Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from POSTGRAD. MED. J. (1965), 41, 356

I. T. DRAPER, M.R.C.P.E. Neurological Unit, Northern General Hospital, Edinburgh.

Definition immune mechanism has been postulated as an MYASTHENIA GRAVIS is a disorder of neuro- atiological factor in the causation of these muscular conduction. It is characterised disorders and it may be that the myasthenic clinically by an excessive degree of weakness patient is genetically predisposed to his disease which develops in the affected muscles during (Simpson, 1960). sustained or repeated contraction. In the early stages of the illness, at least, the strength is Onset partially or fully restored by rest or the The onset of the disease is commonly in- administration of anticholinesterase drugs in sidious, and may at first be neglected by the the appropriate dosage. patient. In such circumstances it is difficult Natural History to establish any precipitating factor. In a Incidence and at onset large number of cases, however, the first age recognised symptoms come on with dramatic The incidence of the disease in the total suddenness. In such a case the precipitating population has been estimated between 1 in factor is more readily identified. This can becopyright. 40,000 (Garland and Clark, 1956) and 1 in a physical or emotional shock, and one may 15 to 20,000 (Eaton, 1958), and it is found be tempted to diagnose hysteria, particularly more commonly in women, in a proportion if the patient is examined after a period of rest 3 to 2 (Schwab and Leland, 1953; Ferguson, when the symptoms and signs have disappeared. Hutchinson and Liversedge, 1955). The stress associated with injury and infection, Although myasthenia gravis may develop at particularly lobar pneumonia, has been related any age, in either sex, it occurs most commonly to the onset of myasthenia gravis. The first between the ages of 15 and 65 years. The in the months of majority of new cases in women appears during symptom may appear early http://pmj.bmj.com/ reproductive life so that the mean age of onset pregnancy, or during the puerperium. In an is 26 years. In men the distribution curve is established case, sudden worsening may appear more symmetrical and the mean age of onset to be precipitated by similar circumstances. is 31 years (Simpson, 1958). The relationship The disease may first be recognised by the of myasthenia gravis to pregnancy and the patient's abnormal response to drugs. The menstrual cycle is considered below. patient with myasthenia gravis is especially occur in sensitive to curare and there may be a failure Progressive myasthenia gravis may to establish normal respiration after surgery on October 2, 2021 by guest. Protected childhood, and a rare, transient form, neonatal when muscle relaxants have been used. There myasthenia is sometimes found in the children is uncertainty about the role of procaine as a born to women with myasthenia. precipitant. I examined an elderly woman Family History with ocular myasthenia, whose first symptoms Several authors have recorded the multiple developed after an operation for cataract, incidence of myasthenia gravis in one family performed under procaine anesthesia. (Oppenheim, 1898; Rothbart, 1937; Teng and Osserman, 1956), but on present evidence this Course of the disease cannot be considered as a familial disease The susceptibility of the affected muscles to (Simpson, 1964). However, a careful scrutiny rapidly increasing weakness or "fatigue" has of the family histories of patients with already been stressed. Unlike normal fatigue myasthenia gravis reveals an unusual incidence myasthenic "fatigue" proceeds to complete of thyroid disease and rheumatoid arthritis. paralysis. Most patients feel stronger in the In common with myasthenia gravis, an auto- morning and fatigue more readily in the Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 357

12-20o '9090 4-8 60-70 copyright. 1-4.u: 50' 60 ONSET TOTAL

FIG. 1.-Percentages of cases in which various muscle groups are affected at the onset (left of key) and

at some time during the illness (right of key). http://pmj.bmj.com/ Simpson, J. A. (1960). Scot. Med. J., 5, 419. afternoon or evening. Paradoxically, some some improvement during the later months patients feel at their worst in the morning (Viets, Schwab and Brazier, 1942). Relapse improving as the day goes on. A comparable may occur during the puerperium (Fraser and situation exists in that some patients feel that Turner, 1953). There is often a transient can "work off" weakness but it is uncertain they incipient by premenstrual worsening, on October 2, 2021 by guest. Protected active effort. Apart from physical effort there whether this represents a true physical impair- are environmental factors which influence the ment. Objective evidence of a disturbance course of the illness. Extremes of temperature associated with menstruation seemed to be cause an increase in weakness: the very local provided by Schrire (1959) who described a increase in temperature experienced in a hot reduction in the excretion of pregnandiol by bath may exaggerate the weakness. One or two non-pregnant myasthenic women, but Simpson patients have described a worsening of ocular (1964) was unable to confirm these findings. symptoms in bright sunshine perhaps provoked The patient's emotional state plays a great by actively screwing up their eyes. part in determining his response. Enthusiasm Reference has been made to the higher and confidence in the patient and the attending incidence of myasthenia gravis in women of physician auger well in the management of the reproductive age and the fluctuations experi- disease. enced during pregnancy and the puerperium. While minor fluctuations in the severity of The likelihood of deterioration is greatest the disease are common, complete remission is during the first trimester of pregnancy, with relatively rare. The most marked variations in Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 358 POSTGRADUATE MEDICAL