Controversies about the treatment myasthenia gravis of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 644-659 Controversies aboutthe treatment of myasthenia gravis LEWISP ROWLAND

Journal of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 644-659

Controversies about the treatment ofmyasthenia gravisLEWIS P ROWLAND

From the Department of Neurology, Columbia University College of Physicians and Surgeons;Neurological Service Presbyterian Hospital; H. Houston Merritt Clinical Research Center for MuscularDystrophy and Related Diseases; Columbia-Presbyterian Medical Center

SUMMARY Clinicians treating patients with myasthenia gravis must choose cholinergic drugs,corticosteroids, immunosuppersive drugs, thymectomy, or plasmapheresis. Clinicians must decidethe sequence or combination of these therapies and when to deem lack of improvement a sign for adifferent therapeutic approach. Because controlled trials have not been done to evaluate therapiesthat may require months or years before benefit is evident, controversy abounds.

It is a privilege to participate in this Festschriftto honour Ian Simpson who has shown us thepower of clinical thought in analysing a medicaldisorder as a biological problem. Among his manycontribuitions, he has been widely applauded forhis studies o'f myasthenia gravis, including an earlyanalysis of thymectomy,l his introduction of theconcept of myasthenia as an autoimmune disease,2and the critical notion that pharmacologicaldeductions about the physiological abnormality inmyasthenia presumed normal morphological geo-metry at the endplate.3 Simultaneously withSimpson's closely reasoned arguments, Nastukand Strauss and their colleagues provided the firstevidence of humoral abnormality4 and AG Engeland his colleagues provided evidence that the mor-phology of the endplate is not normal in humanmyasthenia.5

It is my assignment in this symposium to reviewcontroversies about the therapy of myasthenia.Controversy is the unwanted child of ignorance,and we may be ignorant because we do not havethe means to find the answers to questions, orbecause we have the means but cannot applythem. Too often in medicine, our ignoranceseems to be due to asthenia of the will. We knowhow to find the answers, but we do not. Weknow that we could find out whether this or thatproposed treatment is effective by setting up acontrolled trial. But patients are not rabbits.Patients want to be treated and physicians have

Address for reprint requests: LP Rowland, MD, NeurologicalInstitute 710 West 168th Street, New York 10032, USA.

Supported by Center grants from the Muscular Dystrophy Associa-tion, Inc. and the National Institute of Neurological and Communica-tive Diseases and Stroke (NS - 11766)

their own emotional problems; they want totreat. We adopt therapeutic programmes becausethey seem logical or useful, and these therapiesbecome so embedded in custom that it is ulti-mately deemed unethical to even consider acontrolled trial.We are not alone in this dilemma. When I

was a medical student, standard treatments in-cluded vagotomy for peptic ulcer and sympathec-tomy for hypertension; current controversiesinclude radical mastectomy, tonsillectomy,carotid endarterectomy, and coronary by-pass sur-gery.6 7 Nevertheless, when physicians areentrusted with the care of patients with myas-thenia gravis, they must choose betweencholinergic drugs, steroids, more specific im-munosuppressive drugs, plasmapheresis, andthymectomy. There is uncertainty about thevalue of all of these and there is difference ofopinion about specific details of each therapy,or the sequence to be chosen. Lacking appro-priate evidence, the physician must neverthelessmake a choice.

That is the dilemma. Recognising that thereare differences of opinion, I will try to make thequestions clear, and to provide fair statementsof divergent views. I have my own views, ofcourse, but will try to separate assertion fromfact.

CHOLINERGIC DRUGSLittle attention is being paid to cholinergic drugtherapy for at least two reasons: First, thesedrugs do not ordinarily restore normal life topatients with myasthenia. Second, the apparentclinical benefit of immunot'herapies and evidence

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Controversies about the treatment ofmyasthenia gravis

of abnormal immune mechanisms in the diseasehave shifted therapeutic attention to measuresthat might alter the course of the disease, ratherthan merely reversing symptoms. Revivingarchaic debates may not seem appropriate butalmost all clinicians use anticholinesterase inhibi-tors to start treatment, and it may be useful toindicate that there are still unanswered questions,even about this primeval form of drug therapy.Which anticholinesterase medication is mosteffective? The immediate effects of cholinergicdrugs are so dramatic that the therapeutic re-sponse can be considered part of the definition ofthe disease.8 There is no need for a controlledtrial when ptosis disappears before your very eyesor ophthalmoplegia melts into normal motion.The therapeutic benefit of oral medication, how-ever, is usually much less dramatic. Some dis-abled patients may be returned to normalactivity, but symptoms are rarely relieved com-pletely. Of the three drugs now available(neostigmine, pryridostigmine, ambenonium),pyridostigmine has proven the most popular, butthis choice was never based on any kind of for-mal assessment. Rather, patients were askedwhich drug they preferred, and most chosepyridostigmine because it caused the fewest gas-trointestinal effects. There has never been con-vincing evidence that one drug is better thananother for specific symptoms, or that one drugcan be effective when another is not.How is the optimal dosage of a cholinergic drugdetermined? There is still no way to determinethe optimal dosage of pyridostigmine therapy,except by a trial that depends upon subjectiveresponses of patient and physician. Osserman8introduced the edrophonium test to determineoptimal dosage. A patient already taking oralmedication is given 2-0 mg edrophonium intra-venously. If symptoms improve, the patient isdeemed undertreated and the oral dosage is in-creased. If symptoms worsen, overtreatment ispresumed and the oral dosage is decreased. Ifedrophonium has no effect, oral treatment isdeemed optimal.However, the edrophonium test has never been

assessed formally, to determine whether theseconclusions are justified. It was never demon-strated why 2 0 mg should be the decisive dose,rather than 3 0 or 5-0 or some other quantity,or why it should be the same in every patient.In untreated patients the same dose of edropho-nium may have a diagnostic effect one day, noeffect the next, or may improve function of somemuscles but worsen others; how then can thetest be reliable in treated patients? We never

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assessed this test formally either, but we havenot found it a reliable guide to oral therapy,and the test does not seem to be used very oftennowadays.

