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

Lambert-Eaton myasthenic syndrome is characterized by muscle weakness and fatigability with exertion, which are most pronounced in the proximal lower extremities and trunk and are sometimes accompanied by myalgia. Involvement of the upper extremities and extraocular muscles in Lambert-Eaton myasthenic syndrome is less common than in myasthenia gravis.

Patients with Lambert-Eaton myasthenic syndrome may have particular difficulty rising from a sitting or lying position. However, brief, maximal voluntary muscle tension temporarily improves muscle function. Although severe weakness of the respiratory muscles is rare in Lambert-Eaton myasthenic syndrome, recognizing this complication, which is sometimes the main manifestation of the syndrome, can be life-saving. Most patients with Lambert-Eaton myasthenic syndrome develop autonomic dysfunction, which is manifested by decreased salivation, sweating, loss of pupillary light reactions, orthostatic hypotension, and impotence. Most patients experience weakened or absent deep tendon reflexes, but they may return to normal briefly after brief maximal muscle tension, the tendon of which is struck when eliciting the reflex.

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What causes Lambert-Eaton myasthenic syndrome?

Lambert-Eaton myasthenic syndrome occurs more often in men than in women. In about two-thirds of patients, especially in men over 40 years of age, Lambert-Eaton myasthenic syndrome occurs against the background of a malignant neoplasm. About 80% of them are found to have small cell lung cancer, the manifestations of which may be obvious at the time of diagnosis of Lambert-Eaton myasthenic syndrome, but sometimes become noticeable only after several years. Less often, Lambert-Eaton myasthenic syndrome occurs without connection with malignant neoplasms.

Pathogenesis of Lambert-Eaton myasthenic syndrome

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

The role of immune mechanisms in the pathogenesis of Lambert-Eaton myasthenic syndrome was initially suggested by clinical observations. This was indicated by the frequent combination of Lambert-Eaton myasthenic 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 by passive transfer of the physiological deficit characteristic of Lambert-Eaton myasthenic syndrome using IgG. After injection of IgG from a patient with Lambert-Eaton myasthenic syndrome into mice, a decrease in the release of acetylcholine from nerve endings was observed, similar to what was revealed in the study of intercostal muscle biopsy in patients with Lambert-Eaton myasthenic syndrome. The pathophysiological effect of passive transfer was also observed when acetylcholine release was induced by electrical stimulation and potassium-induced depolarization. Since no postsynaptic changes were observed, the effect was attributed to a disturbance in the functioning of presynaptic motor terminals.

Following passive transfer of LEMS with IgG, changes in extracellular calcium concentration can increase acetylcholine release from motor fiber terminals to normal levels. This suggests that IgG interferes with calcium flow through specific voltage-gated calcium channels in the presynaptic membrane. Since these channels are part of the active zone particles, it is not surprising that freeze-fracture electron microscopy reveals changes in the morphology of the active zone particles in nerve fiber terminals from LEMS patients and from mice passively transferred with IgG. This may provide evidence that voltage-gated calcium channels are the target of immune attack in LEMS. Further studies have confirmed that LEMS IgG downregulates the number of active zone particles by antigen modulation. Lambert-Eaton myasthenic syndrome-specific IgG may also interfere with sympathetic or parasympathetic mediator release by affecting the functioning of one or more voltage-gated calcium channel subtypes.

In vitro, antibodies specific for Lambert-Eaton myasthenic syndrome were shown to impair calcium channel function in small cell lung cancer cells, confirming a link between the presence of calcium channel antibodies and small cell lung cancer-induced Lambert-Eaton myasthenic syndrome. The voltage-dependent calcium channels that influence acetylcholine release by mammalian presynaptic terminals are predominantly of the P- and Q-types. Thus, although Lambert-Eaton myasthenic syndrome IgGs are capable of reacting with various types of calcium channels in small cell lung cancer cells, the impairment of calcium release by presynaptic motor terminals in Lambert-Eaton myasthenic syndrome is most likely explained by their interaction with P-type channels.

Using the immunoprecipitation method with human cerebellar extract and a ligand of P- and Q-type channels labeled with isotope 1125 (omega-conotoxin MVIIC), antibodies to voltage-gated calcium channels were detected in 66 of 72 serum samples obtained from patients with Lambert-Eaton myasthenic syndrome, while antibodies to N-type channels were detected in only 24 of 72 cases (33%). Thus, antibodies to voltage-gated calcium channels of P- and Q-types are detected in the significant majority of patients with Lambert-Eaton myasthenic syndrome and, apparently, mediate the disturbance 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 Lambert-Eaton myasthenic syndrome is the tightly linked proteins rather than the calcium channels themselves. To reject this assumption, it would be necessary to demonstrate the ability of antibodies to react with specific protein components of calcium channels, which was done. Antibodies to one or both synthetic peptides of the alpha2 subunit of P- and Q-type calcium channels were detected in 13 of 30 patients with Lambert-Eaton myasthenic syndrome. In a study of 30 serum samples, 9 reacted with one epitope, 6 with the other, and 2 with both epitopes. Thus, evidence is accumulating that voltage-dependent P- and Q-type calcium channels are the main target of the immune attack. However, further studies are needed to identify the antibodies and epitopes associated with pathophysiological changes in LEMS.

