Recombinant calcium channel is recognized by Lambert-Eaton myasthenic syndrome antibodies

The authors studied sera from 36 patients with Lambert-Eaton myasthenic syndrome (LEMS) by immunoblots using the recombinant protein derived from the DNA sequence encoding for the domain III S5-S6 linker of the P/Q-type voltage-gated calcium channel al subunit. The results of 18 patients were positive for antibodies to this recombinant protein. The results of 2 of 10 patients with lung cancer without LEMS were also positive.     

Distinct evolution of calcium channel antibody types in Lambert-Eaton myasthenic syndrome

To determine whether titers of anti-P/Q type and anti-N type calcium channel antibodies provide distinct information, both types of assay were performed during follow-up of 7 patients with Lambert-Eaton myasthenic syndrome (LEMS). In 4 patients with both antibody responses, titers evolved independently and often in an inverse relationship. Two patients with squamous cell lung carcinoma (SqCLC) produced anti-N type channel antibodies, but no detectable anti-P/Q channel responses. These results suggest that anti-N channel autoantibodies constitute an immune response distinct from the anti-P/Q type channel specificity and can also correlate with clinical evolution. Consequently combined assays may provide more comprehensive information during follow-up of LEMS.     

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an idiopathic or paraneoplastic syndrome producing antibodies against presynaptic voltage-gated P/Q calcium channels. This decreases calcium entry into the presynaptic terminal, which prevents binding of vesicles to the presynaptic membrane and acetylcholine release. LEMS is most often associated with small cell lung cancer, although idiopathic presentations comprise approximately 40% of the cases. The most common initial complaint is proximal muscle weakness involving the lower extremities more than the upper extremities. Depressed deep tendon reflexes and autonomic dysfunction are frequently present. Involvement of the bulbar or respiratory muscles is rare. Diagnosis is confirmed by electrophysiological testing, which demonstrates small compound muscle action potentials and facilitation with exercise or 20-Hz repetitive stimulation. A serum test for voltage-gated calcium channel antibodies is commercially available. Treatment involves removing the cancer associated with the disease. If cancer is not found, immunosuppressive medications and acetylcholinesterase inhibitors are used with moderate success. Patients with idiopathic LEMS should be screened every 6 months with chest imaging for cancer.     

Lambert-Eaton myasthenic syndrome

The Lambert-Eaton Myasthenic Syndrome (LEMS) is characterised by proximal muscle weakness initially affecting gait, autonomic symptoms (dry mouth, constipation, erectile failure), augmentation of strength during initial voluntary activation, and depressed tendon reflexes with post-tetanic potentiation. The disorder is paraneoplastic (small cell lung cancer) in about 60p. cent (P-LEMS); no cancer is associated in the remainder (NP-LEMS). LEMS affects all races. NP-LEMS can occur in childhood as well as adult life; P-LEMS is unusual at<30 Years. The weakness results from a reduction in the quantal release of acetylcholine from motor nerve terminals, caused by autoantibodies to P/Q-type voltage-gated calcium channels (VGCCs) that are provoked by tumour VGCCs in P-LEMS; the stimulus in NP-LEMS is not known. These antibodies may be implicated in the rarely associated cerebellar degeneration. The diagnosis can be confirmed by detecting the specific antibody in a radioimmunoprecipitation assay, and by finding a reduced compound muscle action potential amplitude that increases by>100p. cent following maximum voluntary activation. Most patients benefit from 3,4-diaminopyridine; pyridostigmine is less effective. Specific tumour therapy in P-LEMS will often ameliorate the neurological disorder. In those with severe weakness, IVIg or plasmapheresis confers short-term benefits. Prednisone alone or combined with azathioprine or cyclosporin can achieve long-term control of the disorder.     

P/Q-type calcium channel antibodies, Lambert-Eaton myasthenic syndrome and survival in small cell lung cancer

To assess the survival impact of the presence of P/Q-type calcium channel antibodies in patients with small cell lung carcinoma (SCLC), we examined the frequency of the antibodies and Lambert-Eaton myasthenic syndrome (LEMS) in 148 consecutive patients with SCLC, and in 30 patients with paraneoplastic cerebellar degeneration and SCLC, and studied their relation with survival. In both series, only patients with LEMS had a remarkably long survival, whereas presence of the antibodies without LEMS did not result in a better prognosis.     

Lambert-Eaton myasthenic syndrome

This review of the Lambert-Eaton myasthenic syndrome (LEMS) emphasizes electrodiagnosis and includes a case report. A 50-year-old woman had become progressively weaker over 1.5 years. The suspected diagnosis was confirmed by the clinical electrophysiological findings and was made 6 months before the patient's oat-cell carcinoma was found. After treating with local radiation and chemotherapy, the myasthenic syndrome went into remission as the pulmonary lesion resolved.     

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.     

Calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome.

We have tested 36 patients with the Lambert-Eaton myasthenic syndrome for serum antibodies to voltage-gated calcium channels by using an immunoprecipitation assay with [125I] omega-conotoxin-labeled voltage-gated calcium channels extracted from a human neuroblastoma cell line, SKN-SH. Forty-four percent of these patients had significant levels of antibody (30-1,466 pM) compared with healthy control individuals (less than 15 pM). The incidence of positive sera in patients without associated small cell lung carcinoma (61%) was greater than in those patients with small cell lung carcinoma (28%). Results correlated strongly with results obtained using voltage-gated calcium channels extracted from the small cell lung carcinoma line, MAR5. Anti-voltage-gated calcium channel antibody titers did not correlate with disease severity across individuals, but longitudinal studies in 2 patients receiving immunosuppressive therapy showed a clear inverse relation between antibody titer and an electromyographic index of disease severity. The incidence of positive sera among patients with other neurological disorders was not significant, but 8 of 12 patients with rheumatoid arthritis or systemic lupus erythematosus had raised titers (30-82 pM). We conclude that the antibodies detected in this assay are heterogeneous and that some of them are likely to be implicated in this disorder of neuromuscular transmission. The assay should prove useful as an additional diagnostic aid in patients with Lambert-Eaton myasthenic syndrome.     

