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Objectives: To determine if myasthenia gravis (MG) with antibodies to MuSK is a distinct subgroup of seronegative MG., Methods: We assayed antibodies to muscle specific tyrosine kinase (MuSK) in 55 MG patients who had no antibodies to acetylcholine receptors and looked for the specific phenotype, comparing clinical features of anti-MuSK positive and anti-MuSK negative MG patients., Results: MG with anti-MuSK antibodies was characterised by a striking prevalence of female patients (15 women, two men). Age at onset ranged from 22 to 52 years, with 70.6% of patients presenting at < 40 years of age. The majority of patients (82.4%) had prevalent involvement of facial and bulbar muscles. One third of them did not respond well to anticholinesterase drugs. Steroid immunosuppression was effective in eight patients (44.4%). Nine patients underwent thymectomy; six of these had no thymus pathology, while three had a hyperplastic thymus. At the end of the observation period, six (35.3%) patients were in remission, five (29.4%) improved, four (23.6%) did not change, and two (11.7%) had died., Conclusions: MG patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients. This emphasises the predictive value of anti-MuSK antibody analysis in seronegative MG patients.

Objectives: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features., Methods: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays., Results: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 micros in seropositive patients, 36 micros in MuSK positive patients, and 30 micros in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients., Conclusions: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitation-contraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.

Objective: To investigate repetitive stimulation of the long thoracic nerve as a reliable and technically undemanding method for evaluating respiratory muscle function in myasthenia gravis., Methods: 15 patients with myasthenia gravis and positive single fibre electromyography had repetitive stimulation of the long thoracic nerve together with serratus anterior recordings. There were 20 normal controls., Results: Eight patients with respiratory symptoms all had abnormal results, with an increased response decrement. These patients required intensive monitoring and supplemental oxygen. The remaining seven cases with no respiratory symptoms all had negative studies., Conclusions: This is a simple well tolerated method that shows good correlation with respiratory symptoms and management requirements in myasthenia gravis. It can alert the physician to serious respiratory complications in this disease.

A patient is described with a vertebrobasilar aneurysm who was erroneously thought to have myasthenia gravis on the basis of the clinical presentation and investigations, which were interpreted as supportive of a disorder of the neuromuscular junction. Despite the correct diagnosis being made at a late stage the patient made a full recovery after radiological intervention.

Objective: Before the advanced evaluation of deglutition and selection of a treatment method, objective screening methods are necessary for patients with dysphagia. In this study a new electroclinical test was established to evaluate patients with dysphagia., Methods: This test is based on determining piecemeal deglutition; which is a physiological phenomenon occurring when a bolus of a large volume is divided into two or more parts which are swallowed successively. The combined electrophysiological and mechanical method used to record laryngeal movements detected by a piezoelectric transducer, and activities of the related submental integrated EMG (SM-EMG)-and sometimes the cricopharyngeal muscle of the upper oesophageal sphincter (CP-EMG)-were performed during swallowing. Thirty normal subjects and 66 patients with overt dysphagia of neurogenic origin were investigated after detailed clinical evaluation. Twenty patients with a potential risk of dysphagia, but who were normal clinically at the time of investigation, were also evaluated to determine the specificity of the test. All subjects were instructed to swallow doses of water, gradually increasing in quantity from 1 ml to 20 ml, and any recurrence of the signals related to swallowing within the eight seconds was accepted as a sign of dysphagia limit., Results: In normal subjects as well as in the patients without dysphagia, piecemeal deglutition was never seen with less than 20 ml water. This volume was therefore accepted as the lower limit of piecemeal deglutition. In patients with dysphagia, dysphagia limits were significantly lower than those of normal subjects., Conclusion: The method is a highly specific and sensitive test for the objective evaluation of oropharyngeal dysphagia even in patients with suspected dysphagia of neurogenic origin. It can also be safely and simply applied in any EMG laboratory.

