in an attempt to improve physical activity or to counteract fatigue, the opposite effect will be produced, and progressive muscular weakness may end in a cholinergic crisis (fig. 2). The short acting anticholinesterase edrophonium may be used intravenously (5 to IOmg) between doses to decide whether the patient is under- or overdosed. In using edrophonium it is important to inject 2mg initially and then to pause before administering the remainder in case the patient is already overdosed. Facilities for artificial ventilation should be readily available in case a cholinergic crisis ensues. Often the transitory increase in anticholinesterase renders some muscles stronger and some weaker. Obviously the bulbar and respiratory muscles are the most important and should receive optimum treatment. Myasthenic patients usually learn to regulate their own anticholinesterase medication. It is important for them to realise that changes in medication should be small and not too frequent. It takes several days to establish whether a change in dosage is helpful or not. Some individuals become psychologically dependent on their pyridostigmine dosage and are unwilling to decrease or stop it when the myasthenia improves following thymectomy or the introduction of corticosteroids. Careful explanation of the dangers of overdosage and slow steady reduction are usually effective.

4.1.2 Immunosuppression The main immunosuppressive drugs used in myasthenia gravis are the corticosteroids and azathioprine. Corticosteroids The place of corticosteroids in myasthenia is for those patients who are seriously ill prior to thymectomy, for those patients who are unsuitable for thymectomy, and for those who are insufficiently

MG

MG

MG

.!2

Adverse Effects The side effects of anticholinesterase drugs are mainly those caused by prolongation of the action of acetylcholine at the muscarinic AChR. Colic, diarrhoea, small pupils, lacrimation and salivation are useful monitors of overdosage and for this reason atropine should not be routinely prescribed to prevent them. The long term effects of anticholinesterase medication per se in man are not known. There is little evidence that they alter the course of the disease although some workers claim that the response to thymectomy is better in patients who have never received anticholinesterase drugs. There is evidence from animal studies that in large doses they may be deleterious to the neuromuscular junction but there is no evidence that this is so in man. Long term administration in normal rats causes elongation and simplification of the post-synaptic membrane, changes similar to those produced in myasthenia gravis (Engel et aI., 1973).

1 Myasthenic weakness

A

AC

1 Adequate therapy

A

-.9-.......~l--..-Jci Overdosage (cholinergic weakness)

MG = Myasthenia gravis AC = Anticholinesterases

Fig. 2. Anticholinesterase therapy in myasthenia gravis, illustrating the importance of establishing the optimum dose. If the dose is increased above the level which gives the maximum therapeutic response, progressive muscular weakness ending in a cholinergic criSiS will result.

Myasthenia Gravis

improved postoperatively. They are also useful in patients with ocular myasthenia who as a group respond poorly to anticholinesterases and to thymectomy. In patients with ocular myasthenia, the disability must be severe to warrant long term corticosteroid treatment with its attendant side effects. Therefore, there is a place for artificial aids, such as lid supports attached to spectacles to relieve ptosis, and eye patches for diplopia. There is evidence that corticosteroids reduce anti-AChR levels but they may also exert some of their therapeutic effect directly at the neuromuscular junction. Oral prednisolone (l mg/kg/day) is usually used and there is frequently initial deterioration in the patient's condition before an improvement becomes manifest after some weeks. The deterioration is minimised by starting with a low dose of the corticosteroid and gradually increasing the dose, and also by decreasing the anticholinesterase dose when corticosteroid treatment is started. It is safer to start corticosteroid treatment with the patient in hospital under close supervision by a physician familiar with the disease. Corticosteroid therapy often needs to be continued at I mg/kg/day (of prednisolone); an alternate-day regimen (2 mg/kg) is usually employed to decrease side effects. Azathioprine Azathioprine (2.S mg/kg/day) is also effective in reducing anti-AChR levels and in producing clinical improvement. The response is slower than that to corticosteroids; improvement begins at 6 to 12 weeks and becomes maximal at a mean of 6 to IS months. The results of treating 78 patients with azathioprine over 11 years have recently been reported (Mertens et ai., 1981). 31 of these patients are in complete remission, 40 are much improved and none is worse. Relapses have occurred only in patients taking less than IS0mg daily. In 8 patients in complete remission, azathioprine has been stopped for 6 months to 31f3 years without relapse. The response to azathioprine is more likely to be favourable in men, those over the age of 3S, and after a duration of illness ofless than 10 years. The response is also most favourable in the absence of

