Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis

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.     

Familial infantile myasthenia: a neuromuscular cause of respiratory failure

Acute respiratory failure can be the product of any of a great number of muscular, neuromuscular, and neurologic causes. The family history may be extremely helpful in narrowing the differential diagnosis. We report the case of a girl who, during the course of a slight upper respiratory infection, presented with acute respiratory failure requiring mechanical ventilation. The family history was significant for a brother who had arthrogryposis and died at 15 h of life, also from respiratory failure. The patient herself had a history of palpebral ptosis in the evening. The absence of electromyographic and muscle biopsy abnormalities and the patient's positive response to anticholinesterase therapy supported the diagnosis of familial infantile myasthenia. We emphasize the importance of considering the myasthenic syndromes in the differential diagnosis of acute respiratory failure, since appropriate therapy can rapidly resolve the symptoms. Furthermore, an accurate diagnosis allows appropriate genetic counseling for the hereditary forms.     

Anti-MuSK-positive myasthenia gravis: neuromuscular transmission failure in facial and limb muscles

The presence of antibodies against muscle-specific receptor tyrosine kinase (MuSK) appears to define a subgroup of patients with myasthenia gravis (MG) characterized by weakness predominant in bulbar, facial and neck muscles compared with anti-acetylcholine receptor (AChR) antibody-positive MG. To investigate the patterns and severity of neuromuscular transmission failure in different muscles in MuSK-positive MG, we performed single fiber electromyography (SFEMG) in the facial (frontalis) and limb (extensor digitorum communis, EDC) muscles in three anti-Musk-positive patients, and compared results with those of 11 anti-AChR-positive patients. Only one of the three MuSK-positive patients had abnormal jitter in EDC, but all the three showed clearly increased jitter in the frontalis. By contrast, the AChR-positive patients showed similarly abnormal jitter for the two muscles. These results suggest that when the diagnosis of anti-MuSK-positive MG is suspected, SFEMG should be performed in most prominently affected muscles.     

Ventilatory failure in myasthenia gravis.

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.     

Prednisone-induced worsening of neuromuscular function in myasthenia gravis

In patients with myasthenia gravis who received single doses of prednisone orally (40 to 100 mg), we found acute inhibition of neuromuscular function as manifest by increased decremental responses to repetitive nerve stimulation, reduced twitch tension, and lowered maximum voluntary contraction strength. The time course of these changes correlated with plasma methylprednisolone levels, implying direct drug effects on neuromuscular function.     

Influence of temperature on neuromuscular transmission in myasthenia gravis

Summary The effect of local cooling was studied in 28 patients with myastenia gravis. We stimulated the ulnar nerve with single stimuli and trains at 3/s for 2s and at 50/s for 1.5s. The compound muscle action potential (MAP), the muscle twitch and the isometric tetanic force of the adductor pollicis were registered. 1. At 3/s stimulation the pathological decrement of the MAP decreased after slight cooling. 2. The amplitude of the single MAP was higher at lower temperature when compared to normal temperature. The same increase is however to be found in healthy subjects. 3. After slight cooling, the maximum tetanic force was higher. However, the decrement of the force was higher also, therefore ruling out a practicable application of cooling for the patient. 4. After severe cooling (18–22°C) the tetanic force was much lower and in many cases a complete failure of the neuromuscular transmission occured.

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Zusammenfassung Der Einfluß lokaler Kühlung wurde an 28 Patienten mit Myasthenia gravis untersucht. Wir reizten den N. ulnaris mit einzelnen Impulsen und mit Serien von 3/s für 2s und von 50/s für 1.5s. Das Summenaktionspotential (MAP), die Muskelzuckung und die isometrische tetanische Kraft des Adduktor pollicis wurden registriert. 1. Bei Reizung mit 3/s war das pathologische Dekrement des MAP nach leichter Kühlung geringer. 2. Die Amplitude des MAP war größer. Diese Amplitudenzunahme tritt jedoch auch bei Gesunden nach Kühlung auf. 3. Nach leichter Kühlung war die maximale tetanische Kraft größer. Jedoch nahm die Kraft während der Reizung nach dem Maximum wieder schnell ab. Der praktische Nutzen einer Kühlung ist deshalb für den Patienten gering. 4. Nach starker Kühlung (18–22°C) war die maximale tetanische Kraft sehr niedrig. In vielen Fällen kam es zu einem vollständigen Versagen der neuromuskulären Impulsübertragung.

