David Grob

The Course of Myasthenia Gravis and Therapies Affecting Outcome

The course of 1,487 patients with myasthenia gravis followed between 1940 and 1985 for a mean of 18 years provides further evidence that the distribution, severity, and outcome of the disease are determined during the first 1 to 3 (occasionally 5) years after onset, suggesting that injury to acetylcholine receptors occurs mainly during this time. In 14%, the disease remained clinically localized to the extraocular muscles, and in the remaining 86% became generalized, in 87% within a year, with the disease reaching maximum severity within the first year after onset of symptoms in 55%, during the first 3 years in 70%, and during the first 5 years in 85%. Male patients tended to have more rapid progression of disease, higher mortality, and lower rates of remission and improvement than females. From 1940 to 1957, when management relied on anticholinesterase compounds, endotracheal intubation or tracheostomy and negative pressure assisted ventilation for respiratory failure, and thymectomy in 26% of patients and thymomectomy in 8%, 31% of patients with generalized myasthenia gravis died of the disease (29% of these during the first year after onset, 27% during the second and third years, and 17% during the fourth and fifth years), 32% improved, 23% remained unchanged, 10% went into remission, and only 5% were worse during the last year seen than during the worst of the first 3 years (or 5 years in the minority of patients who reached maximum weakness after 3 years). From 1958 to 1965, during which time the management of respiratory failure was improved by positive pressure and volume controlled ventilation and improved intensive care, mortality fell to 14% (p less than 0.005), and a higher proportion remained unchanged (p less than 0.005). From 1966 to 1985, when over half the patients received adrenal cortical steroids, mortality fell to 7% (p less than 0.005) and the proportion who improved rose to 47% (p less than 0.05). Even though the patients who received steroids usually had more severe myasthenia, they had a higher rate of improvement than those who received no steroid, 54% compared to 39% (p less than 0.005). Thymectomy was performed in one-fourth of patients with generalized myasthenia gravis, more frequently in young females and those with more severe weakness, and less often in older males and those with less severe weakness.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of Repeated Doses of Intravenous Immunoglobulin in Myasthenia Gravis

The authors administered repeated courses of intravenous immunoglobulin (IVIg) to nine patients at the onset of an exacerbation of generalized myasthenia gravis (MG). Anticholinesterase medication (nine patients) and corticosteroid dosage (six patients) had been kept constant for a 2-month period. Six patients received two courses, two patients received three courses, and one patient received five courses. Twenty of 23 courses resulted in satisfactory improvement beginning 4.3 +/- 1.2 days after start of IVIg and becoming maximal 8.2 +/- 2.0 days, with sustained improvement lasting 106.6 +/- 49.1 days. Vital capacity increased from an average of 1845.1 +/- 489 cc to 2894 +/- 762 cc (p less than 0.01) at peak effect. Four of nine patients had a decrease in strength before improvement. There was no significant change in acetylcholine receptor antibody titers before or after therapy. Side effects were minimal. Of the three patients who had nonsatisfactory course, two responded well to additional IVIg. IVIg can produce repeated beneficial effects in patients with MG and may be useful as an adjunct in the management of MG.

CHARACTERISTICS AND MECHANISM OF NEURO‐MUSCULAR BLOCK IN MYASTHENIA GRAVIS

The neuromuscular block of myasthenia gravis has the characteristics of an antidepolarizing (competitive block), similar to that produced by d-tubocurarine in normal subjects: progressive decrease in muscle action potentials evoked by two or more nerve stimuli, posttetanic facilitation, posttetanic fatigue, inhibition of the depolarizing action of acetylcholine (ACh) or anticholinesterase compounds, and reversal of the block by ACh or anticholinesterase compounds. In myasthenic patients spontaneously recurring negative discharges were more difficult to locate in the end-plate zone than in normal subjects, suggesting that the number or density of functioning end plates may be reduced. The threshold dose of intra-arterial ACh that increased electrical activity was higher than in normal subjects; the duration of the increased electrical activity was briefer, and was followed by more depression of negative discharges than in normal subjects and by a greater increase in the threshold dose of ACh. These results indicate that the end-plate zone of myasthenic patients is less responsive than that of normal subjects to the excitatory action of ACh, and may be more readily desensitized by ACh. In both myasthenic patients and normal subjects the intra-arterial injection of ACh produced a prompt transient decrease in evoked potentials, attributable to depolarization of the end plates, followed by recovery (and in myasthenic patients by repair), and then by a more prolonged late decrease in evoked potentials, attributable to desensitization of the end plates to transmitter. This prompt depressant effect of ACh on evoked potentials was less in myasthenic patients than in normal subjects, and the late depressant effect of ACh was greater. In myasthenic patients the late block produced by ACh had the characteristics of an antidepolarizing (competitive) type of block, including inhibition of the depolarizing action of ACh and reversibility by ACh or neostigmine, while in normal subjects the characteristics were those of a depolarizing (noncompetitive) type of block, including little or no inhibition of the depolarizing action of ACh and lack of reversal by ACh or neostigmine. The differences between the late depressant action of ACh in myasthenic patients and normal subjects resembled differences in the effect of other depolarizing compounds, such as choline, succinylcholine, and decamethonium, and are best explained by differences in behavior of the postsynaptic receptor. The disease appears to be due to the presence of abnormal forms of receptor or to abnormal responses of receptor to the transmitter. The predominance of one or other form of receptor may determine the clinical state of the myasthenic patient and his response to anticholinesterase medication.