181

HLA-Bs and when there is histological evidence of abnormality of the thymus, and when a high titre of anti-AChRs is found. As azathioprine can cause bone marrow depression, regular blood counts during treatment are mandatory. The drug is probably dysmorpnogenic and should be avoided if possible in women who may become pregnant. It has recently been reported, however, that normal children were born to all of 9 mothers receiving azathioprine for a variety of autoimmune disorders (Symington, 1977). Azathioprine should be reserved for patients with severe disease that does not respond to other forms of treatment. It may also be used as a steroid-sparing agent in patients needing high corticosteroid dosages. Azathioprine is also useful in association with plasma exchange to prevent rebound hypersecretion of antibodies. 4.1.3 Plasma Exchange A dramatic but short-lived improvement in muscular strength associated with a decrease in antiAChRs can be brought about by plasma exchange. It is therefore useful as a short term measure to improve ill patients while other forms of therapy become effective. However, there is no evidence that repeated plasma exchange combined with immunosuppression confers any greater benefit than immunosuppression alone. 4.1.4 Precautions in Treatment Myasthenia may worsen spontaneously, or because of a change in hormonal state such as menstruation, pregnancy or thyrotoxicosis. Intercurrent infection or surgery can also increase muscular weakness. It is important to remember that certain drugs can aggravate myasthenia or complicate management; for example: (I) bulk laxatives may decrease the absorption of pyridostigmine; (2) myasthenic patients are much more sensitive to the effects of neuromuscular blocking drugs; (3) antiarrhythmic drugs reduce the excitability of muscle membranes and probably also inhibit neuromuscular transmission so that drugs such as quinine, quinidine, procainamide, lignocaine and propranolol should

Myasthenia Gravis

be avoided; (4) aminoglycoside and polymyxin antibiotics can inhibit acetylcholine release and should therefore be avoided (e.g. streptomycin, gentamicin, kanamycin, neomycin and polymyxin B); (5) central nervous system depressants such as morphine, barbiturates and even dextropropoxyphene must be used with caution as they can cause or worsen existing respiratory insufficiency; and (6) diuretics can aggravate myasthenia by causing hypokalaemia. Also, as already mentioned; overdosage with anticholinesterases themselves will increase muscle weakness. Deterioration in a patient's condition may result in crisis, with respiratory failure and paralysis. This may be myasthenic or cholinergic and both are dangerous. Treatment is by intubation and ventilation with all medication stopped. After 24 to 48 hours, anticholinesterase drugs should be restarted and corticosteroids or plasma exchange instituted if the response is unsatisfactory. 4.2 Surgical Treatment (Thymectomy)

4.2.1 Indications and Efficacy Thymectomy was first used to improve a myasthenic patient in 1911 but did not become widely used until Blalock performed a series of operations from 1936 onwards. In England, the practice was taken up by Sir Geoffrey Keynes who observed that on the whole, myasthenic patients without thymomas responded well but those with thymic tumours did not. Since then, thymectomy has become increasingly important in the management of myasthenia gravis and our practice is to offer surgery to all patients who are sufficiently fit for operation unless they have purely ocular disease, minimal symptoms, juvenile myasthenia or are elderly (see fig. 3). The risks of thymectomy are now small; provided the operation is undertaken in a centre with good intensive care facilities and in a unit experienced with the operation. Complete remission or improvement may be expected in 80% of patients without thymomas, although 3 to 5 years may elapse before the benefits of operation become apparent. A retrospective comparison of medical treatment (without corticosteroids) versus surgical

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treatment (Buckingham et aI., 1976) showed that patients treated by thymectomy were more likely to achieve remission and were less likely to die of their disease. In patients with tumours, either surgical excision or radiotherapy can be used to prevent local spread but the prognosis is worse.