JOURNAL June, 1965 severity occur within the first seven years of Permanent "myopathic" changes may develop the illness and the risk of death, directly in affected muscles. Simpson recorded myo- attributable to the myasthenic process is also pathic changes in 10% of the females and greatest during this period. By the same token 20% of the males in his series (Simpson, 1958). any worthwhile remission is more likely to These changes are most commonly found in occur during the first seven years. It is rare the extra-ocular muscles, the triceps brachii, for a patient to have more than one complete iliopsoas, quadriceps femoris and the tongue. remission. Such changes are uncommon in muscles which After seven years, dramatic changes in the have been affected for only a short time. The state of the disease are uncommon and it is duration of weakness is not the only factor, then said to have become stabilised. Thymec- however, as muscles which have been affected tomy as a treatment for myasthenia gravis is for many years may never show myopathic most likely to be effective if undertaken during responses. When assessing the patient's reaction the pre-stable period (Simpson 1958, 1960). to anticholinesterase drugs, the possibility of permanent changes must be considered so that Distribution of the affected muscles a localised failure of response is not necessarily Myasthenia gravis may affect any voluntary as a result. muscle in the body: the smooth muscles are interpreted negative not affected. It is unusual for all the muscles to be affected at any one time. Characteristically, Clinical features some muscles are severely affected, some more The most outstanding symptom is the slightly, and some not at all. By summarising development of unusual weakness after a short the extent of the disease in a large number of period of effort. patients it is possible to construct a statistical Involvement of the extra-ocular muscles gives distribution of the affected muscles (Fig. 1 rise to diplopia, which may increase gradually, (Simpson, 1960)). or may develop suddenly so that objects appear

The muscles around the eyes, the extra-ocular to split or slip to one side. Such symptomscopyright. muscles, the levators of the upper lids and the may occur while the patient is concentrating orbiculares oculi, are most often found to be on close, fine work, and will often be relieved involved. Indeed it is uncommon for a patient by closing the eyes for a few moments or with myasthenia gravis to have no symptoms looking away to a more distant object. When or signs referable to these muscles. A too rigid examining eye movements, the patient's ability adherence to this statement, however, will result to maintain his gaze should be tested. During in some atypical cases remaining undiagnosed. this examination an increasing strabismus may, The muscles of the face, tongue, jaw and develop and nystagmoid jerks are commonly palate, and pharynx are almost as frequently seen. These represent the development ofhttp://pmj.bmj.com/ affected as those around the eyes. These are weakness, with a recovery of strength after a followed by the muscles of the neck, shoulders momentary rest. and pelvic girdle. The peripheral limb muscles, Unilateral ptosis may relieve the patient of muscles of the trunk and respiration are less his diplopia. Ptosis may be seen to develop commonly involved. during the examination and minimal degrees Not infrequently the disease appears to be of ptosis are sometimes compensated by over- limited to one group of muscles, and may action of the frontalis muscle on that side become static. This occurs most commonly in (Fig. 2). The patient may be unable to close on October 2, 2021 by guest. Protected the muscles around the eyes, and it has promp- his eyes tightly, due to weakness of the ted some physicians to regard "ocular orbiculares oculi. He may then complain that myasthenia" as a separate entity (Grob, 1953). soap gets into his eyes when he washes his Careful diagnostic techniques, clinical, pharma- face. When he closes his eyes tightly, the cological and electromyographic, will often eyelashes which are normally buried in the reveal a more widespread involvement. folds of skin, remain visible. The eyelids may In contrast to this static phase, there may also be prised apart with unusual ease. be surprisingly rapid changes in the distribution Weakness of the muscles of mastication of affected muscles. This is seen most strikingly becomes most prominent during a meal. The in the involvement of the levators of the upper patient often complains that he has difficulty eyelids. The patient may describe how he had in chewing meat. As with the other symptoms, a unilateral fixed or fatiguable ptosis, when he can usually start chewing with no difficulty,, quite suddenly, the affected eye opened and but as the meal progresses the weakness in- the other eyelid promptly began to droop. creases. Involvement of the facial muscles and Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 359

FIG. 2.-Patient with florid myasthenia gravis. FIG. 3.-Improvement during the test. tongue adds to the difficulty in eating and clearing the mouth. A fatiguable dysphagia is a common and weakness of complication, the copyright. soft palate results in the nasal regurgitation of fluids. Dysphagia may be demonstrated by the fluoroscopic screening of a barium swallow (Viets, 1947). The barium remains pooled in the pyriform fossa, and the injection of an anticholinesterase drug will then restore normal passage down the esophagus. Facial weakness may let the lips droop open and allow saliva to dribble from the mouth. Attempts to smile http://pmj.bmj.com/ result in the characteristic snarl (Fig. 4). It may be difficult for the patient to protrude his tongue, and selective involvement of the lingual muscles causes a triple groove appearance. This grooving can often be abolished by adequate medication, but myo- pathic changes may make it irreversible. "Bulbar weakness" such as described in this on October 2, 2021 by guest. Protected paragraph, also gives rise to a peculiar thicken- ing of the speech and fading of the voice. FIG. 4.