Lambert-Eaton myasthenic syndrome: II. Immunoelectron microscopy localization of IgG at the mouse motor end-plate

The autoimmune origin of the Lambert-Eaton myasthenic syndrome (LEMS) was documented by passive transfer of its electrophysiological features from humans to mice with IgG. Freeze-fracture electron microscopy has demonstrated a loss of active-zone particles in human LEMS and in its mouse passive transfer model. These data imply that the active zones are targets of the pathogenic LEMS autoantibodies. Immunolocalization of the antibodies has been hindered, however, by a paucity of active-zone particles (about 50/micron2 normally and still lower in LEMS) and by diffusion artifacts in the immunoperoxidase method. To obviate these problems, we employed sensitive avidin-biotin detection systems, both peroxidase and ferritin labels, and quantitative immunoelectron microscopy and end-plate morphometry. We compared mice treated with LEMS IgG, control IgG, and no IgG. In all mice, nonspecific background staining was found in the basal lamina covering the muscle fibers and Schwann cells. When a single 10-mg dose of IgG was injected intravenously, IgG samples from 12 patients produced significant immunostaining of the mouse active zones; from 7 patients they did not. Higher doses of intraperitoneally injected IgG (20 mg, three times a day for 2 days, or 10 mg/day for 15 days) from each of 4 patients (3 of whose IgG previously transferred LEMS to mice) caused significant immunostaining of mouse active zones: (1) the mean density (no./micron presynaptic membrane length) of positive active zones was 0.91 in the immunoferritin study and 0.72 in the immunoperoxidase study (control values, 0.12 and 0.02); and (2) 43% of the ferritin particles in the primary cleft were concentrated at the active zones and the rest were scattered randomly (control value, 5.3%). The findings indicate that LEMS IgG binds to the active zones of the presynaptic membrane.     

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.     

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.     

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.     

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.     

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.     

Lambert-Eaton myasthenic syndrome with ophthalmoparesis and pseudoblepharospasm

We report a patient initially diagnosed as having ocular myasthenia gravis who showed progressive ophthalmoparesis and pseudoblepharospasm together with positive acetylcholine receptor antibodies. Repeated evaluation with high-frequency repetitive stimulation revealed an incremental response and elevated titers of antibodies against presynaptic calcium channels, confirming Lambert-Eaton myasthenic syndrome. Systemic evaluation revealed no malignant neoplasm but revealed euthyroid Hashimoto's disease. Immunomodulative therapy including plasma exchange and administration of an immunosuppressent (azathioprine) combined with a potassium-channel blocker (3,4-diaminopyridine) reduced the ocular abnormalities. We conclude that the ocular manifestations in this patient were probably caused by Lambert-Eaton myasthenic syndrome.     

Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients

The authors characterized the clinical and immunologic features of 110 patients with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated calcium channels (VGCC) antibodies were detected in 85% of the patients (seropositive) but not in the rest (seronegative). Except for the indication that small cell lung carcinoma is less common in seronegative patients, no significant differences were found in the clinical characteristics of patients who had or did not have anti-P/Q-type VGCC antibodies. The results of passive transfer experiments suggest that seronegative LEMS is also an autoantibody-mediated disorder.     

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.     

Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome

Myasthenia gravis (MG) is a heterogeneous disorder, a fact that needs to be kept in mind when considering treatment. Most patients benefit from pyridostigmine. In nonthymomatous ocular MG, prednisolone is often effective. Thymectomy is indicated for thymoma and is an option for acetylcholine receptor antibody-positive patients with generalized weakness developing under the age of 45 years. In older patients and in those failing to respond to thymectomy, prednisone alone or combined with azathioprine is the treatment of choice. Mycophenolate mofetil is an option in those intolerant of azathioprine. Lambert-Eaton myasthenic syndrome (LEMS) can exist in paraneoplastic (P-) and nonparaneoplastic (NP-) forms. Most patients benefit from 3,4-diaminopyridine. In P-LEMS, treatment of the tumor often results in neurological improvement. In both forms, prednisone alone is an option or combined with azathioprine in NP-LEMS. In both MG and LEMS, where weakness is severe, plasma exchange or intravenous immunoglobulin treatment may provide short-term benefit.