If there is no objective way to determine opti-mal dosage, we have to rely upon statements ofthe patient about the response of specific symp-toms. It is my impression that patients andphysicians tend to increase the dosage progres-sively, so long as the patient is not too distressedby side-effects. Often, the dosage can be sharplyreduced without ill effect. Although there is nodirect evidence to support the statement, fewpatients seem to show objective benefit from doseslarger than 120 mg every two or three hours.That is why "pyridostigmine requirement", atleast in terms of daily dosage, should not be usedas a measure of therapeutic effect for thymec-tomy or other measures designed to alter thecourse of myasthenia.How often does cholinergic crisis occur? Yearsago, when irreversible inhibitors of choline-sterase were evaluated in the treatment of myas-thenia, it became apparent that overdosage couldcause weakness and pyridine-aldoxine methio-dide (PAM) was introduced as a specific antidotefor this kind of organophosphate intoxication.That cholinergic crisis may occur is indisputable,and it can be demonstrated experimentally,9 butit is not clear whether or how often it occursin patients treated with the standard drugs nowin use. Indeed, as crisis itself has become lessfrequent, the question has disappeared from theliterature.There are still, however, occasional references

to the use of edrophonium as a method to deter-mine whether weakness is "myasthenic" or"cholinergic". As originally described,8 the testagain required an arbitrary dosage of edropho-nium (1-0 or 2-0 mg), but interpretation nowdepended on only two choices: if weakness im-proved, it was "myasthenic"; if there was noimprovement, or if weakness worsened, theweakness was "cholinergic". Again, however,this interpretation was never assessed formally,and it is not clear why "no response" should bedeemed optimal in one situation but not inanother. We have been sceptical about this inter-pretation because it has been standard practicein our institution for 30 years to discontinuecholinergic medication whenever a patient re-quires respiratory support. Never have we seena patient improve immediately after discontinu-ing cholinergic medication; either there is noimmediate change, or, more often, the weaknessbecomes perceptibly worse. If cholinergic crisis



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occurred, patients should improve promptlywhen the drug is withdrawn. There has been no

convincing documentation of acute cholinergiccrisis in any patient taking only oral medication.Should administration of cholinergic drugs bediscontinued during crisis? We define crisis asan exacerbation of myasthenic symptoms thatrequires mechanical ventilation. In 1949, Randtand Korey gave one patient 18X0 mg neostigmineintravenously in one hour; the equivalent oraldose would be 440 mg or almost 30 standardtablets of 15 mg each. Within 60 hours, thatpatient received 50 mg neostigmine intravenouslyand 95 mg initramuscularly.'0 There were neitherbeneficial nor deleterious effects but they con-cluded that cholinergic drug therapy could notterminate crisis, and continued use could compli-cate management by causing diarrhoea orincreasing pulmonary secretions. For thesereasons, it has become standard practice in our

institution and others to discontinue cholinergicdrug therapy as soon as mechanical ventilation isstarted.One practical effect of this approach is that

the distinction between "cholinergic" and "myas-thenic" crisis becomes inconsequential, since thepossibly offending drug is withdrawn anyway.It does, however, leave the question of whento resume drug therapy, and this is importantafter thymectomy as after crisis of other cause.There are no clear answers to this question butwe view crisis as a temporary exacerbation; it isour task to keep the patient alive until the causeof the exacerbation subsides, assuming that it isdue to transient effects of respiratory infection,aspiration pneumonitis, or surgery. Therefore,pyridostigmine does not seem useful and we can-

not "get the patient off the respirator with pyrido-stigmine" while the patient is febrile, or whileother complications are overtly active. Once thesecomplications subside, respiration begins to im-prove and pyridostigmine can be started again.Could treatment be improved by monitoringblood levels of cholinergic drugs? Little isknown about the pharmacokinetics of pyridostig-mine. After intravenous injection of 14C-labelleddrug, 44-47% of the administered label appearedin the urine within one hour." Because excre-tion of the drug exceeded creatinine excretion,there seemed to be tubular excretion as well as

glomerular filtration.'2 13 Interactions with otherdrugs and hepatic meatabolism have not beendefined, and much of orally administered drugappears in the faeces.'3

There have been few studies of blood levelssince the introduction of gas-liquid chromato-

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graphy. In one study,'4 serum levels were lowerin patients deemed "poorly controlled" than inthose who seemed to be responding to therapy.Because parenteral administration of drug raisedthe low blood levels to the range of those in goodcontrol, the originally low drug levels wereattributed to malabsorption. However, in anotherstudy,15 plasma pyridostigmine content was re-stricted to a narrow range (20-60 mg/ml) despitewide variations in daily dosage (60-660 mg)among different patients. In still another study,peak levels and area under the curve werehigher in poorly controlled patients.'6 Furtherwork seems to be necessary to resolve these dif-ferences, and to indicate whether therapeuticdrug monitoring has a role in myasthenia.Does chronic administration of cholinergic drugshave deleterious effects? From time to time,clinicians wonder whether patients may become"refractory" to the beneficial effects of chol-inergic drugs, perhaps because of desensitisationof receptors or because of drug-induced changesin morphology. Experimentally, chronic admin-istration of these drugs can induce bothphysiological and morphological changes.17-20However, there is virtually no evidence that thisis true in humans. The dosages used in theanimals were much larger than patients take,and there is no clinical evidence of decliningeffect of cholinergic drugs that might be depen-dent upon dosage or duration of treatment (butthat has not been assessed formally either).Mayer et al21 presented evidence that myastheniccrisis might be due to drug-induced changes, butquestions were raised about their data.2' Thepossibly beneficial effects of a "drug holiday"in treatment of myasthenic crisis have not beenevaluated.

THYMECTOMYIs thymectomy effective in the treatment ofmyasthenia? The world over, thymectomy isstandard therapy for myasthenia. There is nodebate about that statement. Yet the beneficialeffects of thymectomy were discovered by acci-dent when Blalock22 removed a cystic thymomafrom a young woman with myasthenia, and themyasthenic symptoms subsequently improved.On the basis of that experience, the operationwas gradually adopted, in large part due to theinfluential work of John Simpson.' But in thosedays shortly after World War II, no one knewthe function of the thymus, so there was notmuch rationale for thymectomy. Even today, itis not known whether benefit is bestowedbecause a source of antibodies is removed,



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because the source of antigen is removed, orfor some other reason.