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.     

Lambert-Eaton myasthenic syndrome in children

Lambert-Eaton myasthenic syndrome is a presynaptic disorder of neuromuscular transmission. It is characterized by muscle weakness, hyporeflexia, and autonomic dysfunction. It is most often associated with small cell carcinomas of the lung. Rare cases have been reported in children. We recently encountered two children with Lambert-Eaton myasthenic syndrome associated with antibodies to P/Q-type calcium channel but without evidence of neoplasms. Both patients showed prolonged and significant improvement following cyclosporin treatment. The diagnosis of Lambert-Eaton myasthenic syndrome should be considered in children with progressive weakness and a negative work-up for the usual causes. High-frequency repetitive nerve stimulation and P/Q-type calcium-channel antibodies may confirm the diagnosis.     

Action of Lambert-Eaton myasthenic syndrome IgG at mouse motor nerve terminals

We have studied the electrophysiological effects of IgG obtained from four patients with Lambert-Eaton myasthenic syndrome (LEMS) (two with small cell carcinoma), using the mouse passive transfer model. Mice received LEMS or control IgG or plasma, 10 to 60 mg daily. Microelectrode intracellular recordings were made from diaphragm muscle. LEMS IgG and plasma decreased end-plate potential quantal content similarly, confirming IgG as the active factor. LEMS IgG was equally effective in C5-deficient mice, indicating that late complement components are not required. The time course of decline and recovery of quantal content closely followed that of the human IgG in the mouse serum, with time to half-maximal effect of about 1.5 days in each case. Binding/dissociation of IgG or down/up regulation of the antigenic determinants, possibly Ca2+ channels, has a half-life of between 2 and 36 hours. The results confirm our concept that IgG antibody to nerve terminal determinants underlies the disorder of transmitter release in LEMS.     

Lambert-Eaton myasthenic syndrome without anti-calcium channel antibody: adverse effect of calcium antagonist diltiazem.

A 59 year old man with ischaemic heart disease, developed the clinical and electromyographic changes of the Lambert-Eaton myasthenic syndrome after taking calcium antagonist, diltiazem. The symptoms appeared periodically with a rise and fall in serum level of diltiazem. Extensive search was made for systemic neoplasms and autoimmune diseases without success. Serum antibody to voltage operated calcium channel was not detected.     

Small cell lung cancer with Lambert-Eaton myasthenic syndrome

Four of 69 cases of small cell lung cancer (SCLC) showed evidence of Lambert-Eaton myasthenic Syndrome (LEMS) were studied neurologically and neurophysiologically in four years. The LEMS appearance were preceded that of SCLC in 3 cases for two years at most. Repeated stimulation of ulnar nerve examination showed diminished amplitude of initial response (0.2-0.9 mv); Amplitude of the response at 3 c/s stimulation for 3 sec was diminished 20-63%. (control 3% decreases-13% increases) but that at 20 c/s stimulation for 10 sec increased 200-800% increases. (control: 20% decreases-56% increases). These findings were important for diagnosis of LEMS. The abnormalities of neurotransmission seems to be due to inadequate release of acetyl choline from nerve terminals at abnormal active zone of Ca++ channels.     

Congenital Lambert-Eaton myasthenic syndrome.

A 4 year old girl had been hypotonic and areflexic since birth with delayed milestones in motor development. Repetitive stimulation at high rates performed at 3 years elicited an incremental response typical of the Lambert-Eaton Syndrome.     

Circulating T cell subsets in the Lambert-Eaton myasthenic syndrome.

Peripheral blood T cell subsets were measured using monoclonal antibodies and a fluorescence activated cell sorter in 15 untreated patients with Lambert-Eaton myasthenic syndrome (nine with small cell carcinoma, one undifferentiated epithelial tumour (ca-LEMS], five with no demonstrable tumour (non-ca-LEMS), 10 age-matched healthy controls and 10 patients with small cell carcinoma without neurological disease. OKT8+ (suppressor/cytotoxic) T cells were significantly decreased in ca-LEMS compared with non-ca LEMS (p less than 0.001) ca-controls (p less than 0.01) and healthy controls (p less than 0.001). In one patient depressed OKT8+ T cells antedated clinically evident tumour by five months. OKT3+ (total) and OKT4+ (helper) T cells were similar in ca-LEMS, non-ca LEMS and controls. The mechanism underlying the loss of circulating OKT8+ T cells in ca-LEMS is unknown, but these changes may help to predict the presence of carcinoma in this disease.     

Autonomic dysfunction in Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by muscle wakness and autonomic dysfunction. Recentex vivo andin vitro studies demonstrate that autoantibodies to the P/Q-subtype of voltage-gated calcium channel inhibit transmitter release from parasympathetic, sympathetic, and enteric neurons, a mechanism likely to underlie the widespread autonomic dysfunction in LEMS. This review summarizes clinical studies characterizing the autonomic symptoms and signs in LEMS and the effectiveness of treatment in alleviating these symptoms. Serological logical assays andin vitro pharmacologic and electrophysilogical studies are also discussed. Funding for the author's research comes from grants from the National Health and Medical Research Council of Australia, Canberra, the Clive and Vera Ramaciotti Foundation, Sydney, and by an AMRAD (Melbourne) Postdoctoral Award.