4.2.2 Rationale for Use The rationale behind thymectomy is not understood. The normal role of the thymus is the education of T lymphocytes, which are not antibody producing cells but subserve a variety offunctions, such as helper cells, suppressor cells and cytotoxic T -cells. B lymphocytes, the precursors of the antibody producing plasma cells, are rare in the normal thymus. In myasthenia gravis, the thymus is frequently histologically abnormal: 10 to 15% of patients have a thymoma and over two-thirds of the remainder show 'thymitis', which is an infiltration of the thymic medulla with lymphocytes forming follicles with germinal centres in which there are B-cells. We have shown (Scadding et aI., 1981) that thymic lymphocytes from most patients with thymitis spontaneously and immediately synthesise antiAChRs in vitro, suggesting that this occurs in vivo and that the thymus may be the site of autosensitisation to the AChR. However, the amount produced is insufficient to account for the total circulating anti-AChRs. Irradiated thymic cells, themselves incapable of anti-AChR synthesis, augmented the production of anti-AChRs by autologous peripheral blood lymphocytes, which usually only produce anti-AChRs after mitogen stimulation. The thymus is probably the site of a helper factor, possibly an antigen-presenting-cell bearing AChRs, which enhances anti-AChR synthesis. There is further evidence that the thymus contains AChRs: these have been demonstrated on muscle-like cells cultured from mouse and rat thymuses, although they are not often found during the culture of human thymic tissues. However, peroxidase conjugated a-BT binding in the human myasthenic thymus has been demonstrated. It is conceivable that tolerance to these is broken by thymic disturbances, such as a viral infection.

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183

Myasthenia gravis Yes

• Anticholinesterases • Corticosteroids • Artificial aids

?Severe disease

• Total body irradiation or • Antithymocyte globulin

Try decreasing anticholinesterase drugs

Yes

Consider decreasing immunosuppressive therapy °Recent reports indicate that the response to thymectomy may be better if anticholinesterase drugs are not used beforehand (Olanow et al.. 1982). Fig. 3. Summary of the current treatment of myasthenia gravis.

Myasthenia Gravis

4.3 Alternative Forms of Treatment Most of these are nonspecific and have been tried only in patients refractory to everything else. Low doses of total body irradiation have been used to decrease circulating lymphocytes. Antithymocyte globulin has been used to decrease thymic lymphocytes, and 8 of lO patients showed some response to this after thymectomy (Pirofsky, 1981). The 2 patients who had refused thymectomy did not respond. It may soon be possible to use specific immunotherapeutic measures for myasthenia gravis. Anti-idiotype antibodies, i.e. antibodies directed against that part of the anti-AChR which is unique by virtue of its affinity for antigen, have been prepared. This is done by first purifying the antiAChRs from a patient and then injecting them together with adjuvant, into an animal. Theoretically, such antibodies could be produced in quantity using hybridoma techniques and could be used acutely to inhibit the action of anti-AChRs. Unfortunately, there appear to be a few shared idiotypes between myasthenic patients, suggesting that anti-idiotypes would have to be manufactured for each individual. Animal studies suggest that a decrease in one idiotype brought about by an antiidiotype leads to an increase in other idiotypes so that the total amount of antibody remains the same. Either a mixture of anti-idiotypes could be used or anti-idiotypes prepared for the most pathogenic anti-AChRs. If the anti-idiotype which is the mirror image of the antigen can be found, this should prove capable of stimulating suppressor T-cells which might switch off the autoimmune response. An alternative strategy would be to prepare antibodies to the helper T-cells which aid B-cells to form anti-AChRs. T-cell antigens are less variable between individuals than are antibodies, so the repertoire of molecules necessary would be smaller.