-The myasthenic "snarl". The extensor muscles of the neck are usually more severely affected than the flexors and the gives rise to difficulty in climbing stairs, or patient with florid myasthenia gravis can often impairs the stability of the hip, so that the be recognised, supporting his head and jaw on patient walks with a waddling gait or falls his hand (Fig. 2). due to sudden weakness of the glutei. Involvement of the muscles of the shoulder It is relatively uncommon for the respiratory girdle is only apparent when the patient is muscles to be affected, but when they are, this obliged to raise his arms above his head. presents a serious problem of management. Women may find that routine hair-dressing Exercise tolerance is severely limited, and causes extreme fatigue: similarly, hanging up failure of the respiratory musculature is washing on a clothes-line can first bring this apparent in the fading voice, and the rapid, symptom to notice. Pelvic girdle weakness shallow respiration. While the respiratory Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 360 POSTGRADUATE MEDICAL JOURNAL June, 1965 excursion may be sufficient for normal breath- and Schotland summarised the 20 cases ing, the cough is often too weak to clear reported in the literature up to that time. accumulated mucus or inhaled food particles. Millichamp and Dodge (1960) added a further In contrast to the striking muscular weakness, 10 cases. In this form of the disease there is the tendon reflexes are retained and are some- a generalised involvement of all the voluntary times unusually brisk. If the associated muscles musculature, although the ocular signs which are affected by the disease, the tendon jerk dominate the adult symptomatology may not will also show progressive fatiguability if it is be so apparent. The child has a feeble cry, elicited repeatedly. The plantar responses are breathes with difficulty, can scarcely feed and always flexor. A widespread absence of tendon lies limp in his cradle. The response to anti- reflexes in a patient who exhibits myasthenic cholinesterase medication is dramatic. The fatiguability should suggest a diagnosis of symptoms resolve within 2 to 10 weeks after symptomatic myasthenia (see below). A which the child flourishes without medication. diminished tricep jerk is not uncommonly It appears that there is a transplacental leak found and is the result of myopathic changes of some unknown humoral substance, from in that muscle. the mother to the child, which interferes with It is most unusual to find objective evidence neuromuscular conduction, but does not cause of sensory change. Osserman, Kornfeld, Cohen, permanent damage to the motor end plate. Lentins, Mendelow, Goldberg, Windsley and Laplan (1958) described sensory symptoms in Myasthenic reactions in the myopathies 14% of the cases in their series. Symptoms Polymyositis, dermatomyositis and carcino- such as aching in neck and shoulders, and matous myopathy may simulate myasthenia headache, may be due to abnormal posture gravis clinically, pharmacologically and electro- and tension on pain-sensitive structures due to myographically (Benedek, 1944; Christensen weakness of the muscles. Tingling paraesthesiae and Levison, 1950; Ragan, 1950; Eaton and in the hands have been ascribed to compression Lambert, 1957; Walton and Adams,

1958;copyright. of the brachial plexus resulting from a dropped Brain and Henson, 1958). There may be an shoulder syndrome. Some sensory disorders abnormal fatiguability of the affected muscles such as anosmia (Alajouanine, Castaigne, Niek, and at first some response to the administration Contamin and Lhermitte, 1957) and ageusia of anticholinesterase drugs. The distribution of may indicate a direct involvement of sensory the affected muscles is unlike that of myasthenia fibres (Simpson, 1964). gravis in that the muscles around the eyes, and the bulbar muscles are usually spared, while Relationship with other diseases the proximal limb muscles bear the brunt of has been in as the disease. In contrast Hyperthyroidism recognised to true myastheniahttp://pmj.bmj.com/ many as 5% of all patients with myasthenia gravis the tendon reflexes are diminished or gravis (Millikan and Haines, 1953). Simpson absent in the myasthenic syndrome and the (1958) who included all forms of thyroid dis- initial response to anticholinesterase is order found an incidence of 18% in females soon lost. drugs and 9% in males. Osserman and others (1958), Simpson (1960) and Storm-Mathisen (1961) Pathology have published large series of cases The thymus recording the occurrence of other diseases, on October 2, 2021 by guest. Protected rheumatoid The thymus is abnormal in the majority of notably arthritis, systemic lupus patients with myasthenia gravis. It may be erythematosus, anaemia, epilepsy and psychotic of normal size or disorders. The occurrence of these conditions hypertrophied, and shows well be but extensive lymphoid hyperplasia throughout its may coincidental, Simpson (1964) structure. Numerous germinal centres are seen insists that significant correlations will be in the medulla (Castleman and Norris, 1949). established only if the attending physicians A tumour adopt a more open-minded approach to the thymic (thymoma) is found in 10 collection of to 20% of all cases. Myasthenia gravis case material. associated with thymoma develops later in life, and is more common in men. The medical Neonatal myasthenia control of symptoms is often difficult and the A transient form of myasthenia in babies results of surgery are frequently disappointing. born to women with myasthenia gravis was The tumour is usually benign and may show first recognised and treated by Strickroot, cyst formation and calcification. Most Schaeffer and Bergo (1942) and in 1960 Greer frequently the tumour lies in the anterior Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 