Lambert–Eaton myasthenic syndrome – Diagnosis,pathogenesis and therapy

Lambert–Eaton myasthenic syndrome (LEMS) describes a rare human autoimmune disorder of the neuromuscular junction (NMJ). Clinically, LEMS patients suffer from characteristic muscle weakness that is caused by the presence of antibodies directed against their voltage-gated calcium channels (VGCC). These channels are localized in the presynaptic membrane of their motor nerve terminals. Binding of autoimmune antibodies to the VGCCs leads to reduced neuromuscular transmission. In approximately 50% of the patients, LEMS is reflected by a paraneoplastic manifestation and most commonly associated with a small cell lung carcinoma (SCLC) whose cells also express VGCCs in their plasma membrane. Better understanding of the pathophysiological mechanisms of LEMS has helped with the development of new diagnostic approaches and has led to targeted symptomatic and immunosuppressive therapy. For LEMS patients with an underlying malignancy, tumor therapy is the first choice to date.     

Interaction of synaptotagmin with voltage gated calcium channels: A role in Lambert-Eaton myasthenic syndrome?

Plasma from patients with Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease of neuromuscular transmission, contains antibodies that bind to the synaptic vesicle protein synaptotagmin. Synaptotagmin associates with calcium channels and appears to regulate synaptic vesicle docking at the plasma membrane prior to rapid neurotransmitter release. Autoantibodies directed against a synaptotagmin-calcium channel complex may be involved in the etiology of LEMS. In the majority of patients LEMS is associated with small cell lung cancer (SCLC). We have detected the expression of proteins of the secretory pathway, including synaptotagmin, syntaxin and N-type calcium channels, in a panel of SCLC tumor lines. These observations are compatible with the hypothesis that the initial autoimmune response in LEMS is triggered by the tumor.     

Cerebellar ataxia in non-paraneoplastic Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.     

Favorable response to rituximab in a patient with anti‐VGCC‐positive Lambert‐Eaton myasthenic syndrome and cerebellar dysfunction

Lambert‐Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is characterized by impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic voltage‐gated calcium channels (VGCC‐ab). Clinical symptoms are usually characterized by proximal muscle weakness and mild dysautonomia. In some patients there are signs of cerebellar dysfunction as well, usually associated with cancer. Here we report the long‐term follow‐up of a patient with VGCC‐ab‐positive LEMS and a severe cerebellar syndrome but without evidence of cancer over 5 years. While conventional immunosuppressive therapy (steroids, azathioprine) failed, he improved with plasma exchange and consecutive treatment with rituximab. Muscle Nerve 40: 305–308, 2009     

Lambert-Eaton syndrome antibodies: reaction with membranes from a small cell lung cancer xenograft

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC). In this study membranes isolated from a human small cell lung cancer xenograft (Mar), that bound [3H]PN200-110, a VGCC antagonist, were subjected to Western blotting using plasma from 12 LEMS patients and eight controls. Although one band recognised by 3/12 LEMS IgGs might be associated with the VGCC, a number of other proteins were recognised both by LEMS plasma, and by plasma from patients with other disorders. The results illustrate the difficulties found using Western blotting with autoimmune plasma to identify specific polypeptides in a crude antigen preparation.     

How to Spot Congenital Myasthenic Syndromes Resembling the Lambert–Eaton Myasthenic Syndrome? A Brief Review of Clinical,Electrophysiological, and Genetics Features

Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases in which neuromuscular transmission is compromised. CMS resembling the Lambert–Eaton myasthenic syndrome (CMS–LEMS) are emerging as a rare group of distinct presynaptic CMS that share the same electrophysiological features. They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation. Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS. CMS–LEMS occurs due to deficits in acetylcholine vesicle release caused by dysfunction of different components in its pathway. To date, the genes that have been associated with CMS–LEMS are AGRN, SYT2, MUNC13-1, VAMP1, and LAMA5. Clinicians should keep in mind these newest subtypes of CMS–LEMS to achieve the correct diagnosis and therapy. We believe that CMS–LEMS must be included as an important diagnostic clue to genetic investigation in the diagnostic algorithms to CMS. We briefly review the main features of CMS–LEMS.     