AUTOANTIBODIES AND MYASTHENIA GRAVIS, WITH SPECIAL REFERENCE TO MUSCLE RIBONUCLEOPROTEIN*

The serum of some patients with myasthenia gravis contains globulins which react with skeletal muscle and other tissues, as demonstrated by immunologic techniques.. The role of these globulins in the pathogenesis of the disease or the defect in neuromuscular transmission is not known. In the present study the serologic reactions in patients with myasthenia gravis have been investigated, with particular reference to binding of serum globulin to the cytoplasm and nuclei of skeletal muscle, thymus and other cells. The factors affecting this binding, and the effect of these globulins on neuromuscular transmission have been investigated. Observations have been carried out on the relation of these globulins to a ribonucleoprotein, previously isolated from skeletal muscle, which has special affinity for acetylcholine and d-tubocurarine. .

ALTERATIONS IN REACTIVITY TO ACETYLCHOLINE IN MYASTHENIA GRAVIS AND CARCINOMATOUS MYOPATHY

The intra-arterial administration of acetylcholine (ACh) was found to produce different effects on muscle response to nerve stimulation in normal subjects’ and patients with myasthenia gravis.’ This suggested that the defect in this disease may be an abnormal response of the muscle end plates to the transmitter, ACh, or to an abnormal product of ACh. However, more recently, the end plates of intercostal muscle excised from myasthenic patients were reported to respond normally to iontophoretically applied ACh3 and carbamin~ylcholine,~ indicating that the defect may be the result of decreased transmitter release. This conflicting evidence, as well as increasing appreciation of variations in response to ACh and anticholinesterase compounds in patients with myasthenia gravis,’ justifies review and further study of reactivity to ACh in this disease and in related “myasthenic” syndromes, including carcinomatous myopathy.

Diclofenac-lnduced Rhabdomyolysis

ABSTRACT: A case is described in which, after administration of diclofenac for 13 days for arthritis attributed to gout, the patient experienced erythema multiforme followed by muscle weakness, elevation of serum creatine Phosphokinase (CPK) level from 101 to 83,770 U/L, 100% muscle isoenzyme, blood urea nitrogen (BUN) level from 15 to 87 mg/dL, creatinine level from 1.0 to 2.1 mg/dL and urine myoglobin level to 1,190 μ g/dL (N

Effect of cocaine on leakage of creatine kinase from isolated fast and slow muscles of rat

Since patients with cocaine overdose were reported to develop rhabdomyolysis involving skeletal muscle damage leading to elevated levels of serum creatine kinase (CK), we determined whether cocaine can directly act on isolated rat skeletal muscles and increase the leakage of CK. In the fast-twitch muscle such as the extensor digitorum longus (EDL), following exposure to normal physiological solution for 1, 2, 3, and 4 hr, the mean leakage of CK was 0.6, 0.7, 0.9, and 1.2 units/mg of muscle respectively. On exposure of EDL to 0.1, 0.5, and 1.0 mM cocaine, there was no significant change in CK leakage. In the slow-twitch muscle such as the soleus, following exposure to normal physiological solution for 1, 2, 3, and 4 hr, the mean leakage of CK was 1.5, 2.2, 2.7, and 3.1 units/mg, which was significantly greater (P < 0.001) than in EDL at each time interval. On exposure of soleus to 0.1 mM cocaine, the CK leakage did not increase significantly, but on exposure to 0.5 mM cocaine, it significantly increased to 2.4, 3.4, 4.4, and 5.7 units/mg, and on exposure to 1.0 mM cocaine, it further increased to 2.7, 4.9, 6.5, and 7.6 units/mg. The CK activity of fresh muscle homogenate was 115.5 units/mg in EDL and 51.9 units/mg in soleus. These results indicate that cocaine can directly act on skeletal muscle and increase the leakage of CK especially from slow-twitch muscle like soleus, but not from fast-twitch muscle like EDL.