In the early days, there was controversy aboutthe therapeutic value of thymectomy, and theconsiderable operative mortality was a restraint.Even at the Massachusetts General Hospital, sixof the first ten thymectomies ended in death.23But, Keynes24 soon pointed out that results werebetter for patients who lacked thymoma, andgradually improvements in surgery, anaesthesia,and respiratory care reduced the mortality rateto virtually nil. For instance, at the Columbia-Presbyterian Medical Center, there were fourdeaths in 21 operations between, 1942 and 1955,but there were no deaths in 33 operations be-tween 1956 and 1966,2, and there have been nodeaths in 101 trans-sternal thymectomies from1963 to 1979.26 Other centres have experiencedthe same changes; as the risks declined, moreoperations were done.

Results of the modern operation have beensummarised in many reports since 197027-46 andthe generally held view can be stated succinctly.When there is no thymoma, thymectomy is fol-lowed by improvement in 66% to 86% of thepatients. There has not really been much debateabout this; McQuillen47 48 is a brave but solitaryvoice, questioning the nature of the EmperorThymectomy's robes, and McQuillen's doubtswere expressed by comparing only the incidenceof complete remission in operated and un-operated cases. It may not be appropriate todisregard improvement short of complete remis-sion, and some35 have questioned McQuillen'sacceptance of possibly brief and early rem(issionsin unoperated cases, in contrast to lasting remis-sions after thymectomy.Whether McQuillen is absolutely correct or

not, other students have been disquieted by thelack of any prospectively controlled study ofthymectomy. Although several authors comparedresults in operated and unoperated cases, onlyone study was concerned with matched cases,comparing patients of the same age, sex, dura-tion of symptoms, and severity of symptoms.27Even in that study, operated and unoperatedpatients were not contemporary; operations wereprobably done more often in recent years, afterimprovements in respiratory care (and also afterthe introduction of steroid therapy).

Therefore, despite the almost universal beliefin the efficacy of thymectomy, its value has notreally been proven. Also, there have been someinexplicable cases, such as improvement of myas-thenia after mediastinal exploration without thy-mectomy,49 or after removal of an echinococcus

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cyst of the lung.50 Some have even claimed thatBlalock's original case was not really a thymec-tomy, because the tumor was entirely cystic.38It is possible, though doubted by most, that im-provement in respiratory care now permitspatients to live after crisis that would have beenfatal years ago, and that the natural history ofthe disease is then one of improvement. Simp-son,51 Genkins et al,52 and others believe thatthe disease is "active" for a finite time, althoughthere is no way to measure "activity" of thedisease except by symptoms. These possibledoubts come rather late in the game and it isnow difficult to conceive of a prospectively con-trolled trial of thymiectomy, but some investiga-tors in the USA are making the attempt.Is cervical thymectomy preferable to trans-sternal thymectomy? Barring the nagging butfundamentai doubts of McQuillen, the majorcontroversy about thymectomy concerns theoperative technique. The standard operation in-volves splitting the sternum and although opera-tive mortality has been essentially obliterated, itis still a major operation; respiratory assistanceis often required in the postoperative periodand patients may have to remain in an intensivecare unit for several days. It was therefore ofgreat interest, in 1967, when Kark and Papa-testas and their associates began to write abouttranscervical thymectomy.33 4153 54 The morbidityof this procedure is much less than the trans-sternal operation and it spares the patients froma disfiguring scar on the chest. The morbidity isso slight that the indications can be extendedto children or the elderly, or to patients withonly slight functional disability, groups notordinarily selected for the trans-sternal opera-tion.

Since the results of the transcervical operationare claimed to be equivalent to the standardprocedure,33 4' 5 54 it is rather strange that theoperation has not been adopted by more thanone centre in the US and one in Europe.36 Themajor argument against the cervical approachhas been stated by Jaretzki26; it is not possible todo a total thymectomy through the neck inevery patient; complete removal of the thymusrequires thorough exploration of the mediasti-num.55 Several other arguments have beenadduced: (1) There has been no prospective com-parison of the two operations and more patientswith mild myasthenia (who might be expectedto have a better prognosis anyhow) are selectedfor the transcervical operation; outcomes ofmild and severe cases operated in different epochscannot be compared. (2) The cervical operation

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was introduced in 1967 and insufficient numbersof patients have been followed long enoughfor evaluation. (3) Takahashi et al46 reportedremissions or improvement in 54% of 13 patientsfour years after cervical thymectomy performedbetween 1969 and 1973. For reasons similar toJaretzki's56 they changed to a trans-sternaloperation in 1973 and among 43 patients whohad this "radical" operation, the rate of remis-sion and improvement was 88-4% at four years,and improvement was seen sooner. (4) Even theproponents of the cervical operation believe thesternum should be split to remove thymomas, butnot all thymic tumors are deteCted before surgeryby standard radiograms (and computed tomo-graphy of the mediastinum may be falsely"positive").57 (5) If the sternal operation is"thorough", it is known that all recognisableglandular tissue has been removed. If the patientdoes not improve after cervical thymectomy,however, physicians may wonder about residualthymus. For instance, Stump et al58 reported thatresidual thymic tissue was found by a trans-sternal operation in all of five patients who hadnot improved after an earlier cervical thymec-tomy. Even the trans-sternal operation may leavetissue behind.26 59

This dispute will only be resolved by the results.What is needed is some evaluation of trulycom,parable patients subjected to the two pro-cedures and foSllowed for a prolonged period ofobservation; this is not available. If the cervicaloperation ultimately proves to be beneficial, itwould mean that "total" thymectomy is not neces-sary for therapeutic effect. This conclusion is notimpossible, since no one knows what deleterioasinfluence is removed by thymectomy, nor whyimprovement may be delayed as long as sevenyears; merely reducing the burden may suffice.Is it possible to predict which patients will benefitfrom thymectomy? Other controversies pale bycomparison to the questions about thymectomyitself, or the surgical approach, but other dif-ferences of opinion should be noted. Originally,it seemed that young women were the bestcandidates for thy-mectomy, but this could havebeen an artefact of selection since young adultpatients would be most likely to be selected fora major surgical procedure, and most young adultpatients with myasthenia (and no thymoma) arewomen; some men and some older patients haveimproved in virtually every report. Short dura-tion of symptoms has been deemed important,especially in recent years,29 3 but in the singlelargest series, improvement rates were the samefor patients with symptoms for more or less than

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five years." The histology of the thymus hasbeen considered important, but some authorsregarded presence of germinal centres a-s favour-able6"; others considered lack of germinalcentres favourable,33 36 46 61 or found that thymichistology was not related to outcome.296264 AsMcQuillen and Leone48 pointed out, these dis-crepancies may not be surprising because it hasnot been proven that germinal centres areactually abnormally numerous in glands ofpatients with myasthenia.65 66There has been concern about doing thymec-

tomies in pre-adolescent children67, but the ratesof improvement seem no different from those inadults and no long-range harm has becomeevident, even when the operation was performedin children as young as two years.45 68-74