     

Effects of napping on neuromuscular fatigue in myasthenia gravis

Introduction: The relationship between sleep and neuromuscular fatigue is understood poorly. The goal of this study was to evaluate the effects of napping on quantitative measures of neuromuscular fatigue in patients with myasthenia gravis (MG). Methods: Eight patients with mild to moderate MG were recruited. Patients underwent maintenance of wakefulness tests (MWT) and multiple sleep latency tests (MSLT). The Quantitative Myasthenia Gravis Score (QMGS) was measured before nap and after each nap to examine the effects of napping and sleep on neuromuscular weakness. Results: Results showed that QMGS improves only after naps where patients slept more than 5 min but not where patients did not sleep or slept less than 5 min. Conclusions: Daytime napping mitigates neuromuscular fatigue in patients with MG, especially if patients slept for more than 5 min. Muscle Nerve 48:816–818, 2013     

Disorders of neuromuscular transmission other than myasthenia gravis

Disorders of neuromuscular transmission in humans are caused by a wide variety of agents including systemic diseases, drugs, environmental toxins, animal envenomation, cations, and hormones. Some are genetically determined. Many are of known etiology. All such disorders interfere with one or more events in the sequence whereby a nerve impulse excites a muscle action potential. In many disorders of neuromuscular transmission, abnormal fatigue occurs, and some cases respond dramatically to treatment. Investigation of the microphysiology, microanatomy, and pharmacology of both normal and diseased neuromuscular junctions has increased our knowledge of these disorders.     

Effect of high temperature on neuromuscular jitter in myasthenia gravis

To examine if the effect of temperature on neuromuscular jitter differs in myasthenics and normals, we performed single fiber electromyography (SFEMG) in 10 myasthenics and 10 healthy controls after heating the upper extremity to 37 and 42 degrees C. In each case, 10-24 mean consecutive difference (jitter) values were obtained at both temperatures. All jitters were pooled appropriately and the groups were compared with each other. The mean jitter was 33.4 +/- 10.4 micros at 37 degrees C and 28.2 +/- 11.4 micros at 42 degrees C in controls, and 48.3 +/- 18.3 micros at 37 degrees C and 54.8 +/- 24.9 micros at 42 degrees C in patients. Seven out of 10 patients showed SFEMG abnormalities at 37 degrees C. The number of patients with SFEMG abnormalities rose to 9 after heating to 42 degrees C. Heating decreases neuromuscular jitter in controls and increases it in myasthenics. SFEMG performed at higher temperatures may increase the diagnostic sensitivity of the method in myasthenia gravis. The change of jitter with temperature in opposite directions in myasthenics and normals could be helpful to detect neuromuscular dysfunction.     

Serum factor blocks neuromuscular transmission in myasthenia gravis: electrophysiologic study with intracellular microelectrodes.

We studied the effects of normal and myasthenic sera on the miniature endplate potential (MEPP) and resting membrane potential (RP) of rat muscle in vitro by conventional intracellular microelectrode techniques. Normal sera had little or no effect on either the amplitude or frequency of MEPP or RP. On the other hand, MEPP amplitude was reduced in each of nine muscles during exposure to myasthenic sera; five of these muscles showed a significant difference, by student's t-test, from the values in a control solution. The half decay time of diminished MEPP remained unchanged. MEPP frequency and RP were not affected by myasthenic sera. The reduced amplitude of the MEPP was almost completely restored when the muscle was washed with a control solution for more than 30 minutes. These observations indicate that myasthenic sera contain factors that bind reversibly with the acetylcholine receptor and reduce postsynaptic responses to acetylcholine.     

Citrate-induced impairment of neuromuscular transmission in human and experimental autoimmune myasthenia gravis

Two patients who underwent plasmapheresis for severe myasthenia gravis showed marked exacerbation of myasthenic weakness at the end of exchange sessions, in which citrate was used for anticoagulation. In one patient, improvement occurred after the administration of calcium but not after edrophonium. In rabbits and in rats with experimental autoimmune myasthenia gravis, decremental muscle response to 3 Hz repetitive nerve stimulation worsened significantly after injection of the citrate anticoagulant. The worsened neuromuscular transmission defect was reversed by the administration of calcium. When used for anticoagulation, citrate reduces serum ionized calcium levels and thus may aggravate myasthenic weakness and endanger patients during or immediately after plasmapheresis.     

