ScienceDirect - Handbook of Clinical Neurology : Chapter 9 The Lambert

Handbook of Clinical Neurology
Volume 91, 2008, Pages 273-283
Neuromuscular Junction Disorders

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Incidence of serum anti-P/Q-type and anti-N-type calciu...
Journal of the Neurological Sciences

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Incidence of serum anti-P/Q-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome
Journal of the Neurological Sciences, Volume 147, Issue 1, 20 March 1997, Pages 35-42
Masakatsu Motomura, Bethan Lang, Irene Johnston, Jacqueline Palace, Angela Vincent, John Newsom-Davis

Abstract

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which autoantibodies are directed against voltage-gated calcium channels (VGCCs) at presynaptic nerve terminals. We first demonstrated the presence of P/Q-type and N-type VGCCs in digitonin extracts prepared from human and rabbit cerebellum using the specific ligands ¹²⁵I-ω-conotoxin MVIIC (¹²⁵I-ω-CmTx) and ¹²⁵I-ω-conotoxin GVIA (¹²⁵I-ω-CgTx), respectively. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using ¹²⁵I-ω-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. Sixty-six of 72 LEMS serum samples (91.7%) were positive for the presence of VGCC antibodies, as defined as a titre greater than 3 standard deviations above the mean for the healthy controls (n = 22). Rabbit cerebellar extract as antigen gave similar results (r = 0.94, P < 0.001, N = 30). By contrast, only 24/72 (33%) LEMS sera were positive in the assay for anti-N-type VGCC antibodies using ¹²⁵I-ω-CgTx. All these 24 were also positive in the ¹²⁵I-ω-CmTx assay. All healthy and disease control sera were negative in both assays. The anti-P/Q-type VGCC antibody titres did not correlate with an electrophysiological index of disease severity across individuals; however, longitudinal studies in a LEMS patient with SCLC receiving chemotherapy, and in a non-SCLC LEMS patient receiving immunosuppressive therapy showed an inverse relation between antibody titre and disease severity. These results support the view that anti-P/Q-type VGCC antibodies are implicated in the motor disorder in LEMS, and show that the ω-CmTx radioimmunoassay is a highly specific and sensitive means of detecting them.

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The Lambert-Eaton myasthenic syndrome 1988-2008: A clin...
Journal of Neuroimmunology

The Lambert–Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients
Journal of Neuroimmunology, Volumes 201-202, 15 September 2008, Pages 153-158
M.J. Titulaer, P.W. Wirtz, J.B.M. Kuks, H.J. Schelhaas, A.J. van der Kooi, C.G. Faber, W.L. van der Pol, M. de Visser, P.A.E. Sillevis Smitt, J.J.G.M. Verschuuren

Abstract

Background

Neuromuscular symptoms in patients with Lambert–Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC.

Patients and methods

In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS.

Results

In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p = 0.0001), distal arm muscles (p = 0.0037), distal leg muscles (p = 0.0002), dysartria (p = 0.0091) and the presence of erectile dysfunction (p = 0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS.

Conclusion

A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

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Lambert-Eaton myasthenic syndrome as an autoimmune calc...
Neuroscience Research

Lambert–Eaton myasthenic syndrome as an autoimmune calcium-channelopathy
Neuroscience Research, Volume 36, Issue 3, March 2000, Pages 183-191
Masaharu Takamori, Takahiro Maruta, Kiyonobu Komai

Abstract

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 α 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.

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Linear B-cell epitopes in Lambert-Eaton myasthenic synd...
Journal of Neuroimmunology

Linear B-cell epitopes in Lambert–Eaton myasthenic syndrome defined by cell-free synthetic peptide binding
Journal of Neuroimmunology, Volume 126, Issues 1-2, May 2002, Pages 190-195
Kevin T. Parsons, William W. Kwok

Abstract

Lambert–Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disorder characterized by autoantibodies that bind to P/Q voltage-gated calcium channels at the neuromuscular junction. Using cell-free direct peptide binding in 12 LEMS patients, we find linear B-cell epitopes that reside on the extracellular peptide linkers between the S5–S6 transmembrane peptides of Domains II and IV. A major epitope is located within the S5–S6 linker peptide of Domain IV defined by the acidic amino acid sequence EDEDSDEDE.