It is probably fair to state that there are noreliable predictors of favourable outcome. Themost common indication for thymectomy is dis-abling myasthenia, but "disabling" permits con-siderable room for subjective choice by thephysician. As the operation becomes safer, andas more physicians become convinced of the valueof the operation, more patients are selected forthymectomy and, increasingly, during the firstyear or two of symptoms.Can "early" thymectomy prevent "progression"of myasthenia? Although it is difficult to findevidence in the literature, it has been stated thatearly thymectomy prevents "progression" of mildmyasthenia to a severe state.33 Because of thisview, the Mount Sinai group has attempted toidentify which patients with solely ocularmyasthenia are destined to have generaliseddisease.75 If a patient with solely ocular symptomsshows either a decremental response to repetitivestimulation of a limb nerve or abnormal sensi-tivity to curare to a local challenge of limbmuscles with this drug, the disease is considered"generalised" and some of these patients havebeen subjected to thymectomy. Bever et al,76however, found no correlation between theresults of curare test or repetitive stimulationand subsequent-course of patients with ocularmyasthenia.Does steroid therapy enhance the results of thy-mectomy? It is probably true that, in mostcentres, steroid therapy is started only after thy-mectomy for most patients, at some time whenphysicians worry that improvement is not evidentsoon enough. This time depends upon the severityof symptoms; the more severe the disease, thesooner steroid therapy will be instituted. How-ever, Johns and his associates77 have urged treat-ment with steroids before thymectomy because



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steroid-induced improvement may make the post-operative course less onerous. For other clin-icians, this policy introduces new problems. Theoutcome of steroid therapy is itself uncertain intime and degree; if patients are chosen on*grounds of disability, why operate on a patientin remission, steroid-induced or spontaneous?To avoid uncertainty about the appropriatetiming of thymectomy after steroid therapy, whynot do the thymectomy first and hope that thiswill avoid the risks of steroid therapy? These aresome of the reasons why most centres do thy-mectomy first.A new aspect of steroid therapy was introduced

by Bolooki and Schwartzman78 who advocateadministration of methylprednisone, given intra-venously in divided doses just before, during andafter the operation for a total of 1000 mg in 24hours. They believe that the regimen greatlyreduced the morbidity of the trans-sternalapproach; all 32 patients so treated left the in-tensive care unit within 24 hours. There havebeen no controlled studies of this approach, norany reports from other centres.Why should thymomas be excised? There is nodebate about the advisability of surgical excisionof thymoma in patients with myasthenia; it isdone routinely. However, when a thymoma ispresent, thymectomy is less likely to be followedby improvement than in patients without thy-moma. The indication for surgery of thymoma istherefore said to be the possibility that thetumour may ultimately invade neighbouring struc-tures. In fact, symptoms are only rarely due toinvasion of pericardium, lung, or superior venacava79 and the myasthenia sometimes does im-prove. Possible improvement of myasthenia isthe "secret indication" in these patients, as inthose without tumour.One of the mysteries of thymectomy is how

it exerts its beneficial effects. This is illustratedby some patients who do not have symptoms ofmyasthenia until some time (often years) aftera thymoma has been removed. At first, it seemedthat some thymic tissue was probably left behindin these cases,80 but Namba and Grob8' providedevidence that there had been apparently completethymectomy in several patients with this kind ofdelayed myasthenia. Does that mean thymic cellshad seeded other lymphoid organs before thetumour and thymic gland were removed? Incontrast, however, myasthenia and tumour mayboth reappear after initial remission82; somepatients experience remissions even if the thy-moma is not removed83; and sometimes there isno autopsy evidence of thymic tissue even in

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fatal myasthenia.10 84 Therelearned about the relationmyasthenia.85

is still much to beof the thymus to

STEROIDSIs steroid therapy effective in myasthenia gravis?Even to raise this question seems almost sacri-legious, because prednisone is now a staple ofcurrent therapy. It was not always so; there wasa lag of almost 20 years from the first use ofACTH to some kind of general acceptance. But,as with other forms of myasthenia therapy,"acceptance" is not to be equated with rigorousproof of efficacy, safety, or clear indications foruse. A brief review of steroid therapy providesa commentary on the sociology of academic neu-rology, especially in the United States.ACTH first became available for therapeutic

trials in 1950; its effects in the treatment ofrheumatoid arthritis led to the award of a NobelPrize and to use in other diseases of unknowncause. At that time, myasthenia was notregarded as an autoimmune disease. The firstneurologists to be entrusted with limited supplieswere Houston Merritt and Harold Wolff. Mer-ritt, with Gilbert Glaser, used the drug in manydifferent disorders, including one patient withsevere myasthenia gravis who had "a partialremission" but died a few weeks later.86 87 Wolff,on the other hand, concentrated on myasthenia,reporting some improvement in ten of 15 cases;the improvement, however, was preceded byexacerbation of weakness and one patient diedon therapy.88 89 Therefore two of the first 16patients treated with ACTH died. Attention wasdirected to the possibly adverse effects of ACTHeven though severe myasthenia was indeed gravein those days; the reported benefits were over-shadowed

Negative views of the effects of corticosteroidswere reinforced by two other early reports, onefrom the Mayo Clinic90 and the other from JohnsHopkins91; both papers were influential becausethe writers were such highly respected auth-orities on myasthenia. The Hopkins paper wasespecially powerful and the story was told inthe title of the paper: a patient was being treatedwith cortisone for rheumatoid arthritis whensymptoms of myasthenia first appeared. If a drugcannot prevent the first symptoms of a disease,how can it be effective in therapy?As a result of these experiences, there were

no reports of steroid therapy from any of themajor myasthenia centres for more than a dec-ade. There were still, however, occasional reportsof benefit92 98 and this provided the background