361 mediastinum and can be recognised on plain vesicles near the nerve ending. The acetyl- X-rays of the chest. Both P.A. and lateral diffuses across the junction to the views should be obtained. The thymoma is membrane of the motor end-plate. Here the occasionally malignant invading the mediastinal molecules of key into the structures and the local lymph glands. receptor protein. This results in an alteration of the permeability of the motor end-plate so Pathology of nerve and muscle that sodium ions diffuse into the cell and an Although attention has been focused on the area of local depolarisation occurs-the end- neuromuscular junction as the site of the plate potential. If the end-plate potential is disorder, pathological changes are also found sufficiently large it will initiate a self-propagating in the motor nerves and the muscle. wave of depolarisation which spreads across Coers and Woolf (1954, 1959), using a the muscle membrane-the muscle action supravital methylene blue stain and a supple- potential, and the contractile elements of the mentary stain for cholinesterase, showed two muscle fibre shorten. The restitution of the distinctive abnormalities in the structure of the ionic constituents of the muscle cell is achieved nerves from patients with myasthenia gravis. by a pump mechanism and the cell is then One they called the "dystrophic type" in which repolarised. Under normal circumstances the there were increased branchings of the terminal acetylcholine is rapidly hydrolysed by the nerve arborisation. In the other, the "dysplasic enzyme cholinesterase which is present in the type", the terminal knobs were reduced in region of the end plates. If acetylcholine number and arranged along elongated motor persists at the receptor site the normal end plates. The relationship of these changes refractoriness of the junction is prolonged. This to the myasthenic defect is the subject of is conventionally called a depolarisation block, controversy. Bickerstaff and Woolf (1960) although the end-plate membrane is in fact regard them as evidence of a coincident process repolarised (Thesleff, 1955; Katz and Thesleff, of degeneration and repair and not necessarily 1957). A disorder of this sequence of events the primary disorder. However, MacDermot results in delay or interruption of the conduction copyright. (1960) described these changes in what were of the impulse across the junction and is known clinically and electromyographically unaffected as neuromuscular block. tissues. A refined electrophysiological technique for Accumulations of mononuclear cells and the investigation of neuromuscular conduction lymphocytes in the perivascular spaces known was described by Harvey and Masland (1941) as lymphorrhages are commonly found in the and a more complete account together with muscles of patients with myasthenia gravis. the results of a series of pharmacological Their distribution bears little apparent relation- experiments was given Grob, Johns and by http://pmj.bmj.com/ ship to the distribution of clinically affected Harvey (1956). These "studies in neuro- muscles. Furthermore such changes are muscular function" were performed on normal commonly found in other disorders. Russell subjects and patients with myasthenia gravis. (1953) classified the muscle changes in The results obtained in the patients with myasthenia gravis in three groups: generalised myasthenia gravis are summarised Type I - an acute coagulative necrosis of briefly- muscle fibres 1. The II - the amplitude of the muscle action Type lymphorrhage potential evoked by a single supramaximal on October 2, 2021 by guest. Protected Type III - focal non-inflammatory swelling nerve stimulus was lower than that in the of the muscle fibre. normal It should be noted that she did not consider subject. of these to 2. If paired supramaximal stimuli were any changes be specific for delivered the amplitude of the second muscle myasthenia gravis. action potential was lower than the first when the interval between the stimuli ranged from Pathophysiology 16 m. secs. to 0.5 or 1.0 sec. (Fig. 5). The transmission of the motor across 3. the impulse Repetitive nerve stimulation at frequencies neuromuscular junction in the normal as low as 5 per second caused an immediate subject comprises the following sequence of reduction in the of the muscle events. The impulse travelled down amplitude action the motor having potentials followed by a return towards normal nerve arrives at the axon terminal. and then a more gradual fall Its depolarisation is the dis- 6 expotential of accompanied by (Figs. & 7). charge acetylcholine from submicroscopic 4. Following a period of tetanic nerve Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 362 POSTGRADUATE MEDICAL JOURNAL June, 1965

Al A2 BI B2 FIG. 5.-Paired stimuli at (i) half minute and (ii) minute intervals, showing the decreased amplitude copyright. of the second muscle action potential in the patient with myasthenia gravis (see legend opposite). http://pmj.bmj.com/ on October 2, 2021 by guest. Protected

FIG. 6.-Repetitive nerve stimulation at 5 per second, showing an immediate reduction in the amplitude of the muscle action potentials followed by a temporary return to normal in the patient with myasthenia gravis (see legend opposite). Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 363

A copyright. http://pmj.bmj.com/ on October 2, 2021 by guest. Protected

