Myasthenic Lambert-Eaton syndrome: causes, symptoms, diagnosis, treatment

Myasthenic Lambert-Eaton syndrome is characterized by fatigue and muscle fatigue during exercise, which are most pronounced in the proximal part of the lower extremities and the trunk and are sometimes accompanied by myalgias. The involvement of the upper limbs and external muscles of the eyes in the myasthenic syndrome of Lambert-Eaton is observed less frequently than with myasthenia gravis.

Patients with myasthenic syndrome Lambert-Eaton can be particularly difficult to get up from a sitting or lying position. However, short-term maximum possible voluntary muscle tension temporarily improves their function. Although severe weakness of the respiratory muscles in the myasthenic syndrome of Lambert-Eaton is rare, recognizing this complication, which is sometimes the main manifestation of the syndrome, can save the patient's life. Most patients with Lambert-Eaton myasthenic syndrome develop autonomic dysfunction, which is manifested by a decrease in salivation, sweating, loss of pupillary reactions to light, orthostatic hypotension and impotence. In the majority of patients, deep tendon reflexes are weakened or drop out, but they can briefly normalize after a short maximum muscle strain, on the tendon of which a stroke is caused when the reflex is called.

[1], [2], [3], [4], [5], [6], [7]

What causes myasthenic Lambert-Eaton syndrome?

Myasthenic Lambert-Eaton syndrome often occurs in men than in women. Approximately two-thirds of patients, especially men over 40 years of age, myasthenic Lambert-Eaton syndrome occurs against a malignant neoplasm. Approximately 80% of them have small cell lung cancer, the manifestations of which can be apparent at the time of diagnosis of the myasthenic syndrome of Lambert-Eaton, but sometimes become noticeable only after several years. Less commonly, the myasthenic Lambert-Eaton syndrome arises out of association with malignant neoplasms.

The pathogenesis of myasthenic syndrome Lambert-Eaton

Experimental data indicate that the violation of neuromuscular transmission and muscle weakness in the myasthenic syndrome of Lambert-Eaton are associated with a decrease in the release of acetylcholine from the endings of motor fibers. It is suggested that the pathological process is triggered by autoimmune mechanisms, primarily antibodies against potential-dependent calcium channels or associated proteins that alter the morphology of the membrane, the number of calcium channels, or the calcium current through these channels.

The assumption of the role of immune mechanisms in the pathogenesis of the myasthenic syndrome of Lambert-Eaton was originally made on the basis of clinical observations. This was indicated by the frequent combination of myasthenic Lambert-Eaton syndrome with autoimmune diseases (in patients without malignant neoplasms) or the importance of immune mechanisms in the pathogenesis of paraneoplastic syndromes (in patients with malignant neoplasms). The first direct evidence of the importance of immune mechanisms was obtained with the passive transfer of a physiological deficit characteristic of the myasthenic syndrome of Lambert-Eaton, with the help of IgG. After injection of IgG mice from a patient with myasthenic Lambert-Eaton syndrome, a decrease in the release of acetylcholine from the nerve endings was observed, similar to that found in the study of the intercostal muscle biopsy in patients with myasthenic Lambert-Eaton syndrome. The pathophysiological effect of passive transfer was noted also in the case when the release of acetylcholine was caused by electrical stimulation and potassium-induced depolarization. Since no postsynaptic changes were detected, the effect was attributed to the disruption of the functioning of presynaptic motor endings.

After passive transfer of myasthenic Lambert-Eaton syndrome with IgG, changes in the extracellular calcium concentration may increase the release of acetylcholine from the endings of motor fibers to normal levels. This indicates that IgG disrupt the passage of calcium through specific potential-dependent calcium channels in the presynaptic membrane. Since these channels are part of the core particles, it is not surprising that with free-chipping electron microscopy, changes in the morphology of core particles in the terminals of nerve fibers in patients with myasthenic Lambert-Eaton syndrome and in mice that are passively transferred by IgG . This can serve as evidence that potential-dependent calcium channels serve as the target of an immune attack in the myasthenic syndrome of Lambert-Eaton. Further studies confirmed that IgG in the myasthenic Lambert-Eaton syndrome reduces the number of core particles by antigen modulation. Specific for IgM of Lambert-Eaton IgG can also disrupt mediator release by sympathetic or parasympathetic termini, affecting the functioning of one or more subtypes of potential-dependent calcium channels.