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for a peculiar episode in the early 60s. At thattime, several clinicians were concerned about thelack of controlled trials to evaluate thymectomyand they met to design a suitable protocol. Thequestion of appropriate controls, however,seemed insurmountable; even then, the notion ofsham operation was theoretically desirable butwas deemed ethically impossible. Also, the co-operation of individualistic centres was difficultto achieve. To prepare for some kind ofcooperative trial of thymectomy, therefore, theparticipants agreed to study the effects of ACTHon ocular myasthenia.For several reasons, this seemed to be an ideal

way to devise methods of cooperative investiga-tion. Eye movements before and after therapycould be photographed and measured, objectivelyand quantitatively, without recourse to subjectiveevaluation and difficult-to-define words such as"improved". Evaluation could be completely"blind"; photographs were sent to another cityand measurements were made without knowl-edge of therapy, whether it was placebo orACTH, or even whether the photographs weretaken before, during, or after therapy. Finally,because the patients had solely ocular symptomsand because the duration of therapy was limited,the patients were not being subject to any seriousrisk.So the trial was initiated. Cooperation among

the participating centres was excellent. The re-sults were unequivocal. ACTH therapy, 580units given in eight days, had no effect.94The issue could have ended there. But,the very

next year, at an international conference onmyasthenia, von Reis et al95 described and pre-sented motion pictures to prove, dramatically,how beneficial ACTH therapy could be inpatients with severe generalised myasthenia.Within a year, Grob and Namba96 and Ossermanand -Genkins97 confirmed these reports andsteroid therapy was established throughout theworld. The next logical step was taken when oraltreatment with prednisone replaced injections ofACTH in 1971.98 The wave of enthusiasm sankthe cooperative trial, which disappeared from theliterature without leaving a ripple. How couldit have been so wrong? Perhaps because gener-alised and ocular myasthenia are not the same.Perhaps the dosage or duration of therapy wasinadequate, but similar dosages and durationwere said to be successful in generalised myas-thenia. Perhaps the controlled trial was notwrong, because a critical review of the literatureof prednisone indicates persisting uncertaintiesdespite uniform endorsement of this form of

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therapy.To evaluate the effects of prednisone therapy,

we have analysed the 15 reports (from 10centres) since 1971.99-112 Of these, only one at-tempted a controlled study; Howard et al'07 foundthat seven of ten treated patients improved butso did three of ten receiving placebo, and thedifference was not statistically significant. Thenumber of patients was small, and the patientsall had mild myasthenia (because, ethically, theinvestigators did not believe they could withholdstandard therapy from patients with severe symp-toms). Therefore, there has been no adequatelycontrolled study, and no controlled study of anykind for patients with severe disease (who aremost likely to be treated with prednisone).

Fischer and Schwartzman'02 described uni-formly beneficial results in eight patients withsolely ocular symptoms. The other reports con-cerned 216 patients with generalised myasthenia,but, taking the most recent reports, only three ofthem described series of more than 20 patientseach.'10 109 11O The results of each report, bar one,were fantastic.Some reported imnprovement in every single

patient treated98-101 104 108 and the rate droppedonly slightly in later reports from three of thesecentres, to 84%,105 89%106 and 92%.110The only dissent from these reports of almost

universal improvement came from Kornfeldet al'09 who found benefit before thymectomy inonly 17% of patients with thymolma and o,nly30% of those witihout thymoma. After thymec-tomy, however, these authors found 100%improvement in patients with thymoma but stillonly 50% of patients without thymoma. Sincenegative therapeutic results are less likely to bereported the ex-perience in some other centresmay be in line with the results of Kornfeld et al,but that, of course, cannot be proven until thedata are published.There are other discrepancies in these published

reports. Transient exacerbation of weakness wasreported by some,99 101 104 107 110 denied byothers 98 100 102 103 and not mentioned by Kornfeldet al.109 Signs of improvement were noted as earlyas the first day or within one week'00 102; withintwo weeks, but later extended to one month106;one month'03; 40 days'04; or 50 days.110

It is important to know the upper limit of time-to-improvement because, if there is no improve-ment, the 'clinician must know when it isappropriate to discontinue therapy as a failure.This question was not specifically addressed inany of these reports but it would seem that twoor three months should be adequate. Time-to-



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maximum-benefit is similarly important, also notspecifically considered, but given as less thanone month,10' 106 8 months,'04 15 months'00 andeven 55 months."10Almost all of these investigators first used a

daily dosage of at least 50 mg (or 100 mg onalternate days). There is virtually no informationabout the longterm use of prednisone; how longfull dosage should be given, when or to whatlevels dosage may be reduced; in how manypatients druig-induced remission is permanent andprednisone therapy can be discontinued; or howoften it must be continued because patientsrelapse when dosage is reduced. Sanders et all"Oroutinely used prednisone before thymectomy sothat the postoperative course will be more benign,but the data of Kornfeld et al'09 suggest that thispolicy may not be appropriate. It is not clearwhether prednisone is more or less beneficial inchildren than in adults, because it has been usedin only a few children,102 110 and similar questionsmay be raised about the elderly."12Is prednisone therapy safe? Do the benefits justifythe risks? Some authors reported no complica-tions99 109 or nothing more than the cosmeticeffects of Cushing syndrome or glycosuria.102 107 Itis not possible to ascertain the incidence of moreserious complications that have included vertebralcollapse98 103 106 110; congestive heart failure98;gastric haemorrhage'06 110; ruptured diverti-culum"10; tracheal abscess'06; psychosis104;cataracts'05 100 aseptic necrosis of bone'05 110;and se-psis."10Two deaths were attributed to steroid

therapy.110 No one has described the signedrelease used to explain these potential side effectsin attempts to obtain informed consent forchronic prednisone therapy.Does steroid therapy have pharmacologicaleflects at the neuromuscular junction? Therationale for use of steroid therapy depends uponimmunological theories of the disease, althoughit is not known precisely how steroids alter thepathological immune state. Several investigatorshave evaluated the possibility that steroids mightrepair the physiological abnormality of myas-thenia113"117 but the balance of evidence suggeststhat this cannot be the basis for the beneficialeffect.'18-119How can we summarise the present state of

prednisone therapy? It is now standard andcustomary, but has not been subject to controlledtrial and the incidence of documented risk hasnot ;been ascertained. It is therefore uncertainwhether it should be used at all in pa,tients whoare not seriously disabled, in children, or in the

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elderly. It is not clear whether it should be usedbefore or after thymectomy. It is uncertain howlong full dosage should be continued beforedeeming any trial a failure. It is not known howlong full dosage should be continued when thereis apparent benefit, or how often treatment canbe terminated without adverse effect. The reportsof almost universal benefit cannot be taken atface value because of a single published dissentand because, if the results were as good asdescribed, there would be little interest in plasma-pheresis or immunosuppressive drugs.