IE I B FIG. 7.-Repetitive nerve stimulation at 10 per second, showing the myasthenic decrement and the post- tetanic facilitation. FIG. 5-7.-Electromyograms from a normal subject A, and a patient with myasthenia gravis B. Supramaximal stimuli to ulnar nerve and the action potentials recorded from the abductor digiti minimi by surface electrodes. Time trace 100 m. secs. Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 364 POSTGRADUATE MEDICAL JOURNAL June, 1965 stimulation the response to a further stimulus a structural abnormality of the affected motor after an interval of more than one second end-plates (Zaimis, 1953). This would raise exceeded the amplitude of the initial stimulus the threshold for depolarisation and possibly (Fig. 7). This they termed post-tetanic bestow a peculiar affinity for the transmitter facilitation; it was never seen in normal subjects. substance or its metabolite. This would account The authors concluded that the type of for the initial weakness and the progressively neuromuscular block exhibited by patients with increasing neuromuscular block. The likelihood myasthenia gravis resembled that seen in the of a structural abnormality at the motor end- experimental animal as a result of partial plate can be questioned on the grounds of curarisation. The molecule of curare bears a the variability of the course of the disease with structural similarity to that of acetylcholine relatively sudden and complete remissions and and thus competes for receptor sites at the relapses. There is the further evidence of membrane of the motor end-plate. It does neonatal myasthenia in which case the neuro- not cause depolarisation of the membrane muscular block is initially severe but resolves (Castillo and Katz, 1957) but it prevents the within a few weeks. autogenous acetylcholine released from the Simpson (1960) proposed the hypothesis of nerve endings from finding a receptor site and an auto-immune mechanism which would in turn depolarising the motor end-plate. account for many of these apparently anomalous Unlike the block induced by curare, the features. A circulating antibody if derived from myasthenic defect is progressively intensified by the motor end-plate would presumably have continuous nerve stimulation. Grob and his a molecular structure which was similar to colleagues postulated that choline derived from that of acetylcholine and would compete with the break-down of autogenous acetylcholine it for the receptor sites. Furthermore, the might be the blocking agent. The hypothesis antibody would have a specific life-span and of a circulating curare-like substance gains thus dramatic changes in the clinical state support from a paper by Walker (1938). She would be accounted for. It might also pass described how the muscles of the forearm were the placental barrier and give rise to neonatalcopyright. fatigued by exercise while the circulation was myasthenia gravis. occluded with a tourniquet. The tourniquet Independently Nastuk and others (1960) had was then released and the patient developed found that the injection of serum from a patient ptosis. This experiment was repeated by Wilson with myasthenia gravis caused cytolysis in frog and Stoner (1944) with essentially similar muscle. They, too, concluded that an auto- results. Blood samples were also taken from immune mechanism might be responsible. the occluded arm before and after exercise. Strauss and others (1960) reported the presence The serum was then applied to a frog nerve- of a muscle-binding, complement-fixing globulin muscle preparation and it was shown that a in the serum of patients with myasthenia gravis.http://pmj.bmj.com/ considerable degree of neuromuscular block Beutner, Witebsky, Licken and Adler (1962) developed. However, in this department we and Feltkamp, Geld, Kruyff and Oosterhuis have been unable to reproduce the Walker (1963) confirmed these results, but paradoxically effect and our failure has been shared by other Simpson (1964a) reported a failure to show the authors (Nastuk, Straus and Osserman, 1959; specific changes with the immunofluorescence Lammers and Most van Spijk, 1954). technique.

The occurrence of neonatal myasthenia is There are many discrepancies in these reports on October 2, 2021 by guest. Protected still perhaps the best evidence of a humoral and it appears significant that positive results neuromuscular blocking agent. correlate with the presence of a thymoma. Desmedt (1957) published results which were Strauss's report of pauscle-binding globulin similar to those of Grob and others (1956), and would be out of keeping with the fluctuating compared the myasthenic defect with that state of true myasthenia gravis and more like obtained by the administration of hemicho- the severe and progressive form of the disease linium (1958). Hemicholinium inhibits the which is found accompanying a thymoma. As synthesis of acetylcholine at the nerve ending yet unrecognised antibodies with different organ and Desmedt reasoned that in myasthenia gravis specificities may well be present. the conduction block was due to a prejunctional failure of acetylcholine synthesis. However, Diagnosis the published evidence for such a hypothesis The methods of diagnosis are threefold: is inconclusive (Simpson, 1964b). clinical, pharmacological and electromyo- It has been suggested that there might be graphic. Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 365 The Clinical Diagnosis cholinesterase drugs (Viets and Schwab, 1935). The essential criterion for a clinical diagnosis Two anticholinesterase drugs, edrophonium of myasthenia gravis is evidence of an abnormal chloride (Tensilon) and methyl degree of weakness developing during sustained sulphate (Prostigmin) are routinely used in or repeated muscular effort. The diagnosis may diagnosis. be suggested by the history, and the examination Edrophonium (Osserman and Kaplan, 1952) of the patient must be designed to test his acts rapidly and is thus very convenient for use response to exercise. Whenever possible an in an outpatient department. The anti- objective measurement should be made in cholinesterase effect is similarly shortlived so preference to the examiner's subjective that any ill effects disappear within 5 minutes. assessment. In experienced hands it alone is often sufficient (1) With the patient lying on the examination to establish the diagnosis, but I do not agree couch he is asked to raise his right leg and to with Osserman (1958) who claimed that all the keep it elevated for as long as possible. This information required could be obtained with is timed