References Almon, R.R.; Andrew, CG. and Appel, S.H.: Serum globulin in myasthenia gravis: Inhibition of alpha-bungarotoxin binding to acetylcholine receptors. Science 186: 55-57 (1974). Buckingham, J.M.; Howard, Jr. F.M.; Bernatz, P.E. et al.: The

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value of thymectomy in myasthenia gravis. A computerassisted matched study. Annals of Surgery 184: 453-458 (1976). Chang. CE. and Lee, CY.: Archives Internationales de Pharmacodynamie et de Therapie 144: 241 (1962). Compston. D.A.; Vincent, A.; Newson-Davis, J. and Batchelor, J.R.: Clinical. pathological HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 103: 579-601 (1980). Donat. J.F.: Donat, J.R. and Lennon, V.A.: Exchange transfusion in neonatal myasthenia gravis. Neurology 31: 911-912 (1981). Engel. A.G.: Lambert, E.H. and Santa, T.: Study of long-term anticholinesterase therapy. Neurology 23: 1273-1281 (1973). Garlep. M.J.: Dawkins, R.L. and Christiansen, F.T.: HLA antigens and acetylcholine receptor antibodies in penicillamine induced myasthenia gravis. British Medical Journal 286: 338341 (1983). Kennedy. F.S. and Moersch, F.P.: Canadian Medical Association Journal 37: 216 (1937). Lindstrom. J.M.; Seybold, M.E.; Lennon, V.A. et al.: Antibody to acetylcholine receptor in myast.henia gravis. Prevalence, clinical correlates and diagnostic value. Neurology 26: 10541059 (1976). Mertens. H.G.: Hertel, G.; Reuther, P. and Ricker, K.: Effect of immunosuppressive drugs (azathioprine). Annals of the New York Academy of Sciences 377: 691-699 (1981). Olanow. CW.: Wechsler, A.S. and Roses, A.D.: A prospective study of thymectomy and serum acetylcholine receptor antibodies in myasthenia gravis. Annals of Surgery 196: 113-121 ,1982). Oosterhuis. H.J.: in Satoyoshi (Ed.) Myasthenia Gravis: Pathogenesis and Treatment (University of Tokyo Press, Tokyo 1981). Pirofsky. B.: The effect of anti-thymocyte antiserum in progressive myasthenia gravis. Annals of the New York Academy of Sciences 377: 779-785 (1981). Rowland. L.P.: Controversies about the treatment of myasthenis gravis. Journal of Neurology, Neurosurgery and Psychiatry 43: 644-659 (1980). Rowland, L.P.; Hoefer, P.R.A.; Aranow, H.J.R. and Merritt, H.H.: Fatalities in myasthenia gravis. A review of 39 cases with 26 autopsies. Neurology 6: 307-326 (1956). Scadding, G.K.; Vincent, A.; Newson-Davis, J. and Henry, K.: Acetylcholine receptor synthesis by thymic lymphocytes: Correlation with thymic histology. Neurology 31: 935-943 (1981). Simpson, J.A.: Myasthenia gravis: A new hypothesis. Scottish Medical Journal 5: 419-436 (1960). Smithers. D.W.: Tumours of the thyroid gland in relation to some general concepts of neoplasia. 1. Facult. Radiol. 10: 3-16 (1959). Symington. G.R.; Mackay, I.R. and Lambert, R.P.: Cancer and teratogenesis. Infrequent occurrence after medical use of immunosuppressive drugs. Australia and New Zealand Journal of Medicine 7:368-372 (1977). Author's address: Dr C W.H. Havard. Royal Free Hospital, Pond Street, Hampstead. London NW3 2QG (England).