IMMUNOSUPPRESSIVE DRUGSAt the 1970 international meeting on myasthenia.1 was asked to review experience with immuno-suppressive drugs.'20 There had been reports ofimmunosuppressive drug therapy in only 46patients and 38 of them had improved,'20 but38 of these patients (including 32 who improved)had been reported from one centre by Mertenset al.'12 By means of a poll of centres in the US,we could obtain information about 14 casestreated with immunosuppressive drugs, but with-out detailed data; improvement was reported infour of these cases and the drug was discontinuedin three. In sum, at that time, 60 patients wereknown to have been treated and 36 had im-proved.A decade later, Hertel et al122 held my paper

responsible for a chilling effect on the use ofthese drugs, but that view exaggerates any in-fluence I might have (or anyone else, for thatmatter). What stopped research on the use ofimmunosuppressive drugs in the US was thelitiginous nature of American society. At the1970 meeting, I described the tragic case of awoman with life-threatening myasthenia who hadan exaggerated bone marrow response to 6-mer-captopurine, became infected, suffered a myas-thenic crisis, and died. That case resulted in alaw-suit, euphemistically called "professionalliability" here; the patient died in 1963 and legalaction continued until the case was settled in1973. The case was widely known among Ameri-can investigators and probably did more toinhibit the use of these drugs than anything else;no physician wants to be accused of malpractice.For that reason, now, as in 1970, we have tolook to European experience to evaluate im-munosuppressive drug therapy.

Since 1971, there have been reports of onlyfour series of patients who were treated withazathioprine without simultaneous prednisonetherapy. Matell et al123 found that 78% of 26patients improved and three patients were in



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complete remission; the dosage was 2 mg/kgbody weight. Improvement was not seen untilafter six to 12 weeks and the maximal effectappeared in six to 15 months. Because the"gradual effect makes it difficult to evaluate theeffect properly", azathioprine was discontinuedevery year or two to determine whether therehad been a spontaneous remission, but theresults of this test were not stated. The drughad to be withdrawn because of agranulocytosisin only one patient. Sepsis and pneumoniaaffected two patients, one fatally.

Hertel et al'22 used 150-200 mg azathioprinewithout steroids, to treat 64 patients. Thirty-three patients were given the drug after thymec-tomy, so that the prolonged improvement includedthe effects of both treatments but they impliedthat azathioprine hastened or enhanced the re-

sults of thymectomy (although specific data were

not given); four years after thymectomy, theywere still improving. Very severe myasthenia was

treated with both corticosteroids and azathioprinein 15 cases and all but one improved. Only one

patient had severe bone marrow depression thatlasted for several months, and therapy did nothave to be discontinued in any patient becauseof hepatic or gastrointestinal toxicity. Onepatient died of sepsis and another had orchitis.Reuther et al'24 studied AChR antibody re-

svonses in nine of the patients mentioned byHertel et al'22; three had thymectomies. Titresdeclined to about 70% of the initial values bythree years and to 40% after five years. Althoughall patients improved and seven were in remis-sion, abnormal antibody titres persisted in allof them.Newsom-Davis et al'25 gave azathioprine in a

daily dosage of 2-5 mg/kg, to six patients; fivehad thymectomy and five were receiving pred-nisone. They were compared to seven patientswho received the drug (concomitant with pred-nisone in four and who were also treated byplasma exchange. Six of the 13 patients improvedin the observation period of four to 12 weeks,and all patients showed a decline in antibodytitres, but there were no significant differencesbetween the two groups. No serious side-effectswere reported.There have been reports of treatment with

other immunosuppressive drugs that are notgenerally available126 or with antithymocyteglobulin'27 128 but the numbers of patients were

too small to evaluate critically.Since 1970, there has been one major change;

there is now a clear rationale for the use ofimmunosuppressive drugs. Because of a single

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law-suit in the United States, there has beenlittle experience with these drugs in this country.As in 1970, the reports of azathioprine seempromising. As in 1970, there has been no con-trolled trial of effects that only appear gradually.Three deaths have been attributed to azathio-prine or its metabolite, mercaptopurinel20 123 129

but it is not known whether azathioprine is moreor less hazardous than prednisone, whether itshould be given alone or in combination withprednisone, or whether it improves the results ofthymectomy alone. Even the proper dosage isuncertain. That is, it is not clear whether anarbitrary dosage of 2-5 mg/kg is appropriate forall patients or whether the dosage should beincreased to cause mild leucopenia as evidenceof biological effect (but, presumably, with in-creased risk). The situation is not tidy.

PLASMAPHERESISThat myasthenia might be an autoimmune dis-order was first suggested by Smithers in 1959130;the theory captured attention after the seminalpaper of Simpson2 and the demonstration of anti-bodies to muscle striations by Strauss et a14 in1960. By the end of the decade, however, therewas much uncertainty because the striation-bind-ing antibodies were lacking in most cases, couldnot explain the disorder of neuromusculartransmission, and could not be demonstratedconsistently in neonatal myasthenia. Attentionwas therefore being directed to alterations ofcell-mediated immunity, when the first attemptswere made in 1969 to remove immunopathogensfrom the myasthenic patient. Since cell-mediatedmechanisms were suspected, it was thereforesurprising that the benefits of thoracic ductdrainage seemed to be due to something inplasma rather than the lymphocytes.131 132 Inretrospect, another observation of that time couldhave been due to removal of plasma, for aninfant with neonatal myasthenia improvedpromptly after an exchange transfusion for Rh-incompatibility.'33These early observations made more sense a

few years later, after the elucidation of experi-mental autoimmune myasthenia and the demon-stration of antibodies to AChR in humanpatients. The technology of human blood separa-tion had also advanced and it was thereforelogical to attempt to remove the pathogenic anti-bodies by plasma exchange, or plasmapheresis.The first report, by Pinching et al,134 had a majorimpact; there is now published information aboutthe use of this technique in 94 patientS'25 135-142

and 11 patients have been studied at the Colum-



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bia-Presbyterian Medical Center.143As usual, the first reports were most enthusias-

tic, reporting universal improvement in patientswho received prednisone and either azathioprineor cyclophosphamide in addition to plasma ex-change.134 135 But there have been some dis-appointments. Howard et al'37 reported improve-ment in all eight patients who received prednisoneas well but "not adequately" in five. Behanet al142 reported six failures in 21 patients whowere receiving both prednisone and azathioprineat the time of plasma exchange.With a procedure so new, it is not appropriate