In vitro, it was shown that antibodies specific for myasthenic Lambert-Eaton syndrome disrupt the function of calcium channels in small cell lung cancer cells, which confirms the relationship between the presence of antibodies to calcium channels and the myasthenic Lambert-Eaton syndrome induced by small cell lung cancer. Potential-dependent calcium channels that affect the release of acetylcholine by presynaptic mammalian terminals belong predominantly to P- and Q-types. Thus, although IgG in the myasthenic syndrome of Lambert-Eaton are able to react with various types of calcium channels in small cell lung cancer cells, the disruption of calcium release by presynaptic motor termini in the myasthenic Lambert-Eaton syndrome is most likely due to their interaction with P-type channels.

Using immunoprecipitation with human cerebellar extract and ligand of P and Q channels, labeled with isotope 1125 (omega-conotoxin MVIIC) in 66 of 72 serum samples obtained from patients with myasthenic Lambert-Eaton syndrome, antibodies to potential- dependent calcium channels, while antibodies to N-type channels were detected only in 24 of 72 cases (33%). Thus, antibodies to potential-dependent calcium channels of P- and Q-types are detected in a significant majority of patients with myasthenic Lambert-Eaton syndrome and, apparently, mediate a violation of neuromuscular transmission. However, the results obtained by immunoprecipitation with labeled extracts could also be interpreted in such a way that the target of the autoimmune reaction in the myasthenic Lambert-Eaton syndrome is tightly adherent proteins, rather than the calcium channels themselves. To reject this assumption, we should demonstrate the ability of antibodies to react with specific protein components of calcium channels, which was done. Antibodies to one or both of the synthetic peptides of the alpha2 subunit of the calcium channels of the P and Q types were detected in 13 of 30 patients with the myasthenic syndrome of Lambert-Eaton. In a study of 30 serum samples, 9 reacted with one epitope, 6 with another, and 2 with both epitopes. Thus, data are accumulating that the potential-dependent calcium channels of the P and Q types are the main target of the immune attack. However, additional studies are needed to identify the antibodies and epitopes with which pathophysiological changes are associated with the myasthenic Lambert-Eaton syndrome.

As with other autoimmune diseases, antibodies in the myasthenic Lambert-Eaton syndrome can be directed against several proteins. Thus, in patients with myasthenic Lambert-Eaton syndrome, antibodies to synaptotagmine, immunization which can induce a model of myasthenic Lambert-Eaton syndrome in rats, have also been revealed. Antibodies to synaptotagmine, however, have been detected only in a small proportion of patients with myasthenic syndrome Lambert-Eaton. More research is needed to determine whether antibodies to synaptotagmine play a role in the pathogenesis of myasthenic Lambert-Eaton syndrome, even for this small proportion of patients, or is it the manifestation of an "antigenic overlap" with the production of antibodies to proteins that are closely related to potential-dependent calcium channels that do not have pathogenetic significance.

Symptoms of myasthenic syndrome Lambert-Eaton

An idiopathic version of the myasthenic syndrome of Lambert-Eaton can occur at any age, more often in women, and be combined with other autoimmune diseases, including thyroid pathology, juvenile diabetes and myasthenia gravis. Myasthenic Lambert-Eaton syndrome is usually easily distinguished from myasthenia by the distribution of muscle weakness. At the same time, the symptoms of myasthenic syndrome Lambert-Eaton are able to simulate motor polyneuropathy and even motor neuron disease. To confirm the diagnosis and exclude other neuromuscular diseases, additional research methods are often needed.

