Immunopathology of the Lambert-Eaton myasthenic syndrome

Summary LEMS is an antibody-mediated autoimmune disease that can occur in isolation, or as a paraneoplastic disorder in association with SCLC (60% of patients). The underlying defect is a reduction in the quantal release of the neurotransmitter ACh from the presynaptic nerve terminal at the neuromuscular junction. Experimental evidence indicates the autoantibodies are directed against nerve terminal VGCCs causing downregulation in the number of functional channels by cross-linkage. Functional VGCCs have been detected in SCLC cell lines. In cancer-associated LEMS it appears likely that antibodies initially provoked by tumour VGCCs cross-react with VGCCs at the nerve terminal, causing the clinical disorder.Antibodies against L-, N- and P-/Q- subtypes of the calcium channels have been identified and radioimmunoassays have been developed to help diagnose the disease. Using peptide toxin ^125I--CmTx MVIIC to label P-/Q-type VGCC solubilised from human cerebellum, positive antibody titres can be detected in 85% of patients. However, autoantibodies in LEMS are heterogenous; the antigenic targets include different VGCC subtypes, the intracellular beta subunit and the synaptic vesicle protein synaptotagmin. The disease phenotype may reflect the diversity and titre of these different antibodies.     

Lambert-Eaton myasthenic syndrome as an autoimmune calcium-channelopathy

Lambert-Eaton myasthenic syndrome (LEMS), often associated with small cell lung carcinoma (SCLC), is a disease of neuromuscular transmission in which antibodies directed against voltage-gated calcium channel (VGCC) in the motor nerve terminal play a crucial role in causing a deficient quantal release of acetylcholine. We focused attention on the P/Q-type VGCC, against which a majority of LEMS patients carry the specific antibody. Since the P/Q-type VGCC expresses in SCLC, the motor nerve terminal and SCLC may share a common VGCC antigen. In search for antigenic sites at the molecular level, We employed peptides or recombinant protein corresponding to the S5-S6 linker of each of four domains forming the alpha 1A subunit and tested their antigenicity. As the result, we specified the domain II, III and IV as immunodominant sites by the induction of an immune-mediated animal model of LEMS and the assay for antibodies in LEMS patients. Also, by use of peptides or recombinant protein corresponding to the synaptotagmin I, we found that in this VGCC-associated protein, the segment which exposes extracellularly during exocytosis can be antigenic for LEMS.     

Amifampridine for the treatment of Lambert-Eaton myasthenic syndrome

ABSTRACT

Introduction: The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed.

Areas covered: All relevant literature identified through a PubMed search under treatment of LEMS, aminopyridine, and amifampridine are reviewed. An expert opinion on AFP was formulated.

Expert opinion: AFPs, 3,4-DAP and 3,4-DAPP, are the most studied drugs in neuromuscular diseases. Randomized and non-randomized studies showed the most effective drug as symptomatic medication for LEMS. AFPs are safe and tolerable. Thus, AFPs should be the drug of choice for the symptomatic treatment in LEMS.

As long as the daily dose is less than 80 mg a day, there is no concern for the serious side-reaction, seizure. Because of short-acting drug effects, it should be given three or four times a day. Peri-oral and finger paresthesia, the most common side-reaction, is accepted as a sign of drug-intake by many patients. Gastro-intestinal side reactions, the next common side-reaction of AFPs, are tolerable. AFPs are also the drug of choice and life-saving for LEMS crisis. For the long-term usage, it is proven to be safe and AFPs can be supplemented with liberal amount of pyridostigmine to sustain a symptomatic improvement without any undue side-reaction.     

3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction, which result from impaired release of acetylcholine from cholinergic nerve terminals. It is frequently associated with cancer, it is autoimmune-mediated, and treatment has been unsatisfactory. 3,4-Diaminopyridine enhances the release of acetylcholine. In this prospective, double-blind, placebo-controlled crossover study of 12 patients with Lambert-Eaton myasthenic syndrome (7 of whom had cancer), 3,4-diaminopyridine in doses up to 100 mg per day was effective in treating both the motor and the autonomic deficits of the syndrome. Muscle strength increased from an average of 70 percent of normal to 81 percent of normal in the upper extremities, and from 45 to 65 percent of normal in the lower extremities. The amplitudes of compound-muscle-action potentials nearly doubled, increasing from an average of 2.9 mV to 5.0 mV in the arm and from 1.6 mV to 3.1 mV in the leg. Autonomic symptoms were relieved. One patient had a seizure after 10 months of treatment, but other side effects from the drug were minimal and dose-related. We conclude that 3,4-diaminopyridine, either alone or in conjunction with other therapies, may be useful in the treatment of Lambert-Eaton myasthenic syndrome.     