to speak of "controversy" but there are certainlyunanswered questions, and we shall pose someof these.What are the risks of plasma exchange?Apparently not many. The worst on recordwere one fatality attributed to azathioprine142and one case of subacute bacterial endocarditis134in which a Scribner shunt had been used; venouscatheterisation usually provides adequate access.Susceptiibility to infection may increase andinfluenza-like syndromes may be more frequentafter plasma exchange.137 147 Mild transientworsening of myasthenia was reported only byLisak et al138 and there is no evidence of adverseeffect from loss of pyridostigmine or prednisonein the discarded plasma.How expensive is plasma exchange? In NewYork, it costs $350 for the disposable tubing usedin each exchange. To this must be added thecost of purchasing and maintaining the cellseparator, professional costs for physicians andnurses who perform the exchange, and hospitalcosts. The total could be at least $800 for eachtreatment. The procedure could be performed onsome ambulatory patients, but laboratory testsare necessary so hospital costs cannot be com-pletely eliminated.Can we predict, on clinical grounds, whichpatients are most likely to improve? Theanswer seems to be "No". Improvement hasbeen reported in patients with mild or severesymptoms, in the young and the elderly (althoughnot yet in many children); before or afterthymectomy; with or witihout prior or con-comitant administration of prednisone or im-munosu,ppressive drugs; and with or withoutthymoma. Con-genital myasthenia may or maynot be an exception; the procedure failed in twochildren'4' and one adult with lifelong symp-toms'43 but this need not imply universal failurein these cases.Can we predict improvement on the basis ofantibody titres? Because plasma exchange was

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introduced to decrease the titre of circulatingantibodies to AChR, it would seem logical toreserve the procedure for patients with hightitres of these antibodies, but there are severaltheoretical reasons why this might not be so: (1)Antibodies are not detected in all patients withmyasthenia gravis; depending upon the laboratoryand the method, abnormal ititres were present inas many as 85 %144 of patients or as few as50%. In either case, a substantial number lackthe antibodies. In six patients with congenitalmyasthenia antibodies were lacking.147 (2) Whenantibodies are present, there is no strict relationbetween the titre and severity of symptoms. (3)If antibodies to AChR cause the symptoms ofmyasthenia, these observations suggest that theamount of antibody bound to neuromuscularjunctions may not be proportionate to the titre ofcirculating an.tibody. (4) Alternatively, thebeneficial effects of plasma exchange could bedue to removal of a substance other than anti-body to AChR. For instance, plasma content ofthymic hormone decreases after thymectomy147and is probably also removed by plasma ex-change, or there may be changes in immunecomplexes'48 or other plasma constituents thathave not yet been identified.However, efficacy of a treatment can force us

to revise theory, and it is therefore necessary toevaluate the data. In general terms, and in mostpatients, AChR antibody titres have declined aspatients improved after plasmapheresis,136 '141

and two patients with congenital myasthenia wholacked antibody both failed to improve.'14 Butthere have been some notable exceptions.Newsom-Davis et al14' reported a significantdrop in antibody titre in one clinical failure ofplasma exchange. Dau et al'36 found comparablechanges in antibody titres of patients who showedlittle or much improvement. Howard et al'37reported improvement in two patients who lackeddetectable antibody, and we have seen one suchpatient.'43 It is therefore necessary to gather moredata about the relation of antibody responses toclinical improvement after plasma exchange.Is it necessary to administer prednisone or im-munosuppressive drugs for therapeutic benefit ofplasma exchange? This question cannot beanswered from available data and it is of majorpractical importance because of the risks of thedrugs. The question cannot be answered becausealmost all of the published cases were receivingsteroids or immunosuppressive drugs. BothNewsom-Davis et al'41 and Dau et al'36 wereimpressed by the theory (that drugs arenecessary to delay reappearance of the pathogenic



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antibodies) and by a few failures in patients whodid not respond without these adjuvants. Ad-ditionally, the two groups noted "rebound" infour patients who were not receiving azathio-prine; that is, antibody titres after -plasma ex-change gradually increased to levels higher thanthe original as symptoms returned. However, oneof the patients of Dau et al"36 was apparentlybetter clinically at the time of antibody "re-bound" and symptoms returned only later. Lisakand Schotiand'38 reported that seven of ninepatients 'shave done well without additionaltreatment".

Therefore, the role of prednisone and im-munosuppressive drugs is not yet defined.Does plasmapheresis add to the benefit of chronicazathioprine therapy alone? While documentingthe acutie benefits of plasma exchange, NewEom-Davis et al141 found that the long-term effects ofazathioprine alone were not improved by inter-mittent plasma exchange.What are the indications for plasmapheresis?Considering the costs and still unknown risks,almost all investigators have reserved plasma-pheresis for patients who are seriously disabled,usually after other forms of tre-atment havefailed. However, the procedure could be usedbefore other treatments in some circumstances.For instance, it may be effective in the treatmentof myasthenic crisis (defined as the need forassisted respiration) if patients do not recoverindependent ventilation in a few days. Or it couldbe used to improve the clinical condition ofa patient who is being prepared for thymectomy,hoping to make the postoperative course lessarduous. For patients who have failed torespond to thymectomy. prednisone or im-munosuppressive drugs, plasma exchange hasalready been of value in providing sustainedimprovement for weeks or months. For somepatients, intermittent plasma exchange may be asuitable alternative to the risks of chronictherapy with steroids or immunosuppressivedrugs.Are controlled trials necessary to evaluate thetherapeutic effects of plasmapheresis? If apatient has staible and disab-ling symptoms ofmyasthenia for several months, and if thesesymptoms improve obiectively within a few daysof a series of plasma exchanges, controlled trialsseem superfluous. Indeed, it would probably beethically impossible to design a controlled trialthat would include sham plasmapheresis. In thisregard plasmapheresis differs from the problemsgenerated by interventions that may take weeks,months or years to have an effect, as in the use of

Lewis P Rowland

thymectomy, steroids, or immunosuppressivedrugs. Another aspect of plasma exchange, how-ever, poses a different problem. The procedure isalready being used to treat patients in respiratorycrisis, and this may be one of the most importantindications. However, it will be difficult to as-certain that treatment with plasmapheresisactually shortens the duration of these episodesof crisis. Because crisis seems to be becomingless frequent, it is not likely that controlled trialscan be done in any one institution and we willprobably have to compare the duration of crisisbefore and after the time plasma exchange wasintroduced.