Editorial introduction: from the structure and functions of the neuromuscular junction to the diseases

The neuromuscular junction has been recognized as a site for autoimmune and genetic disorders. Myasthenia gravis (MG) is mainly caused by postsynaptic nicotinic acetylcholine receptor (AChR) IgG1 antibodies that are directed against α-subunit 67-76 and 125-147 and activate complement. Thymic abnormalities are present in the autoimmune background. A proportion of MG patients without conformation-dependent AChR antibodies assayed by the cell-based method have muscle-specific tyrosine kinase (MuSK) antibodies which are largely IgG4 and partially IgG1. MuSK is activated by Dok-7 and Lrp4 (agrin receptor) and contributes to AChR clustering at the postsynaptic membrane via various kinase cascades in collaboration with Wnt-MuSK/Frizzled-Dishevelled signaling. Rapsyn interacts with MuSK-linked chaperones to stabilize postsynaptic architecture and also contributes to AChR phosphorylation. MG-associated thymomas express antigens that trigger antibody responses which play a part in disease generation and modification. Among these, ryanodine receptor-1 (RyR1; acts on sarcoplasmic Ca2+ release) antibodies cause muscle contractile weakness. Transient receptor potential canonical-3 (TRPC3) antibodies are also detected in thymoma-associated MG patients; they may participate in muscle contractile weakness because TRPC3 acts on RyR1, and may also impair the refill of sarcoplasmic Ca2+ stores since TRPCs contribute to the receptor-operated Ca2+ influx via the phospholipase C (PLC)-diacylglycerol (DAG) pathway in cooperation with the store-operated, STIM1/Orai1-mediated Ca2+ influx and TRPCs-Homerl-IP3R interaction. Lambert-Eaton myasthenic syndrome (LEMS) is caused by reduced ACh quantal release that occurs mainly because of presynaptic P/Q-type voltage-gated Ca2+ channel (VGCC) antibodies. Physicians should be vigilant for LEMS because it may predict an underlying malignancy, particularly small-cell lung carcinoma; SOX-1 antibodies are usually present in these patients and are absent in those who do not have caucer. Some patients with LEMS have antibodies against synaptotagmin-1, which associates with SNARE complex and functions as Ca2+ sensor for exocytosis. The stimulation of the M1-type presynaptic muscarinic AChR (mAChR)(G-proterin-coupled receptor) can compensate for the deficiency of Ca2+-mediated ACh quantal release via the PLC/DAG-mediated mechanism; This acts in a manner similar to the BDNF/NT4-TrkB interaction. The detection of M1 mAChR antibodies in LEMS suggests an impaired compensatory mechanism and corresponds, at least in part, to autonomic symptoms. Congenital myasthenic syndromes are classified into presynaptic, synaptic basal lamina and postsynaptic defects.     

Autoimmune disorders of the neuromuscular junction

The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-specific kinase antibodies which define a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immune-mediated disorders of the NMJ.     

Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies

Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular autoimmune disease that has served as a model for autoimmunity and tumour immunology. In LEMS, the characteristic muscle weakness is thought to be caused by pathogenic autoantibodies directed against voltage-gated calcium channels (VGCC) present on the presynaptic nerve terminal. Half of patients with LEMS have an associated tumour, small-cell lung carcinoma (SCLC), which also expresses functional VGCC. Knowledge of this association led to the discovery of a wide range of paraneoplastic and non-tumour-related neurological disorders of the peripheral and central nervous systems. Detailed clinical studies have improved our diagnostic skills and knowledge of the pathophysiological mechanisms and association of LEMS with SCLC, and have helped with the development of a protocol for early tumour detection.     

Rats immunized with cholinergic synaptosomes: a model for Lambert-Eaton syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by reduced acetylcholine release at the neuromuscular junction. We report a model of the disease developed by active immunization of rats with purely cholinergic nerve terminals (synaptosomes) isolated from the Torpedo electric organ. Electromyographic studies of neuromuscular transmission in these rats showed a weak initial response followed by a pronounced incremental response to paired supramaximal stimuli (8 msec apart). There was no such response in control rats. There was no evidence of a postsynaptic transmission deficit in the synaptosomes immunized rats. We conclude that immunizing rats with Torpedo cholinergic nerve terminals causes a specific presynaptic dysfunction and may serve as a model for the study of LEMS.     