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Neurogenic bladder in Lambert-Eaton myasthenic syndrome...
Journal of the Neurological Sciences

Neurogenic bladder in Lambert–Eaton myasthenic syndrome and its response to 3,4-diaminopyridine
Journal of the Neurological Sciences, Volume 183, Issue 1, 15 January 2001, Pages 1-4
Katsuya Satoh, Masakatsu Motomura, Hiroshi Suzu, Yoko Nakao, Takeshi Fujimoto, Taku Fukuda, Shunya Nakane, Tatsufumi Nakamura, Katsumi Eguchi

Abstract

Autonomic dysfunction, as well as neuromuscular involvement, is a common manifestation of Lambert–Eaton myasthenic syndrome (LEMS). Dry mouth and impotence have been described as typical features of autonomic dysfunction, but neurogenic bladder is infrequent or subclinical in LEMS. We report a patient with neurogenic bladder secondary to LEMS whose condition responded to 3,4-diaminopyridine (3,4-DAP). In this patient’s serum, results of repeated measurement with P/Q-type VGCC antibodies proved positive, but not with N-type VGCC and synaptotagmin antibodies. A review of the literature turned up a few patients with voiding dysfunction related to LEMS, but no urodynamic studies were done on these patients. Ours is the first case in which 3,4-DAP was efficacious in treating LEMS and neurogenic bladder. Responses of 3,4-DAP in urodynamic studies suggest that in this LEMS patient neurogenic bladder was caused by defective neurotransmission both in the autonomic detrusor and skeletal abdominal muscles.

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doi:10.1016/S0072-9752(07)01509-6

Chapter 9 The Lambert–Eaton myasthenic syndrome

Donald B. Sanders ^,^a^, and Vern C. Juel^a

^aDuke University Medical School, Durham, NC, USA

Available online 14 June 2008.

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Article Outline

9.1. Introduction
9.2. Clinical presentation 9.2.1. Symptoms 9.2.2. Physical findings
9.3. Cancer in LEMS
9.4. Pathophysiology
9.5. Immunopathology
9.6. Epidemiology
9.7. Diagnostic procedures 9.7.1. Electrodiagnostic tests 9.7.2. Voltage-gated calcium channel antibodies
9.8. Other tests
9.9. Associated diseases
9.10. Differential diagnosis of LEMS
9.11. Treatment of LEMS 9.11.1. Medications that exacerbate LEMS
9.12. Prognosis
9.13. MG/LEMS overlap syndrome
References

Fig. 9.1. Age onset in 96 LEMS patients seen in the Duke MG Clinic since 1980. CA—associated cancer; NCA—no associated cancer detected. Most patients less than 50 have no associated cancer. With increasing age, more LEMS patients have cancer, but even over 70, cancer is not detected in half the patients.

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Fig. 9.2. Electron microscopy of freeze-fractured human presynaptic membrane preparations. (From Fukunaga et al., 1982, with permission from Muscle and Nerve.) (A) Control presynaptic membrane, P-face ×55 000, bar = 0.1 μm. Intramembrane particles representing VGCC are abundant and organized in active zones with double parallel rows of particles (arrows). (B) LEMS presynaptic membrane, P-face ×61 000, bar = 0.1 μm. Active zones are markedly depleted. A solitary short active zone (arrow) is identified. The cluster of large intramembrane particles (arrowhead) may reflect cross-linkage of VGCC antibody-receptor complexes. (C) Schematic reconstruction of 5 μm² regions of presynaptic membrane P-faces based upon data from membrane preparations in 9 LEMS patients and 14 controls. Control membranes had a mean of 13 active zones and 2 intramembrane clusters, while LEMS membranes had a mean of 3 active zones and 5 intramembrane clusters.

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Fig. 9.3. Repetitive nerve stimulation studies in LEMS. A CMAPs recorded from the hypothenar muscles during stimulation of the ulnar nerve at 3/s. The initial CMAP amplitude is less than normal and there is a decrementing response. B Immediately after maximum contraction of the muscle for 10 s, the amplitude of the initial response has increased by more than 100% from A. C During 20/s stimulation the CMAP amplitude falls slightly, then increases by more than 100% of the initial value. (From Sanders, 1993, with permission.)

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Fig. 9.4. Compound muscle action potentials in LEMS elicited before (left) and immediately after (right) maximum voluntary contraction of the tested muscle for 10 s. (From Sanders, 2005, with permission.)

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Fig. 9.5. Electrodiagnostic findings in 57 patients with LEMS. The percentage of patients in whom each abnormality was found on repetitive nerve stimulation studies. APB—abductor pollicis brevis; ADQ—abductor digiti quinti; EDB—extensor digitorum brevis; TRAP—trapezius (tested in 34 patients); Decrement—>10% decrement at 3 Hz; Low CMAP—CMAP amplitude less than normal; >100% facilitation—CMAP amplitude increased at least 100% after maximum voluntary contraction for 10 s; Abnormal facilitation—CMAP amplitude increased more than control values after maximum voluntary contraction for 10 s.

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Table 9.1

Demographics of 96 LEMS patients seen in the Duke MG Clinic since 1980