3,4-diaminopyridine for the treatment of Lambert-Eaton myasthenic syndrome

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which antibodies against voltage-gated calcium channels inhibit cholinergic neurotransmission. LEMS is clinically characterized by muscle weakness and autonomic dysfunction. 3,4-diaminopyridine (3,4-DAP) blocks potassium channels in nerve terminals, resulting in an increase in acetylcholine release. This article describes the four randomized placebo-controlled trials of 3,4-DAP in patients with LEMS. All trials demonstrated a significant effect on muscle strength and compound muscle action potential amplitude. Furthermore, the safety and tolerability of 3,4-DAP are reviewed. The side effects of 3,4-DAP are generally mild and most frequently consist of paresthesias, but epileptic seizures and arrhythmias have been described in patients using high doses. Given the efficacy and safety of 3,4-DAP in LEMS, this drug is the mainstay for symptomatic treatment of LEMS.     

A case of Lambert-Eaton myasthenic syndrome with possible myasthenia gravis

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission (NMJ) that shares many clinical features with myasthenia gravis (MG). We report a 73 year-old lady who presented 10 years previously with stiffness of both calves, dry mouth, fatigue, proximal weakness and areflexia in lower limbs. Neurophysiological studies were consistent with LEMS. Her work up for an underlying neoplasm was negative. She recently developed unilateral ptosis and diplopia which dramatically improved with pyridostigmine suggesting concomitant MG.     

Lambert-Eaton myasthenic syndrome. Clinical and electrophysiological findings in seven cases

We report the clinical and electrophysiological findings in seven patients with Lambert-Eaton myasthenic syndrome (LEMS). All patients were males aged 40-73 years old. Six presented proximal muscle weakness and one both proximal and distal. The tendon reflexes were absent in four patients, depressed in two and normal in one patient. Three patients presented ophthalmic and four autonomic symptoms. The syndrome was diagnosed 3-12 months after the onset of symptoms in six patients and 4 years later in one. Acetylcholine receptor antibodies were negative in all patients. Voltage-gated calcium channel antibodies (VGCC) were measured in five patients and were positive in four. All patients had low compound muscle action potential (CMAP) at rest, a decrement in CMAP amplitude of 20-47% at 3 Hz repetitive nerve stimulation, and an increment of 200-700% at 40 Hz. In three patients the syndrome was associated with histologically verified small-cell lung cancer (SCLC). In the younger patient (40 years old), a lymph node biopsy performed nine years before the diagnosis of LEMS, had shown an atypical microcellular cancer of undetermined origin, which was treated with chemotherapy. LEMS 9 years after the diagnosis of cancer has not been described previously. The fifth patient had a two years history of bladder cancer (grade II). Three years after the diagnosis of LEMS he presented chronic lymphogenic leukemia. No malignancy was found in the remaining 2 patients.     

Pathologic evaluation of thymic hyperplasia in myasthenia gravis and Lambert-Eaton myasthenic syndrome

Eleven thymectomy specimens from patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome were thoroughly sectioned. The results were compared with the routine surgical pathology reports that were based on a median of four sections. Routine sampling was found to be inadequate because the thymectomy specimens were inhomogeneous--some random sections contained germinal centers while others did not. Thus, on more thorough examination, about half of the specimens should have been diagnosed as showing "follicular hyperplasia" rather than "no diagnostic change" or "involution." This helps explain the conflicting results of previous studies, based when stated on a mean of three sections, in which favorable response to thymectomy in patients with myasthenia gravis was either not correlated with the thymus histologic state or correlated variously with few or numerous germinal centers. Thus, nondiagnostic histologic findings based on only one or two thymus sections should be suspect, and if in doubt a larger number of sections should be examined for accurate pathologic diagnosis.     

Clinical analysis of 12 Korean Lambert-Eaton myasthenic syndrome (LEMS) patients

The Lambert-Eaton myasthenic syndrome (LEMS) heralds the occurrence of malignancy, especially small-cell lung cancer (SCLC), but it can also occur in the absence of cancer. Twelve patients were diagnosed as LEMS by clinical features and the classical electrophysiological triad, which includes a low amplitude of compound muscle action potentials (CMAP), decremental responses on low-rate stimulation, and incremental responses on high-rate stimulation on the repetitive nerve stimulation (RNS) test. There were 6 male and 6 female patients, ranging in age from 49 to 66 years. Malignancy(all were SCLC) was found in 7 patients. Males predominantly expressed the paraneoplastic form; whereas the primary autoimmune form was found only in women, who showed a good response to corticosteroid treatment. The neurological features were similar in both groups: proximal lower limb weakness, depressed muscle stretch reflexes, and dryness of mouth in nearly all patients. Bulbar dysfunction and limb paresthesia were a little more frequent in the paraneoplastic form. In RNS tests, the characteristic electrophysiological abnormalities were found in all patients and were more profound in the paraneoplastic form. We concluded that LEMS is commonly associated with malignancy, especially SCLC, but it should also be stressed that there are many female LEMS patients who do not harbor any malignancy at all, and that other treatment strategies such as immunotherapy should be considered for these patients.     