Diagnosis of myasthenic syndrome Lambert-Eaton

In the diagnosis of myasthenic syndrome Lambert-Eaton, EMG is especially useful. A short-term increase in muscle strength after their maximum load with EMG corresponds to an increase in the M-response at the maximum arbitrary effort. The amplitude of the M-response in nerve stimulation by single supramaximal stimuli is usually reduced, which corresponds to a reduced release of acetylcholine, which is insufficient to generate action potentials in many neuromuscular synapses. However, after the maximum arbitrary muscle tension, the amplitude of the M-response increases for a period of 10-20 s, which reflects the increased release of acetylcholine. When stimulated at a frequency exceeding 10 Hz for 5-10 s, the amplitude of the M-response temporarily increases. Stimulation with a frequency of 2-3 Hz can cause a decrement with a decrease in the amplitude of the M-response, whereas after the load, recovery and an increase in the amplitude of the M-response are 10-300%. With needle EMG, low-amplitude short-time potentials of motor units and variablely increased polyphase potentials are recorded. With EMG of individual fibers, the average interpotential interval can be increased even in clinically intact muscles, which reflects a violation of neuromuscular transmission. Changes in EMG after maximum exercise and stimulation help distinguish myasthenic Lambert-Eaton syndrome from motor polyneuropathy, motor neuron disease and myasthenia gravis.

A study of muscle biopsy with myasthenic Lambert-Eaton syndrome usually does not reveal pathology, but sometimes nonspecific changes are observed, for example, atrophy of type 2 fibers. Despite the fact that the available data indicate the important role of neuromuscular transmission disorders, primarily at the level of presynaptic endings, conventional electron microscopy usually does not reveal changes. Only an advanced method of electron microscopy with freezing and shearing reveals specific changes, but this method is usually not used in clinical laboratories.

[8], [9], [10], [11], [12]

Treatment of myasthenic syndrome Lambert-Eaton

With myasthenic Lambert-Eaton syndrome, which occurs against the background of malignant neoplasm, treatment should be directed primarily at combating the tumor. Successful tumor therapy can lead to regression of symptoms and MCLI. With myasthenic Lambert-Eaton syndrome, not associated with malignant neoplasms, treatment should be directed to immune processes and increased calcium intake. The latter can be achieved by blocking the release of potassium from the cell at the level of the presynaptic end. To obtain this physiological effect, 3,4-diaminopyridine can be used. It is shown that this compound is able to reduce the severity of motor and autonomic manifestations of the myasthenic syndrome of Lambert-Eaton. The effective dose of 3,4-diaminopyridine varies from 15 to 45 mg / day. Taking the drug at a dose exceeding 60 mg / day, is associated with the danger of epileptic seizures. When taking lower doses, side effects such as paresthesia, increased bronchial secretion, diarrhea, and palpitations are possible. Currently, the drug is not used in a wide clinical practice.

Symptomatic improvement in myasthenic Lambert-Eaton syndrome can be achieved with guanidine, but this drug is very toxic. At the same time, it was reported that the combination of small doses of guanidine (below 1000 mg / day) with pyridostigmine is safe and able to provide a lasting symptomatic effect in the myasthenic syndrome of Lambert-Eaton.

In the long term, treatment of myasthenic syndrome Lambert-Eaton should be aimed at eliminating the main reason for limiting the entry of calcium into the cell, that is, the immune processes and the production of antibodies against the potential-dependent calcium channels of presynaptic terminals. In the myasthenic syndrome of Lambert-Eaton, the efficacy of corticosteroids, plasmapheresis, and / or immunoglobulin has been demonstrated. However, the experience of using these tools is limited, accordingly, there are no relevant scientific data on the basis of which it would be possible to make a rational choice of the treatment method for this particular patient. In a randomized, double-blind, placebo-controlled, cross-over, 8-week trial, 9 patients with IV immunoglobulin (2 g / kg for 2 days) improved after 2-4 weeks, but by the end of 8 weeks, the therapeutic effect was gradually depleted. It is curious that a short-term improvement occurred against a background of a decrease in the antibody titer to the calcium channel. However, this decrease was observed for such a short period of time that, apparently, was caused by direct or indirect neutralization of immunoglobulin antibodies to the calcium channels - this may have been the reason for the clinical improvement. However, we can not exclude the delayed effect of anti-idiotypic antibodies or some other mechanisms. In one of the reports, the monthly administration of iv immunoglobulin (2 g / kg for 5 days) led to a persistent improvement in the patient with myasthenic syndrome Lambert-Eaton, which occurred in the absence of an explicit oncological process. As already mentioned, the side effects of IV immunoglobulin are relatively small. The use of immunoglobulin and plasmapheresis is constrained mainly by the high cost and relative short-term effect, which requires regular repeated procedures. It is possible, however, that the addition of intravenous corticosteroids to the intravenous immunoglobulin potentiates its effect and allows maintaining the clinical effect without resorting to its frequent repeated administration.