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction, and approximately 60% of patients with LEMS have a tumor, mostly small cell lung cancer (SCLC), as a paraneoplastic neurological syndrome. The clinical data of Japanese patients in the present study are as follows: the ratio of men to women is 3: 1 (mean age, 62 years; age range, 17-80 years). Of the patients with LEMS, 61% have SCLC, whereas the others do not have cancer. Clinical symptoms are usually characterized by proximal muscle weakness and dysautonomia. In less than 10% of the patients, there are signs of cerebellar dysfunctions (paraneoplastic cerebellar degeneration with LEMS; PCD-LEMS), and these are usually associated with SCLC. The diagnosis can be confirmed by detecting a specific antibody in a radioimmunoprecipitation assay and finding reduced amplitude of compound muscle action potential that increases by over 100% after maximum voluntary activation or 50Hz of nerve stimulation. The pathomechanism of LEMS is characterized by impaired transmission across the neuromuscular junction because of autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels (P/Q-VGCCs). Histopathologic evaluation of the cerebellum in patients with PCD-LEMS showed a reduced number of P/Q-type VGCCs in the molecular layer. Therefore, it was hypothesized that P/Q-VGCC antibodies may induce cerebellar dysfunction after entering the CNS in patients with PCD-LEMS. Specific tumor therapy in patients with LEMS as well as cancer often improves the neurologic deficit. Tumor removal is the primary treatment for LEMS. If the result of the primary screening is negative, screening should be repeated after 3-6 months and thereafter every 6 months for up to 2 years. Most patients benefit from 3, 4-diaminopyridine administered with pyridostigmine. In those with severe weakness, intravenous gamma globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone when administered alone or in combination with immunosuppressive drugs can achieve long-term control of the disorder.     

Proteasome inhibitors for malignancy‐related lambert‐eaton myasthenic syndrome

Lambert‐Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by autoantibodies against presynaptic voltage‐gated calcium channels that impair neuromuscular transmission. Malignancies, especially small cell lung cancer (SCLC), have been associated with LEMS and account for approximately 60% of cases, making malignancy management a central step in LEMS therapy. In addition, immunosuppressive therapy is also recommended for symptomatic control. Interestingly, both pathological and epidemiological data suggest that the autoimmune response can inhibit progression of tumors in malignancy‐associated LEMS. Thus, conventional broad‐spectrum immunosuppressants may not be effective agents for treatment of LEMS, especially in those with malignancy‐associated LEMS. Recent preclinical and clinical studies have indicated that proteasome inhibitors can eliminate antibody‐producing cells efficiently, block dendritic cell maturation, and have anti‐tumor activity. We hypothesize that proteasome inhibitors may be promising agents for treatment of malignancy‐related LEMS. Muscle Nerve 49 :325–328, 2014     

Lambert-Eaton myasthenia syndrome--review with case report

The pathogenetic and therapeutic concepts in Lambert-Eaton Myasthenic Syndrome (=LEMS) are changing. The disease has been proved to be an autoimmune reaction to voltage-dependent calcium channels of the presynaptic membrane at the neuromuscular junction. As pointed out in a case report, autonomic dysfunction can be an early sign and symptom of LEMS. The update review of the literature deals with the diagnosis, aetiology and therapy of the often but not exclusively paraneoplastic induced disease.     

Adverse effect of verapamil in myasthenia gravis.

Verapamil, a class IV anti-arrhythmic drug that blocks voltage-dependent calcium channels in cardiac and smooth muscle, also has effects on presynaptic and postsynaptic voltage-dependent calcium channels at the neuromuscular junction. In a postoperative patient with pre-existent myasthenia gravis, oral verapamil caused a marked exacerbation in myasthenic weakness.     

Autoantibodies against M1 muscarinic acetylcholine receptor in myasthenic disorders

The Lambert–Eaton myasthenic syndrome (LEMS), often associated with small-cell lung carcinoma (SCLC), is a disorder of acetylcholine (ACh) release from motor nerve terminals. In most patients, it is caused by autoantibodies against the P/Q-type voltage-gated calcium channels (VGCC) that trigger ACh release. However, these antibodies are not detected in approximately 15% of clinically and electrophysiologically typical cases. The M1-type pre-synaptic muscarinic ACh receptor (M1 mAChR) modulates cholinergic neuromuscular transmission by linking to P/Q-type VGCC, and may partially compensate for the reduced calcium entry. Immunoblotting against solubilized human M1 mAChR, we detected autoantibodies in: (a) 14 of 20 (70%) anti-VGCC-positive LEMS patients; (b) all five anti-VGCC-negative LEMS patients, one of whose serum had previously passively transferred LEMS-type electrophysiological defects to mice; (c) all five LEMS patients with autonomic symptoms; (d) seven of 25 (28%) myasthenia gravis (MG) patients in whom increased ACh release partially compensates for post-synaptic defects; (e) none of 10 SCLC patients without LEMS. Although not proving primary pathogenicity of anti-M1 mAChR antibodies, the present results highlight their potential to affect synaptic compensatory mechanisms, more in LEMS than MG.     

Myasthenia gravis and myasthenic syndrome

Neurological Sciences - Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune ion channel disorders mediated by antibodies to postsynaptic acetylcholine receptors and...     

Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome

A retrospective literature review of the electrodiagnosis of myasthenia gravis (MG) and Lambert--Eaton myasthenic syndrome (LEMS) through July 1998 was performed for the purpose of generating evidence-based practice parameters. There were 545 articles identified, of which 13 articles met at least three of the six criteria set previously by the American Association of Electrodiagnostic Medicine (AAEM). An additional 21 articles were identified from review articles or the references of these first 13 articles leading to a total of 34 articles. Results of studies utilizing repetitive nerve stimulation (RNS) showed that a 10% decrement in amplitude from the first to fourth or fifth intravolley waveform while stimulating at 2--5 HZ is valid for the diagnosis of MG. The degree of increment needed for the diagnosis of LEMS is at least 25% but most accurate when greater than 100%. Abnormal jitter or impulse blocking are the appropriate criteria for diagnosis of neuromuscular junction (NMJ) disorders when using single fiber electromyography (SFEMG). SFEMG is more sensitive than RNS for the diagnosis of disorders of neuromuscular transmission, but may be less specific and may not be available. Therefore, RNS remains the preferred initial test for MG and LEMS.     

Lambert–Eaton syndrome antibodies target multiple subunits of voltage‐gated Ca2+ channels

Introduction: Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune presynaptic neuromuscular disorder. Autoantibodies against subunits of voltage‐gated calcium channels (VGCCs) associated with acetylcholine release are thought to cause LEMS. Methods: HEK293 cells expressing specific individual recombinant subunits of α_1A, α_1B, α_1C, and α_1E; β₃; and α₂δ of human neuronal VGCCs were exposed to antibodies from 3 LEMS patients, 1 patient with small‐cell lung carcinoma, and 1 with myasthenia gravis. Results: All LEMS patient antibodies bound to cells containing any of the α₁ or β₃ subunits alone or combined with α₂δ subunits, but not α₂δ alone. Autoantibodies from the patient with small‐cell lung carcinoma but not the myasthenia gravis patient targeted the same VGCC subunits. Conclusions: Autoantibodies from LEMS patients bind directly to multiple VGCC α₁ subunits as well as the β₃ subunit. Thus, multiple components of the presynaptic VGCC complex are prospective targets for antibodies in LEMS. Muscle Nerve 51 : 176–184, 2015     

Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder

The Lambert-Eaton myasthenic syndrome (LEMS) is a disorder of neuromuscular transmission, often associated with small cell lung carcinoma (SCLC), and characterized by reduced quantal release of acetylcholine from the motor nerve terminals. Another neuromuscular transmission disorder, myasthenia gravis, has a well-understood autoimmunological cause. This review discusses the evidence for a similar autoimmunological effect in the development of LEMS. Injection of LEMS IgG into mice passively transfers the physiological and morphological abnormalities, which include paucity and disorganized arrangement of active zone particles believed to represent the voltage-gated calcium channels (VGCCs). Calcium influx via VGCCs into SCLC cells is reduced by LEMS IgG suggesting that in SCLC-associated LEMS, antibodies may be triggered by VGCCs expressed on these cells; this immunological cross-reactivity may lead to the neurological abnormality. Similar VGCCs on neuronally derived cells may trigger the disorder in those without a tumour. The disorder provides another example of the complicated relationships between the nervous and immune systems and tumorigenic processes.     

Clinical aspects of neuromuscular transmission disorders

Autoimmune disorders of neuromuscular transmission are caused by antibodies (abs) directed against membrane proteins at the motor end-plate. Myasthenia gravis (MG) is due, in most cases, to abs against the nicotinic acetylcholine receptor (AChR). Anti-AChR-positive MG actually includes different disease entities: weakness can be confined to extrinsic ocular muscles or can be generalized; patients with generalized MG (G-MG) can be subdivided on the basis of age of onset, HLA association and thymic pathology. About 15% of G-MG patients are anti-AChR-negative; in a proportion of these cases serum abs against the muscle- specific kinase (MuSK) are found. Anti-MuSK-positive MG is characterized by predominant involvement of bulbar muscles and very low frequency of thymic pathology. The Lambert-Eaton myasthenic syndrome (LEMS) is caused by abs against voltage-gated calcium channels at nerve terminal. LEMS is characterized by muscle weakness and autonomic disturbances and it is paraneoplastic in over 50% of the cases. In neuromyotonia and cramp-fasciculation syndrome, that are thought to be due to anti-voltage-gated potassium channel abs, signs of peripheral nerve hyperexcitability can be associated with CNS features.