and the test is repeated with the left Tensilon. The very brevity of its effect allows leg. the physician to examine only one or two (2) He is asked to lift his head from the muscle groups, so that the occurrence of couch and to keep his neck flexed for as long permanent myopathic changes may give rise as possible. This is timed. to a false negative interpretation. (3) Sitting upright he is asked to raise his Edrophonium (Tensilon) Test. Having made arms to the horizontal and to maintain this a baseline examination of the patient, 2 mg. posture. This is timed for the right and left (0.2 ml.) of edrophonium are given by intra- arm. venous injection. If there is no response within (4) The vital capacity should be estimated, one minute a further 8 mg. (0.8 ml.) are either by spirometry or by asking the patient injected. Non-myasthenic subjects show no to count out loud during one breath after improvement in their muscle strength and maximum inspiration. Normal individuals can fasciculations are frequently seen in the copyright. count beyond 30 on one breath. Any fading orbicularis oculi, with watering of the eyes. of the voice is recorded. The strength of the The patient with myasthenia gravis shows an cough is noted. improvement in strength within one minute (5) The range of eye movements is assessed of the injection, and the occurrence of side and the palpebral fissures are measured. The effects is minimal (Fig. 3). The betterment palpebral fissures are again measured after the usually persists for less than three minutes and patient has tried to maintain a maximum ver- a repeated examination after this time shows tical gaze for one minute. that the weakness has returned. previous http://pmj.bmj.com/ (6) The strength of jaw closure, jaw opening Neostigmine (Prostigmin) Test. The delayed and eye closure are assessed. onset and prolonged effect allow the examiner While attempting to maintain the required to make a more complete assessment than is posture, the limbs may fall apparently possible during the edrophonium test. A base- exhausted, only to recover strength a moment line physical examination is made and 0.6 mg. later. This may also affect the eyelids, causing atropine sulphate are given i.m. The patient a fluttering effect. This response should not be is re-examined after 15 as a minutes. Any change regarded hysterical manifestation, but can be discounted as a false positive response. on October 2, 2021 by guest. Protected may be accounted for by the phenomenon of 1-1.5 mg. neostigmine methyl sulphate is in- post-tetanic facilitation (p. 361). jected i.m. The effect is seen within 10 to An accurate record of these results is 30 minutes. The duration of the effect is from essential, as it is only by comparison of 2 to 3 hours, and a complete physical and muscular strength on different occasions and at electromyographic evaluation can be made different times of the day that the fluctuations during this period. There should be an of the disease can be recognised. This is unequivocal objective improvement in the especially important when the response to performance of the physical tests if a positive treatment is being assessed. diagnosis of myasthenia gravis is to be made. In rare instances it may be necessary to use The Pharmacological Diagnosis one of the provocative tests. The patient with The diagnosis is not complete until it has myasthenia gravis may be extremely sensitive been shown that the patient's muscular strength to a small dose of curare. The curare sensitivity can be restored by the administration of anti- test is thus a dangerous procedure and should Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 366 POSTGRADUATE MEDICAL JOURNAL June, 1965 not be undertaken unless there is serious doubt conditions an adequate control of symptoms about the diagnosis and only if adequate can be achieved in most cases with the ap- measures for resuscitation including assisted propriate drugs. The underlying disease is respiration are available. seldom cured and the fluctuations in its severity Curare Sensitivity Test. 3 mg. of d-tubo- necessitate frequent reappraisal of the drug curarine per 18 kg. body weight is the requirements. There is no standard dose of intravenous curarising dose for a normal medication, but the appropriate dose must be individual. The patient is given 2% of this determined for the individual. Overdosage dose. If no weakness develops within 5 minutes gives rise to a clinical picture which to the of the injection, 5% of the estimated dose is inexperienced observer may be confused with given (Bennet and Cash, 1943). A larger dose underdosage. should not be used, as some otherwise normal Although there is still controversy regarding subjects are made weak by as little as 10% the site of action of the anticholinesterase drugs of the usual curarising dose. The test seems it is generally agreed that they increase the even less valuable in light of a report of a effectiveness of autogenous acetylcholine at the normal resistance to curare shown by some neuromuscular junction. This is the nicotinic patients with myasthenia gravis (Pelikan, Tether effect. They also have a muscarinic effect, and Unna, 1953). stimulating smooth muscle and increasing A similar sensitivity test utilising quinine glandular secretion. These are regarded as bisulphate was described by Eaton (1943). It side effects, and include excessive bowel action has the serious disadvantage that the weakness with borborygmi, colic and diarrhoea; sweating, induced by quinine bisulphate, unlike that hypersalivation and excessive production of resulting from curarisation, is not reversible by tears and bronchial secretions; and constriction anticholinesterase drugs. of the pupils. Patients with myasthenia gravis The unusual tolerance of patients with develop a tolerance to the muscarinic effects myasthenia gravis to decamethonium iodide more readily than normal individuals. forms the basis for another diagnostic test The ideal dosage of anticholinesterase