The influence of thymectomy and long term immunosuppression on the phenotype of CD4 T lymphocyte subsets, which were defined by the restricted expression of CD45RA and CD45RO markers, was studied by double immunofluorescence in 29 patients in different clinical stages of generalised myasthenia gravis. In the acute stage of myasthenia, before thymectomy and immunosuppression, no differences in CD4 subsets were observed in the peripheral blood from nine patients and 21 matched controls. Four to seven weeks after thymectomy, there was a slightly decreased proportion of CD4+CD45RO+ (UCHL1+) memory cells (p < 0.05, paired t test). Patients on steroids showed a more pronounced decrease of CD4+CD45RO+ cells suggesting, in addition, a drug-related effect. CD4 subsets (CD45RA, CD45RO, and CD29 positive) in the peripheral blood compartment remained largely stable over 18 to 24 months thereafter. In addition, CD4 subsets were examined in 20 patients with myasthenia gravis who had had a thymectomy between two and 17 years before. With the exception of patients on steroids, there were no differences in CD4 subsets in patients on or off azathioprine. These data did not show any relation of CD4 T cell subsets to the clinical course of myasthenia, or significant changes due to thymectomy, or immunosuppression with azathioprine. These results also complement the authors' clinical experience that thymectomy in adults does not leave a deficit in cell-mediated immunity. The slight change associated with steroid treatment might deserve further attention.

The effectiveness of intranasal neostigmine (9.3-13.8 mg) was tested in 20 subjects with myasthenia gravis, classified as Osserman grades 2A and 2B. In all cases the drug produced significant clinical and electromyographic improvement. No side effects were reported during the treatment.

In a patient with myasthenic syndrome neuro-muscular transmission was characterised by depression and facilitation. The relative extent of these two processes varied between muscles, and in the one muscle with time. Guanidine HCl treatment corrected the electrophysiological defect. Oral choline increased muscle action potential amplitude in response to single shocks. Intravenous choline produced features indicating cholinergic autonomic stimulation. Pimozide and plasmapheresis had no effect. Animal in-vivo and in-vitro studies performed to detect a circulating factor which interferes with neuro-muscular transmission were negative.

Effective diagnostic methods are of great importance in order to recognise myasthenic patients among those with muscle fatigability. Intracellular recordings are useful for research work within the field and for detailed description of the motor end-plate's physiology in the individual case. The method is not used for the routine diagnosis of myasthenia gravis. The decrement of the electrical muscle response with nerve stimulation is the most commonly used method. The diagnostic yield is higher in proximal muscles, in warmed muscles, after exercise, and after ischaemia. A significant number of patients may be undiagnosed with this technique. The mechanical response with nerve stimulation shows the same type of decrement but also an abnormal response to long stimulation. The diagnostic value of this is under dispute. Single fibre ENG needs more patient cooperation than do these tests. The diagnostic yield is significantly higher. Some patients considered to have myasthenia gravis do not show any abnormalities with this technique, particularly those with the pure ocular form. Conventional EMG is not useful for the diagnosis of myasthenia, but may be indicated in these patients when concurrent nerve or muscle disease is in question. Tests for eye movement fatique have not proved useful. Stapedius reflex fatigability is demonstrated in about the same proportion of patients as have positive SFEMG findings. The technique is not uncomfortable for the patient and requires minimal cooperation. The general usefulness must be assessed by further routine use. Even with the advent of immunological tests, neurophysiological investigations are indispensable in helping establish the diagnosis of myasthenia gravis. Discrepancies between the results comparing electrophysiological and immunological tests may indicate that myasthenia gravis is a heterogenous entity within which subgroups may be identified.

A technique is described of measuring the motor end plate jitter in the orbicularis oculi muscle activated by extra-muscular nerve stimulation, standardised for routine use in diagnosis and evaluation of neuromuscular transmission disorders. Among the advantages of the technique are comparatively quick and easy sampling of adequate number of single motor end-plates, convenient control of discharge rate between less than 1 and up to 20 Hz, absence of direct muscle fibre responses, and little discomfort for the patient. The jitter in the orbicularis oculi is significantly lower than that in the extensor digitorum communis muscle. There is a positive correlation between the jitter and the latency of the individual muscle fibre responses, possibly indicating that smaller diameter muscle fibres have slightly lower safety factor of neuromuscular transmission. The data collected in a group of healthy volunteers suggest the following upper normal limits for the mean of absolute consecutive difference of the latency: 30 microseconds for individual motor end plates (one out of 20 values may be higher), and 18 microseconds for a median of 20 motor end plates.