Investigation of the ultrastructure of neuromuscular synapses in the Lambert-Eaton myasthenic syndrome

The ultrastructure of neuromuscular synapses of patients with the Lambert—Eaton myasthenic syndrome was investigated. An increased content of synaptic vesicles in the axon terminals and an increase in the number and depth of anastomosing synaptic folds were found in most synapses. Local destructive changes were detected in the terminals of some synapses. The observations confirm the view that this syndrome is based on a disturbance of the liberation of mediator from the presynaptic structures.Laboratory of Experimental Pathomorphology and Ultrastructural Characteristics of Pathological Processes, and Laboratory of Clinical Pathophysiology, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 1, pp. 79–80, January, 1976.     

A case of Lambert-Eaton myasthenic syndrome associated with atypical bronchopulmonary carcinoid tumor

The Lambert-Eaton myasthenic syndrome (LEMS) is typically recognized as a paraneoplastic syndrome associated with a small cell lung carcinoma (SCLC), whereas LEMS with other neuroendocrine lung tumors, including carcinoids or large cell lung carcinoma, are highly unusual. Here, we report a rare case of LEMS with atypical bronchopulmonary carcinoid tumor: a 65-yr-old man presented with progressive leg weakness and a diagnosis of LEMS was made by serial repetitive nerve stimulation test. Chest CT revealed a lung nodule with enlargement of paratracheal lymph nodes, and surgically resected lesion showed pathological features of atypical carcinoid tumor. We concluded that LEMS could be associated with rare pulmonary neuroendocrine tumor other than SCLC, which necessitates pathologic confirmation followed by aggressive treatment for optimal management in these rare cases.     

HLA class I and II in Lambert-Eaton myasthenic syndrome without associated tumor

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder, in which antibodies against voltage-gated calcium channels located at nerve terminals cause muscle weakness and autonomic dysfunction. In approximately half of the patients the autoimmune process is initiated by a tumor. In the other half of patients no tumor is found and the etiology is unknown. The aims of this study were to investigate the strength of HLA-associations with nontumor LEMS (NT-LEMS) and to study the relation of HLA-haplotypes with age at onset of LEMS and other clinical features. Therefore, typing of HLA class I and II was performed in 19 patients with NT-LEMS, who were clinically evaluated. NT-LEMS was significantly associated with alleles of both HLA-class I (i.e. HLA-B8) as well as -class II (i.e. HLA-DR3 and -DQ2). HLA-B8+ patients had significantly younger age at onset of LEMS and tended to be female. This study shows that HLA-class I haplotype is associated with a distinct phenotype in NT-LEMS.     

Antibodies against the beta subunit of voltage-dependent calcium channels in Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome is an autoimmune disease that impairs neuromuscular transmission. Several studies suggest that neurotransmitter release is reduced by an immune response directed against the calcium channel complex of nerve terminals. The immunoglobulin G fractions from Lambert-Eaton myasthenic syndrome patients immunoprecipitate solubilized neuronal N- and P/Q-type channels and in certain cases brain, skeletal and cardiac muscle L-type channels [El Far O. et al. (1995) J. Neurochem. 64, 1696-1702; Lennon V. A. and Lambert E. H. (1989) Mayo Clin. Proc. 64, 1498-1504; Sher E. et al. (1989) Lancet ii, 640-643; Suenaga A. et al. (1996) Muscle Nerve 19, 1166-1168]. These channel immunoprecipitation assays are considered as useful for the diagnosis of this syndrome. In this study, we demonstrate that two predominant neuronal voltage-dependent calcium channel beta subunits (beta3 and beta4, of mol. wt 58,000) are general targets of Lambert-Eaton myasthenic syndrome autoantibodies. Of 20 disease sera tested, 55% were able to immunoprecipitate 35S-labeled beta subunits. All five patients affected with small-cell lung carcinoma were positive for the beta-subunit immunoprecipitation assay. Interestingly, only a fraction of the beta-subunit-positive sera was also able to immunoprecipitate N- and P/Q-type channels, suggesting that several of the beta-subunit epitopes are masked in native channels. In accordance with this observation, we found that several beta-positive sera were able to prevent the interaction between calcium channel alpha1 and beta subunits in vitro. In cases where sera were able to immunoprecipitate beta subunits, N- and P/Q-type channels, the immunoprecipitation of both channel types was either partially or entirely mediated by beta-subunit antibodies. Our results suggest that assays based on the immunoprecipitation of beta subunits can be used as an additional test to assist in the diagnosis of Lambert-Eaton myasthenic syndrome.     