drugscopyright. (Churchill-Davidson and Richardson, 1952). increases the strength of the initial muscular The procedure is lengthy, requiring electro- effort, and defers the development of weakness myographic control, and is seldom necessary ("fatigue"). An excessive dose gives rise to an in clinical practice. increase in muscle weakness and fasciculation due to the persistence of acetyl choline at the The Electromyographic Diagnosis neuromuscular junction-"depolarisation" or Direct needle electromyography does not block. provide diagnostic evidence, and the electro- As the severity of the myasthenic defecthttp://pmj.bmj.com/ physiological diagnosis is based on the recorded varies in different muscle groups, so will their response of the muscle to supramaximal nerve drug requirements differ. If one group of stimulation. The technique was described by muscles is ideally dosed, others will show over- Harvey and Masland (1941), and a summary of dosage while some remain underdosed. One the findings in myasthenia gravis are listed on must often accept a relative underdosage in p. 361. These are taken from the extended some parts of the body if essential muscles, such account by Grob and others (1956). These as the respiratory muscles, are not to be tests may conveniently be combined with the overdosed. on October 2, 2021 by guest. Protected pharmacological tests described in the previous section, thus providing objective evidence of The exact timing of doses varies according the myasthenic phenomenon and its repair with to the patient's routine, e.g. meal times, etc. anticholinesterase In general the interval between doses should drugs. be 4 to 5 hours, the approximate duration of drug action. Some patients require more Management frequent doses and others less frequent. I prefer Drug treatment that there should be a slight "let-down" of effect Neostigmine (Prostigmin) bromide, 15 mg./ at the end of a dose period, with a consequent tablet. resurge of strength when the next dose takes (Mestinon) bromide, 60 mg./ effect. This allows both the patient and the tablet. physician to recognise any fluctuations in the The management of the patient with myas- severity of the disease and the drug require- thenia gravis has been likened to the manage- ments. ment of the diabetic (Johns, 1960). In both The choice between neostigmine and pyrido- Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from June, 1965 DRAPER: Myasthenia Gravis 367 largely depends upon the response of patient is overdosed. Edrophonium normally the patient. The duration of effect is roughly has a very rapid and brief action so that any equal, although neostigmine seems to reach worsening is short-lived. However, it has been its peak activity a little sooner than pyrido- postulated that it also has a direct effect on the stigmine, which has the reputation for a motor end-plate membrane so that at critical "smoother" effect. Some physicians use neo- levels of overdosage it may induce a persistent stigmine during the day, giving the patients "depolarisation" block (Tether, 1951; Osserman pyridostigmine on retiring. This often obviates and Kaplan, 1952; Westerberg, Magee and the necessity for waking for a dose during the Shideman, 1953). If unexpected, this response night. might be fatal. For a patient with mild to moderately severe In more severe cases, when weakness has myasthenia gravis, a suitable trial regime would proceeded to collapse, all anticholinesterase be, one tablet of neostigmine (15 mg.) at 7.30 medication should be withdrawn and the patient a.m., 11.30 a.m., 3.30 a.m., 7 p.m. and 11 p.m. given atropine sulphate 2 mg. i.m. The ven- The patient should be examined at hourly tilatory capacity should be estimated and if intervals through the day according to the necessary, artificial respiration instituted. method described in the previous section. This Mouth-to-mouth resuscitation may be life- should indicate the degree of response to each saving. An airway must be maintained, pre- dose, and the size of the individual doses can ferably with an endotracheal tube so that a then be varied until the optimum response is mechanical respirator can be used. A obtained. Side effects can be controlled with tracheostomy should be performed if it appears atropine sulphate 0.6 mg. orally or by intra- that assisted respiration will be required for muscular injection, remembering that atropine more than a few hours. Bronchorrhoea is a may mask an increase in side effects which common complication of the cholinergic state heralds overdosage. The ease with which the and the tracheostomy will facilitate bronchial disease can be controlled varies from patient toilet. to patient; like diabetics, some patients with Further anticholinesterase medication should copyright. myasthenia gravis are notoriously "brittle" and be withheld until there is an unequivocally should be reviewed at frequent intervals. positive response to edrophonium. The period Pyridostigmine, 60 mg., can be introduced without drugs may extend for as long as 4 days. in place of the neostigmine. The rate of The oximes, pyridine-2-aldoxime (2 PAM), excretion of anticholinesterase drugs varies from its methane sulphonate (P2S) and diacetyl patient to patient and some patients show a monoxime (DAM) have been shown to re- tendency to accumulate pyridostigmine. For activate cholinesterase which was inhibited by this reason we do not use the and longer acting organo-phosphates (Wilson Ginsburg, 1955; http://pmj.bmj.com/ anticholinesterase drugs such as bis-neostigmine, Childs and others, 1955). Grob and Johns bis-pyridostigmine and ambenonium chloride (1958 a & b) showed a reversal of the anti- (Mytelase). cholinesterase effect of neostigmine. In this department PAM and PS have been used Cholinergic crisis in the emergency treatment of cholinergic crisis. Sudden worsening in a previously well-con- In the recommended dosage the clinical effect trolled patient, particularly if there seems to be was slight and delayed by more than 