This retrospective study over the decade 1969-1978 examines the precipitating factors and outcome in thirty-one patients with myasthenia gravis who developed ventilatory failure. An unusual example of chronic alveolar hypoventilation is discussed in detail. The most favourable outcome occurred in younger patients with a hyperplastic thymus, in contrast to a poorer outlook for older patients with an atrophic gland. Eleven patients died during the period of follow up: three deaths were unrelated to myasthenia but the remaining eight were attributed directly or indirectly to it. The mortality of 36% represents a marked improvement on a 70% mortality in a similar group of patients, reported from this hospital for the years 1960-1968.

A new method, incorporating on-line computer analysis, is described for the estimation of the numbers of motor units in human muscle. The results obtained in the extensor digitorum brevis muscle in normal subjects and patients with myasthenia gravis are presented. These indicate that the numbers of motor units in that muscle in patients with myasthenia gravis are within the normal range, in contrast with the reduction in numbers reported by other workers using a different technique. Evidence is presented to suggest that the discrepancy in these results is due to increased sensitivity and discrimination of the computerized method. Several hypotheses on the aetiology of a number of neuromuscular diseases, based on the results of the other method, may require reevaluation.

The technique of the macro-EMG was used to estimate the number of motor units in the tibialis anterior muscles of healthy subjects in a wide range of ages, and of patients with myasthenia gravis and patients with amyotrophic lateral sclerosis or spinal muscular atrophy. The results obtained suggest a decrease in the number of motor units in the tibialis anterior muscle with increasing age in normal subjects. In myasthenic patients the motor unit count was within the normal range for their age group. Patients with motor neuron disorders on the average had a very low number of motor units.

The distinction between myasthenia gravis and Lambert Eaton myasthenic syndrome can usually be made by the clinical and neurophysiological features. A patient was observed with features which suggested a combination of both disorders. This has been described in few patients before. The importance of electromyography in both distal and proximal limb muscles for a correct diagnosis is demonstrated. Only in proximal nerve stimulation tests was proof found of the existence of both syndromes.

Sporadic reports have suggested central involvement in myasthenia gravis, a disorder in which there is an antibody-mediated loss of peripheral nicotinic acetylcholine receptors. Five patients with symptomatic myasthenia gravis performed an auditory vigilance test of ability to direct and sustain attention, presumed to reflect central cholinergic function. No deficits were found, either in comparison with the same subject's performance when muscle strength had improved after plasma exchange, or compared with that of healthy controls. The results thus failed to substantiate reports of functionally significant central cholinergic deficits in myasthenia gravis.

Patients with myasthenia gravis have been investigated with single fibre electromyography. In all myasthenic muscles recordings were obtained where there was an increase of the jitter and occasional blocking of different degree of single fibre action potentials. The jitter is the variability at consecutive discharges in the time interval between action potentials from two muscle fibres from the same motor unit. During prolonged activity the jitter increased and blockings occurred more and more frequently. The size of the jitter and the degree of blocking also depended on the discharge rate. At a low rate the jitter was lower and the degree of blocking less than at the high rate. Injection of edrophonium could decrease or increase the jitter or leave it unaffected. Single fibre electromyography is a sensitive way of studying the transmission in individual motor end-plates in myasthenia gravis and is also a valuable diagnostic aid.

Shoulder abduction fatiguability has been measured using a hand held myometer in normal subjects and patients with peripheral neuromuscular diseases. An index of fatiguability was based on the decline in force over a series of ten maximum voluntary contractions performed in under a minute. The technique was repeatable and well tolerated. Patients with myasthenia, mitochondrial myopathy and motor neuron disease tended to show excess fatiguability independent of muscle strength. Serial measurements demonstrated alterations in fatiguability but not necessarily strength, associated with changes in symptoms.

A method is described for repetitive stimulation studies in myasthenia gravis using submaximal stimulation and single muscle fibre recording techniques. It was found that there were no impulse blockings due to neuromuscular transmission factors in normal subjects with 2 Hz stimulation, although there was a decrease or increase in the number of potentials which was caused by axonal stimulation factors. In myasthenia gravis a pathological picture was obtained, consisting of impulse blockings and facilitation at this rate in all of the eight patients studied, even those with only the ocular form of myasthenia and without surface decrement in the ADM. This technique allows study of both the minimally involved motor endplates and those with pronounced neuromuscular disturbances.