A neuromuscular transmission disorder: combined myasthenia gravis and Lambert Eaton syndrome in one patient.

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.     

Analysis of anticholinesterase-induced neuromuscular transmission failure

To define the underlying mechanism of neuromuscular transmission failure induced by anticholinesterases, we simultaneously performed surface recordings of compound muscle action potentials (CMAPs) and intracellular recordings of miniature end-plate potentials (MEPPs), miniature end-plate current (MEPCs), and end-plate potential (EPPs) in rat diaphragms exposed in vitro to 1 × 10^?4 to 2 × 10^?2 mmol/L neostigmine methylsulfate. At low concentrations of neostigmine, repetitive stimulation of the phrenic nerve resulted in decrement followed by complete recuperation of CMAP amplitudes. This bimodal pattern was associated with maximal end-plate depolarization at the beginning of the stimulation period, increased MEPP amplitudes, and prolonged time constants of MEPC decays. Higher concentrations of neostigmine resulted in a unimodal decline of amplitudes of CMAPs and EPPS, reduced MEPP amplitudes, and a double exponential time course of MEPC decays. These results indicate that low concentrations of anticholinesterases impaired neuromuscular transmission by producing transient depolarization of the end-plate region. Higher concentrations induced desensitization and direct blockade of the end-plate receptor channel, probably in its open conformation. © 1993 John Wiley & Soncs, Inc.     

Further electrophysiological studies of neuromuscular transmission in an animal model of myasthenia gravis

The development of experimental autoimmune myasthenia gravis (EAMG) in rats produces a significant reduction in the amplitude of spontaneously occurring miniature end-plate potentials (MEPPs) and impulse-evoked end-plate potentials (EPPs). This junctional abnormality, however, does not impair the ability of the affected fibers to produce propagated muscle action potentials of normal amplitude. Quantal content analysis indicates that in Mg²⁺-blocked EAMG muscle the mean number of acetylcholine (ACh) quanta released per nerve impulse closely approximates the corresponding normal value. At EAMG end-plates, the depolarization produced by either saturating or nonsaturating doses of carbamylcholine was significantly less than that seen at normal end-plates, suggesting a reduced acetylcholine receptor (AChR) content. When the depolarizing response to 250 μm carbamylcholine was examined at various EAMG end-plates with different sizes of MEPPs, there was a direct correlation between the carbamylcholine-induced depolarization and the MEPP amplitude; this correlation, however, was much less pronouced in normal end-plates, which supports the concept that the MEPP size in the receptor-immunized muscle reflects the content of the functional postsynaptic AChR. In control solution, the indirect twitch tension produced in EAMG muscle was normal. The twitch tension in EAMG muscle however, was almost completely abolished by a dose of d-tubocurarine that reduced the tension in normal muscle by only 50%. When 4-aminopyridine, a drug known to increase the quantum content of EPPs, was applied to curarized normal or EAMG muscles, normal muscle contraction was restored and the decremental response to repetitive nerve stimulation was abolished. We conclude that the major defect of neuromuscular transmission in EAMG results from postsynaptic abnormalities at the end-plates, presumably secondary to reduction of the number of functional AChRs. Chronic EAMG in rats is a reasonable model of human myasthenia gravis in which a similar defect of neuromuscular transmission is present.     

Quantitative correlation between plasma pyridostigmine levels and neuromuscular function in myasthenia gravis

In 10 patients with myasthenia gravis, we studied the relationship between plasma pyridostigmine levels and five measures of neuromuscular function (NMF) following single oral doses of 60 to 120 mg. The NMF measures were percent decrement of the evoked muscle compound potential, maximum force, force-time integral, vital capacity, and outstretched-arm time. The combined mean improvement was most significant 2 hours after pyridostigmine ingestion and coincided with the peak plasma pyridostigmine levels in eight patients. In seven patients, there was a positive correlation between plasma pyridostigmine levels and the mean percent improvement.