Conclusion

This essay mav seem nihilistic to some; it is notmeant to be. In our centre, we tend to recom-mend thymectomy more and more. If thepatient does not then improve within a reasonableperiod of time (and "reasonable" permits con-sideratble laititude, depending upon the severityof symptoms and the patient's desires as well asthe judgement of one or more physicians), thenwe use prednisone. If there is still no im-provement after some uncertain period of time,or if there have been serious side-effects, wethen use azathioprine. We have begun to useplasmapheresis, but everyone recognises the un-certainty of the proper application of thistechnique. Sometimes, if a patient has a crisisbefore thymectomy, steroids or immunosuppres-sive drugs are used before the operation.

In practice, therefore, we behave like mostother physicians who care for patients withmyasthenia. Therapeutic nihilism can go just sofar. But I am repeatedly concerned about whatseems to 'be uncritical acceptance of newtherapies. Each of the major approaches to alterthe course of the disease (thymectomy, pred-nisone, immunosuppressive drugs) has bfeenendorsed enthusiastically without controlledtrials. Yet if any were the panacea that originalreports claimed, would plasmapheresis be greetedso warmly?

Indeed, where do all the subjects forplasmapheresis come from, if thymectomy,prednisone and azathioprine are uniformlybeneficial?These techniques are now all encrusted as

"accepted practice" and they bear the sacredimprimatur of "the literature". It becomes in-creasingly difficult to justify, on ethical grounds.a controlled trial. Yet for treatments that requiremonths or years to bestow benefit, and for a



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Table Thirty unanswered questions about thetherapy of myasthenia gravis

I How should we determine the optimal dose of a cholinergicdrug ?

2 Is one cholinergic drug more effective than another?3 Does cholinergic crisis occur in patients taking, by mouth, con-

ventional reversible inhibitors of anticholinesterase?4 Is the edrophonium test of value in determining optimal dosage

or in defining cholinergic crisis?5 In the management of myasthenic crisis, should cholinergic drug

therapy be discontinued? If so, when should it be re-instituted?6 Would management be improved by monitoring blood levels of

cholinergic drugs?7 Is thymectomy of proven value in the treatment of myasthenia?8 If so, how does it work?9 Which patients are most likely to improve after thymectomy?10 Does thymectomy prevent progression of myasthenia to a more

serious disease? Should every patient with generalised myastheniahave thymectomy? As soon as the diagnosis is made?

11 Should prednisone be given routinely before thymectomy?12 Should thymectomy be done before adolescence or after some

arbitrary older age (for example after 65 years)?13 Is cervical thymectomy as effective as trans-sternal thymectomy?14 Is prednisone of proven value in treating myasthenia?15 Is one corticosteroid preferable to another?16 What dosage should be used? For how long?17 If there is no improvement, how long should steroid therapy be

continued before deeming the trial a failure?18 Are steroids safer or more hazardous than azathioprine?19 How should properly informed consent be obtained before a

patient embarks upon prolonged steroid therapy?20 Are immunosuppressive drugs of proven value in treating

myasthenia?21 Is any one immunosuppressive drug preferable to another?22 Should immunosuppressive drugs be given before, after, or with

steroid drugs?23 What dosage should be used? Should it be arbitrary, according

to body weight, or should mild leucopenia be induced?24 Which patients will benefit most from plasmapheresis?25 Does plasmapheresis shorten the duration of myasthenic crisis?26 Is plasmapheresis of benefit in preparing patients for thymectomy?27 Is there a role for plasmapheresis in long-term management of

myasthenia?28 Is plasmapheresis beneficial because it removes antibody to

AChR or because it removes something else?29 Can plasmapheresis be beneficial if antibodies to AChR are not

detected in an individual patient?30 Is it necessary to administer prednisone or azathioprine for either

acuLte or long-lasting benefit of plasmapheresis?

disease whose "natural" history is not nowknown, controls would certainly seem desirable.If controlled studies had been done early, wewould not be left with so many unansweredquestions (table). Clinicians must decide whethqrto use thymectomy, plasmapheresis, steroids orimmunosuppressive drugs, in what sequence orcombinations, and when to deem lack of im-provement a sign for a different therapeuticapproach. Even proponents of specific regimensmust admit that the guidelines are not clear.That is the problem, in general terms. It may

all sort out in time. In the meantime, eachcentre will proceed according to the preferencesof local physicians. Certainly, myasthenia is notthe grave disease it was only 20 years ago; wemust be doing something right.

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The author's views have been tempered byassociation with other clinical investigators,including Paul FA Hoefer, Henry Aranow Jr,Audrey S Penn, Robert E Lovelace, MROlarte, and Richard Schoenfeldt. Alfred JaretzkiIII has provided thoughful leadership in questionsabout thymectomy. George Zito gave generousassistance in the analysis of data about steroidtherapy. To all of them I am indebted, but noneof them is responsible for any errors, intemperatecomments, or apparent lapses of judgement inthis essay.

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2 Simpson J. Myasthenia gravis: a new hypoth-esis. Scot Med J 1960; 5:419-36.

3 Simpson JA. A morphological explanation of thetransmission defect in myasthenia gravis. AnnNY Acad Sci 1971; 183:241-7.

4 Strauss AJL, Seegal BC, Hsu KC, BurkholderPM, Nastuk WL, Osserman KE. Immunofluor-escence demonstration of a muscle-bindingcomplement-fixing serum globulin fraction inmyasthenia gravis. Proc Soc Exp Biol Med 1960;105:184-91.

5 Engel AG, Santa T. Histometric analysis of theultrastructure of the neuromuscular junction inmyasthenia gravis and in the myasthenic syn-drome. Ann NY Acad Sci 1971; 183:46-63.

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12 Kornfeld P, Mittag TN, Genkins G, Horowitz S,Papatestas AE. Studies in myasthenia gravis:pyridostigmine-Cl4 metabolism after thymectomy.Neurology (Minneap) 1975; 25:998-9.

13 Chan K, Calvey TN. Renal clearance of pyri-dostigmine in patients with myasthenia gravis.Eur Neurol 1977; 16:69-72.

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Controversies about the treatment myasthenia gravis of Neurology, Neurosurgery, and Psychiatry, 1980, 43, 644-659 Controversies aboutthe treatment of myasthenia gravis LEWISP ROWLAND