Electrical and mechanical muscular responses to single and repetitive stimuli were recorded in 24 patients with myasthenia gravis. Findings in the platysma were compared with those in m. adductor pollicis (ADP). In the platysma, but not in the ADP, electrical and mechanical responses to single stimuli were often lower than normal, and could be normalised after tetanus and by endrophonium. The decrement of electrical and mechanical responses to repetitive stimuli was two to three times greater in the platysma than in the ADP; post-tetanic facilitation of the action potential was four times greater. The staircase phenomenon was abnormal in the platysma in patients with moderate and severe myasthenia, and also in the ADP in some patients without decrement in the action potential. Edrophonium was more effective in alleviating decrement in the platysma than in the ADP. In the platysma, block of neuromuscular transmission could account for most abnormalities. The finding in some patients of an abnormal staircase after correction for block of fibres indicates a lesion in excitation-contraction coupling. In six patients only the platysma showed abnormalities, in 10 patients abnormalities were more pronounced in the platysma than in the ADP, and in three patients more pronounced in the ADP than in the platysma; in five patients the platysma and the ADP were equally affected.

Three patients with myasthenia gravis had transient retraction of the upper eyelids which usually followed prolonged upgaze and which persisted for many seconds. This could result from post-tetanic facilitation, myotonia, or a transient contracture. Retraction of this type is to be distinguished from both the long-standing unilateral retraction associated with ptosis of the contralateral eyelid and the fleeting lid twitch sign.

Two cases of Lambert Eaton syndrome unassociated with an underlying malignancy are described. Both had mild autonomic symptoms but markedly abnormal autonomic function tests. These results are suggestive of a widespread defect in cholinergic transmission in addition to that at the skeletal neuromuscular junction.

A new drug, 4-aminopyridine, was prepared for use in humans and tested by repeated injections in six patients with myasthenia gravis. The drug caused improvement of muscle strength and neuromuscular transmission as demonstrated by clinical observations and repetitive electrical nerve stimulation. The drug was effective in cases without any other treatment as well as in cases undergoing treatment with anticholinesterases. It is concluded that 4-aminopyridine may be of value as a supplementary drug in the treatment of myasthenia gravis.

Using the mouse passive transfer model the mean amplitude of miniature endplate potentials and endplate potentials of mice treated with myasthenic immunoglobulins was markedly decreased. Miniature endplate potential frequency and quantum content of endplate potentials were normal, arguing against a major presynaptic disarrangement. Under electron-microscopy no gross structural alterations of endplates were demonstrated. It is concluded that the mouse passive transfer model closely resembles human myasthenia gravis of recent onset.

The jitter, obtained by SFEMG recordings, mainly reflects the neuromuscular transmission time variability and is usually Gaussian distributed. Here is reported the bimodal distribution of the interpotential intervals, the flip-flop phenomenon. Long flip-flop in cases of reinnervation may indicate alternatively continuous and saltatory nerve conduction. Short flip-flop in normal subjects may be due to muscle fibre interaction or nerve conduction irregularities.

An on-line computer method is described for the isolation of single motor unit potentials, evoked by stimulation of the anterior tibial nerve at the ankle, from the compound action potential recorded from surface electrodes over the extensor digitorum brevis muscle. The latencies, durations, amplitudes, and areas of the potentials were measured in a group of control subjects and patients with myasthenia gravis. In myasthenic patients there is a significant reduction in the durations of motor unit potentials and a significant increase in latencies while their amplitudes and areas remain unchanged. The results are consistent with the presence of a `terminal neuropathy' in myasthenia gravis.

In patients with myasthenia gravis neuromuscular transmission has been tested in individual hypothenar and thenar motor units using trains of near threshold electrical stimuli delivered to the motor nerve. The most important observations included: (1) the proportion of motor units with pathological decrements varied from 0 to 90%, (2) the decrements in surface voltage were frequently much more normal in individual motor units than in the corresponding maximum compound potentials evoked by supramaximal nerve stimulation, and (3) the most abnormal decrements were observed in motor units at the low end of the surface voltage range. These observations can be interpreted to suggest important neurogenic factors in the pathogenesis of myasthenia gravis. An attractive alternative would be to suggest that the small motor units have the most abnormal neuromuscular transmission because they normally have a lower margin for safe neuromuscular transmission and, as a consequence, fail first in diseases of neuromuscular transmission.