SPONTANEOUS END‐PLATE ACTIVITY IN NORMAL SUBJECTS AND IN PATIENTS WITH MYASTHENIA GRAVIS*

Insertion of a needle or wire electrode into any part of a muscle provokes a burst of electrical activity which has been attributed to injury of muscle or nerve fibers. This insertion activity outlasts movement of the electrode by a fraction of a second, following which normal muscle, if relaxed, is electrically silent everywhere except in the region where the motor end plates are localized. It has been known for many years from the studies of Jones and B ~ c h t h a l * ~ ~ and their associates that in this region spontaneous negative discharges can be recorded in man for minutes, and that these discharges resemble, in their configuration and duration, miniature end-plate potentials recorded with intracellular microelectrodes in excised muscle of experimental animals by Katz and his ass0ciates,4,~ Liley,s and others. Recently, Wiederholt has provided additional evidence from studies in the rabbit that this spontaneous end-plate activity is due to miniature end-plate potentials. Dahlback and his associates8 reported that miniature end-plate potentials recorded with intracellular electrodes in excised intercostal muscle of patients with myasthenia gravis had normal amplitude and decreased frequency. A later study from the same laboratory by Elmqvist and his associatess reported that these potentials had normal frequency and reduced amplitude (one-fifth of normal). Reduction in amplitude of end-plate potentials could be due to a decrease in the release of transmitter from the motor nerve terminals, to a decrease in the action of transmitter on the end plates, or to both. Elmqvist and his associates also reported that the chemosensitivity of excised intercostal muscle of myasthenic patients to bath-applied acetylcholine ( ACh) ,* carbaminoylcholine or decamethoniums was normal, which led them to conclude that the reduced amplitude of end-plate potentials and the weakness in these patients are due to decreased transmitter release. However, the threshold doses of intraarterially injected ACh necessary to produce a visible muscle twitchsa or to depress the muscle action potential response to nerve stimulation were found to be higher in myasthenic patients than in normal subjects.10 Furthermore, the injection of ACh was followed by much more marked elevation in this threshold dose of ACh, and more depression of the muscle action potential response to nerve stimulation in myasthenic patients than in normal subjects.lO*ll These observations were interpreted as indicating decreased reactivity of the muscle of myasthenic patients to ACh, and aggravation of this decreased reactivity after exposure to ACh.l0J1 Since the studies on miniature end-plate potentials of myasthenic patient^^,^ were carried out on excised intercostal muscles which may have had varying degrees of involvement by the disease, observations in the current study were made on spontaneous end-plate activity of intact, weak muscles of myasthenic

Peripheral mechanisms of fatigue in muscles of normal and dystrophic mice

We evaluated the contribution of different processes to fatigue of normal and dystrophic mouse muscles using an in vitro electromyography chamber. Fatigue was induced by repetitive nerve stimulation at 30 Hz for 0.5 s, every 2.5 s until tension decreased by about 50%. We monitored the compound nerve action potential (AP), compound muscle AP, and isometric tension responses to nerve stimulation, and compound muscle AP and tension responses to direct muscle stimulation. In normal mice, about 50% reduction in nerve-evoked tension occurred by 2.4 min in extensor digitorum longus (EDL), 4.8 min in diaphragm, and 9 min in soleus. Analysis of the responses revealed that the fatigue was caused by failure of more than one process in all muscles, and failure of nerve conduction did not contribute to fatigue in any muscle. Failure of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 55, 45, and 0%, respectively, of the fatigue in EDL, for 21, 74, and 5% of the fatigue in diaphragm, and for 2, 54, and 44% of the fatigue in soleus. In dystrophic mice, while about 50% reduction in nerve-evoked tension occurred by 8.1 min in EDL and 5.6 min in diaphragm, only 29% reduction in tension occurred by 80 min in soleus. Failure of neuromuscular transmission, muscle membrane excitation, E-C coupling and contractility accounted for 22, 63 and 15% of the fatigue in EDL, for 21, 79, and 0% of the fatigue in diaphragm, and for 15, 59, and 26% of the fatigue in soleus. The proportion of slow-twitch oxidative fibers was more than normal in dystrophic EDL, but the same as normal in dystrophic diaphragm and soleus. The slower onset of fatigue was attributable to lesser failure of neuromuscular transmission in dystrophic EDL, and to lesser failure of E-C coupling and contractility in dystrophic soleus.