Immunocytochemical characteristics of small cell lung carcinoma associated with the Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome (LEMS) is characterized by the presence of IgG antibodies to motor nerve terminals, and associates with small cell lung carcinoma in more than 60% of cases. We have carried out a comparative immunocytochemical study on small cell lung carcinoma (SCLC) in five LEMS cases and six non-LEMS cases, using antibodies to tumor markers, MHC Class I and II, macrophages and lymphocytes. The authors found a reduced expression of the 200Kd neurofilament antigen and of MHC Class I antigens in the LEMS cases as well as a greater infiltration of activated macrophages. It is suggested that these findings are consistent with the view that SCLC antigenic determinants trigger the autoantibody response in SCLC-LEMS.     

Autonomic function in patients with hereditary motor and sensory neuropathy type I and Lambert-Eaton myasthenic syndrome.

Noninvasive tests of four autonomic organ systems (vasomotor control, baroreceptor reflexes, sudomotor function and pupillary reflexes) were performed on nine patients with hereditary motor and sensory neuropathy (HMSN) type I and three patients with Lambert-Eaton myasthenic syndrome (LEMS). The results were compared with those of 33 control subjects. Autonomic dysfunction was considered present when at least two of the four organ system tests were abnormal. The three patients with LEMS had abnormal results in two or more different systems, whereas only one of the nine patients with HMSN type I had two abnormal test results. This study demonstrates that autonomic dysfunction is not a common finding in patients with HMSN type I and its presence should alert us to find the cause of this autonomic disorder.     

Increased frequency of HLA class II alleles DRB1*0301 and DQB1*0201 in Lambert-Eaton myasthenic syndrome without associated cancer

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular disorder characterized by pathogenic autoantibodies directed against the presynaptic voltage-gated calcium channels (VGCC), resulting in a clinical syndrome of proximal muscular weakness and autonomic dysfunction. Sixty percent of LEMS cases are associated with cancer, most commonly small cell carcinoma of the lung. In the 40% of LEMS patients without carcinoma, the stimulus for the production of VGCC autoantibodies is unknown; however, these LEMS patients have multiple other organ-specific autoantibodies. To investigate the autoimmune basis of noncancer associated LEMS (NCA-LEMS), high resolution typing of major histocompatibility loci was performed in 23 patients with NCA-LEMS. NCA-LEMS was strongly associated with DRB1*0301 (p<0.0001) and DQB1*0201 (p<0.0001), suggesting that NCA-LEMS is an autoimmune disorder associated with the DR3-DQ2 extended haplotype.     

Increased frequency of IgG heavy chain marker Glm(2) and of HLA-B8 in Lambert-Eaton myasthenic syndrome with and without associated lung carcinoma

In view of the evidence for an autoimmune pathogenesis of the Lambert-Eaton myasthenic syndrome, we have sought associations with IgG heavy chain allotypes (Gm) and HLA antigens in 30 patients, of whom 20 had evidence of lung carcinoma (histologically proven small ("oat") cell type in 17). A highly significant overall increase in frequency of Glm(2) (chi 2 = 10.95; p less than 0.001; n = 30) and of HLA-B8 (chi 2 = 19.07; p less than 0.001; n = 23) was observed. These two factors apparently occurred independently of each other. The Glm(2) frequency in 36 non-myasthenic small cell carcinoma cases was the same as in a control panel (n = 167). We conclude that Glm(2) and HLA-B8 both associate with increased susceptibility to the Lambert-Eaton myasthenic syndrome, and suggest that Glm(2) may be in linkage disequilibrium with a limited number of VH genes coding for antibodies to restricted antigenic determinants at the nerve terminals, which may be shared by the carcinoma cells.     

Lambert-Eaton myaesthenic syndrome: a possible association with Hodgkin's lymphoma

Lambert-Eaton myasthenic syndrome is a presynaptic neuromuscular junction disorder typically associated with small cell lung carcinoma. The characterstic electrophysiological abnormality is a low amplitude compound muscle action potential that shows a marked increment after maximal voluntary contraction or brief tetanic nerve stimulation. We describe a patient who had LEMS in association with Hodgkin's disease. A 61 year old woman presented with proximal muscle weakness 6 years following successful treatment of Hodgkin's disease. Her symptoms responded well to treatment with diaminopyridine. 9 additional patients have been described with LEMS in association with lymphoproliferative diseases. A systemic malignancy is usually found within 2 years of LEMS diagnosis but may present later. LEMS should be considered in patients with Hodgkin's disease presenting with muscle weakness.