An investigation was made into the occurrence of muscular atrophy and muscular pathology in a series of 170 patients with myasthenia gravis. The results can be summarized as follows: (1) Of the 148 patients with generalized myasthenia gravis, 14 showed local muscular atrophies. Of 10 biopsies from atrophic muscles, eight showed neurogenic changes, with or without lymphocytic infiltrations. One biopsy showed lymphocytic infiltrations only, and one showed type II-fibre atrophy (Table 1). No relationship was demonstrable between the presence of clilnical muscular atrophy and age, sex, duration of the disease, severity of the disease, presence of a thymoma, or drug resistant ophthalmoplegia. (2) In this group of patients 61 biopsies were examined from 46 individuals; 40 of these biopsies were taken from the quadriceps muscle. A thymoma was present in 17 patients. Examination disclosed neurogenic changes in 17 biopsies, lymphocytic infiltrates in 21, and myositis in one biopsy (Table 2). A distinct correlation was established between the presence of a thymoma and lymphocytic infiltrates, but none was demonstrable between thymoma and neurogenic changes (Table 3). (3) An enzyme-histochemical study was carried out in 35 cases, including 12 with neurogenic changes. A normal differentiation of type I- and type II-fibres was observed in eight instances, type grouping of type II-fibres in three, and type II-fibre atrophy in two cases. (4) In 21 patients and 19 controls, the smallest mean diameter was determined in the quadriceps muscle. Both type I- and type II-fibres proved to have a smaller mean diameter in the female patients than in the controls. In the male patients this could not be proven. (5) Of the eight patients who had died without disorders of ventilation, 90 muscle specimens were examined postmortem. Four of these patients had a thymoma. Lymphocytic infiltrations, found in 32 biopsy specimens, were mostly observed in the presence of a thymoma. Neurogenic changes were apparently unrelated to the presence of a thymoma (Tables 5 and 6). The post mortem examination included the spinal cord in five, and peripheral nerves in three cases. No abnormalities were found. (6) The muscular atrophy found in patients with myasthenia is not a myopathy but an affection of the lower motor neurone. Neurogenic changes were regularly found in the muscles of patients with myasthenia, even without muscular atrophy. The finding of these changes is no reason to reject the diagnosis. It is postulated that denervation occurs at the neuromuscular junction as a result of permanent absence of acetylcholine.

An account is given of four cases of myasthenia gravis in the dog. All animals showed fatigue, and considerably reduced tolerance to exercise. Recovery followed rest or treatment with neostigmine. Three animals, two of which are still alive, had dilatation of the oesophagus. The fourth eventually died from an aortic body tumour. The occurrence of myasthenia in the dog may be of value in elucidating the cause of the disease in man.

Two cases of severe myasthenia gravis are described, with histological findings. Both cases showed severe neurogenic atrophy of the muscles of the tongue, with fatty pseudohypertrophy and a remarkable proliferation of terminal nerve fibres. Similar, but less severe, changes were present in other bulbar muscles. The findings are in keeping with the view that functional interruption at the neuromuscular junctions results first in failure to transmit the contractile impulse, and at a later stage in denervation atrophy. Terminal proliferation of axons is regarded as an attempt, on the part of motor fibres, to compensate for the breakdown of normal neuromuscular interaction.

A technique is described for the electrophysiological investigation of motor-point muscle biopsies and the data from 13 biopsies are reported. It was not possible to demonstrate any influence of disease upon the resting potentials of individual biopsies, but resting potentials were in general lower than those reported for limb muscle in vivo. Miniature end-plate potentials (MEPPs) in clinically normal limb muscle were smaller and more frequent than those previously described in isolated intercostal muscle. In two biopsies from myasthenic patients very small amplitude MEPPs were recorded and, in one of these, MEPPs were also of very low frequency, possibly associated with the severity of the disease. The frequency and amplitude of MEPPs in muscular dystrophy and neurogenic disease have been reported and the possible significance of these findings is discussed.

Guinea-pigs were immunized with antigen prepared from calf thymus and muscle, and from guinea-pig thymus, and rats were immunized with antigen prepared from rat thymus and rat muscle. There was an increased incidence of delayed hypersensitivity and circulating thymus antibodies in the immunized guinea-pigs and an increased incidence of thymitis in the immunized guinea-pigs and rats. However, when compared with control animals, there was no electrophysiological evidence of impairment of neuromuscular transmission in the immunized animals.