As in other autoimmune diseases, antibodies in Lambert-Eaton myasthenic syndrome may be directed against several proteins. Thus, in patients with Lambert-Eaton myasthenic syndrome, antibodies to synaptotagmin have also been identified, immunization with which can induce a model of Lambert-Eaton myasthenic syndrome in rats. Antibodies to synaptotagmin have been identified, however, only in a small proportion of patients with Lambert-Eaton myasthenic syndrome. Further studies are needed to determine whether antibodies to synaptotagmin play any role in the pathogenesis of Lambert-Eaton myasthenic syndrome at least in this small proportion of patients or whether this is a manifestation of "antigen overlap" with the production of antibodies to proteins closely associated with voltage-dependent calcium channels, which have no pathogenetic significance.

Symptoms of Lambert-Eaton myasthenic syndrome

The idiopathic variant of Lambert-Eaton myasthenic syndrome can occur at any age, more often in women, and be combined with other autoimmune diseases, including thyroid pathology, juvenile diabetes mellitus, and myasthenia. Lambert-Eaton myasthenic syndrome is usually easily distinguished from myasthenia by the distribution of muscle weakness. At the same time, the symptoms of Lambert-Eaton myasthenic syndrome can imitate motor polyneuropathy and even motor neuron disease. Additional research methods are often necessary to confirm the diagnosis and exclude other neuromuscular diseases.

Diagnosis of Lambert-Eaton myasthenic syndrome

EMG is particularly useful in the diagnosis of Lambert-Eaton myasthenic syndrome. A short-term increase in muscle strength after maximal load on EMG corresponds to an increase in the M-response during maximal voluntary effort. The amplitude of the M-response during nerve stimulation with single supramaximal stimuli is usually reduced, which corresponds to a reduced release of acetylcholine, insufficient to generate action potentials in many neuromuscular synapses. However, after maximal voluntary muscle tension, the amplitude of the M-response increases for a period of 10-20 s, which reflects an increase in the release of acetylcholine. With stimulation at a frequency exceeding 10 Hz for 5-10 s, a temporary increase in the amplitude of the M-response occurs. Stimulation at 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 by 10-300% occur. Needle EMG records low-amplitude short-term motor unit potentials and variably increased polyphasic potentials. In individual fiber EMG, the mean interpotential interval may be increased even in clinically intact muscles, reflecting impaired neuromuscular transmission. EMG changes after maximal load and stimulation help differentiate Lambert-Eaton myasthenic syndrome from motor polyneuropathy, motor neuron disease, and myasthenia.

Muscle biopsy examination in Lambert-Eaton myasthenic syndrome is usually normal, but nonspecific changes such as type 2 fiber atrophy are occasionally found. Although the available data point to an important role for disturbances in neuromuscular transmission, especially at the presynaptic level, conventional electron microscopy usually does not reveal changes. Only an advanced freeze-fracture electron microscopy technique reveals specific changes, but this technique is not routinely used in clinical laboratories.

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Treatment of Lambert-Eaton myasthenic syndrome

In Lambert-Eaton myasthenic syndrome that occurs against the background of a malignant neoplasm, treatment should be aimed primarily at combating the tumor. Successful tumor therapy can lead to regression of symptoms and MI. In Lambert-Eaton myasthenic syndrome not associated with malignant neoplasms, treatment should be aimed at immune processes and increasing calcium intake. The latter can be achieved by blocking the release of potassium from the cell at the level of the presynaptic terminal. 3,4-diaminopyridine can be used to achieve this physiological effect. This compound has been shown to be able to reduce the severity of motor and vegetative manifestations of Lambert-Eaton myasthenic syndrome. The effective dose of 3,4-diaminopyridine ranges from 15 to 45 mg/day. Taking the drug in a dose exceeding 60 mg/day is associated with the risk of developing epileptic seizures. When taking lower doses, side effects such as paresthesia, increased bronchial secretion, diarrhea and palpitations are possible. The drug is currently not used in widespread clinical practice.

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

In the long term, treatment of Lambert-Eaton myasthenic syndrome should be aimed at eliminating the underlying cause of calcium entry restriction into the cell, i.e., immune processes and antibody production against voltage-dependent calcium channels of presynaptic terminals. In Lambert-Eaton myasthenic syndrome, corticosteroids, plasmapheresis, and intravenous immunoglobulin have been shown to be effective. However, experience with these agents is limited, and there are no relevant scientific data to guide a rational choice of treatment for a given patient. In a randomized, double-blind, placebo-controlled, crossover 8-week trial in 9 patients, intravenous immunoglobulin (2 g/kg for 2 days) resulted in improvement within 2-4 weeks, but by the end of 8 weeks, the therapeutic effect gradually wore off. Interestingly, short-term improvement occurred against the background of a decrease in the titer of antibodies to calcium channels. However, the decrease was observed for such a short period of time that it was probably due to direct or indirect neutralization of calcium channel antibodies by immunoglobulin, which may have been the cause of the clinical improvement. However, a delayed action of anti-idiotypic antibodies or some other mechanism cannot be excluded. In one report, monthly administration of intravenous immunoglobulin (2 g/kg for 5 days) resulted in sustained improvement in a patient with Lambert-Eaton myasthenic syndrome that developed in the absence of an overt oncologic process. As already mentioned, the side effects of intravenous immunoglobulin are relatively few. The use of immunoglobulin and plasmapheresis is limited mainly by the high cost and the relatively short duration of the effect, requiring regular repeat procedures. It is possible, however, that the addition of orally administered corticosteroids to intravenous immunoglobulin will potentiate its action and allow the clinical effect to be maintained without resorting to frequent repeat administrations.