30 minutes. a "resistance to drugs" is most often due to Used in this way, they are of little practical on October 2, 2021 by guest. Protected overdosage. If the situation is not life-threaten- value. ing, the patient should be rested in bed and the previously effective drug regime continued. Ancillary drug treatment Hourly observations of muscle strength and the The patient with myasthenia gravis may occurrence of side-effects should be instituted. develop hypokalaemia due to diarrhoea, and It should be apparent after the first one or two may respond favourably to potassium supple- doses if the weakness increases after each dose. ments, e.g. potassium bicarbonate 1 gm. q.i.d. The edrophonium test is a useful adjunct to Desmedt (1945) suggested that potassium actu- the diagnosis of cholinergic crisis. One to one- ally supplemented the effect of neostigmine. and-a-half hours after the routine medication Ephedrine, 25 mg. t.d.s., introduced by Edge- an edrophonium test is performed. If there is worth in 1930, is still used. It is thought to a prompt improvement in strength, the patient act bv inhibiting amine oxidase and so to is underdosed. If the response is equivocal or potentiate the action of adrenalin. It is difficult if there is an increase in the weakness then the to show any measurable effect. Postgrad Med J: first published as 10.1136/pgmj.41.476.356 on 1 June 1965. Downloaded from 368 POSTGRADUATE MEDICAL JOURNAL June, 1965 BICKERSTAFF, E. R., and WOOLF, A. L. (1960): The Thymectomy Intramuscular Nerve Endings in Myasthenia The value of thymectomy in the treatment Gravis, Brain, 83, 10. of myasthenia gravis is still the subject of con- BLALOCK, A. (1944): Thymectomy in the Treatment troversy. Blalock, who was responsible for of Myasthenia Gravis, J. thorac. Surg., 13, 316. the re-introduction of this form of BLALOCK, A., HARVEY, A. M., FORD F. R., and treatment, LILIENTHAL, J. L. (1941): Treatment of Myasthenia (Blalock, Harvey, Ford and Lilienthal, 1941), Gravis by Removal of the Thymus Gland, J. Amer. and the other workers from the Johns Hopkins med. Ass., 117, 1529. Hospital, became increasingly dissatisfied with BRAIN, R., and HENSON, R. A. (1958): Neurological their results 1944; 1948; Syndromes Associated with Carcinoma: The (Blalock, Harvey, Carcinomatous Neuromyopathies, Lancet, ii, 971. Grob, 1953). Keynes had a quite different CASTILLO, J. DEL, and KATZ, B. (1957): A Study of impression (Keynes, 1946, 1949, 1953, 1954, Curare Action with an Electrical Micro-method, 1955), stressing the necessity for a discriminat- Proc. roy. Soc. (B.), 146, 339. ing selection of suitable patients for the opera- CASTLEMAN, B., and NORRIS, E. H. (1949): The tion. Pathology of the Thymus in Myasthenia Gravis. A Study of 35 Cases, Medicine (Baltimore), 28, 27. Patients with a tumour of the thymus or CHILDS, A. F., DAVIES, D. R., GREEN, A. L., and myopathic changes in the muscles in general RUTLAND, J. P. (1955): The Reactivation by a com- Oximes and Hydroxamic Acids of Cholinesterase responded poorly. Simpson published Inhibited by Organophosphorus compounds, Brit. prehensive evaluation of Keynes' cases (Simp- J. Pharmacol, 10, 462. son, 1958) which in general confirmed Keynes' CHRISTENSEN, E., and LEVISON, H. (1950): Chronic earlier reports. He concluded that the apparent Polymyositis, Acta psychiat. scand., 25, 137. discrepancies between his results and those CHURCHILL-DAVIDSON, H. C., and RICHARDSON, A. T. of the (1952): The Action of Decamethonium Iodide Americans (Blalock, 1944; Harvey, 1948; (C.10) in Myasthenia Gravis. J. Neurol. Neuro- Eaton and colleagues, 1949, 1950. 1953; Schwab surg. Psychiat., 15, 129. and Leland, 1953) were due to different methods COERS, C., and WOOLF, A. L. (1954): Etude Histo- of analysis and different criteria for improve- logique et Histoclinique de la Jonction Neuro- C.R. Med. Alieniste. ment. Simpson found that young women with musculaire, Congres Neurol.,copyright. a of (Liege), 1. history myasthenia gravis of less than COERS, C., and WOOLF, A. L. (1959): The Inner- five years most consistently benefitted from vation of Muscle. A Biopsy Study. Oxford: operation. Some men and some older patients Blackwell. who had a longer history of the disease also DESMEDT, J. E. (1945): L'action du Potassium sur showed marked la Transmission Neuromusculaire dans la Myas- improvement. Viets and Schwab th6nie Grave, J. Physiol. (Paris), 47, 655. (1961) reviewing their cases in the light of this DESMEDT, J. E. (1957): Nature of the Defect of paper corroborated Simpson's results. Simpson Neuromuscular Transmission in Myasthenic Patients, recommends to 'Post-tetanic Exhaustion', Nature (Lond.), 182, 1673. (1964) currently thymectomy L. M. Tests for all under the EATON, (1943): Diagnostic Myas-http://pmj.bmj.com/ patients age of 50 years with a thenia Gravis with Prostigmine and Quinine, Proc. history of generalised myasthenia gravis of not Mayo Clin., 18, 230. more than five years' duration. EATON, L. M. (1958): quoted by Osserman, K. E., in 'Myasthenia Gravis', New York and London: Grune and Stratton. I am most grateful to Mr. A. Folkarde and Dr. EATON, L. M., CLAGETT, O. T., GOOD, C. A., and I. D. Sanderson for technical assistance, to Dr. I. B. MACDONALD, J. R. (1949): Thymectomy in the Stanton for permission to study his patients, and to Treatment of Myasthenia Gravis. Report based on Professor J. A. Simpson, who made his material 32 Cases, Arch. Neurol. Psychiat. (Chic.), 61, 467. freely available. Figure 1 is reproduced by per- EATON, L. M., and CLAGETr, O. T. (1950): Thymec- on October 2, 2021 by guest. Protected mission of the Editor of the Scottish Medical Journal. tomy in the Treatment of Myasthenia Gravis, J. Amer. med. Ass., 142, 963. REFERENCES EATON, L. M., CLAGET, O. T., and BASTRON, J. A. (1953): The Thymus and its Relation to Diseases ALAJOUANINE, T., CASTAIGNE, P., NICK, J., CONTAMIN, of the Nervous System. Study of 374 Cases of ., and LHERMrrTE, F. 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