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Organized anatomically into categories spanning from the lower motor neuron to muscle, this chapter describes the neuromuscular complications of systemic medical disease. The text focuses on diagnosis and treatment of the disorders. The neuromuscular effects of toxic exposures are also discussed. Numerous tables are included to help with the diagnostic process.

Myasthenia is a Greek term for muscle weakness. Gravis is a Latin word meaning severe. The hallmark of myasthenia gravis (MG) is fluctuating, fatigable, painless muscle weakness that becomes worse with exertion or exercise and toward the end of the day. The weakness is dynamic rather than fixed. Diplopia and ptosis are commonly seen as the initial presentation. On physical examination, eliciting fatigable weakness is usually the key feature of MG. The MG antibody (Ab) testing is commonly used in clinical practice for diagnosis. Pyridostigmine and different types of immunotherapy have been used successfully to treat MG. Autoimmune Lambert–Eaton myasthenic syndrome (LEMS) and botulism are the most common presynaptic neuromuscular junction disorders. LEMS is caused by IgG Abs directed against voltage-gated calcium channels at the presynaptic motor nerve terminal. Botulism is caused by the bacterium Clostridium botulinum , which secrets different types of botulinum neurotoxins.

The neuromuscular junction represents a synapse between the motor nerve terminal and the surface of the muscle fiber, but the synaptic and postsynaptic elements are somewhat different from those in a central synapse. The neuromuscular junction is vulnerable to a variety of disease largely because it has no blood-brain barrier and is accessible to circulating factors. Poisoning by environmental insecticides or self-administered insecticides are common, and there are varieties of plant extracts that interfere with neuromuscular transmission. One of the most common disorders is caused by autoantibodies, to molecules on the postsynaptic membrane that cause autoimmune myasthenia gravis (MG). This chapter concentrates on the mechanisms at the neuromuscular junctions, which lead to various autoimmune disorders like MG. There are now four well-defined disorders in which autoantibodies are thought to be pathogenic, namely MG, muscle-specific kinase antibody-Associated MG, Lambert-Eaton myasthenic syndrome, and acquired neuromyotonia. Their identification depends on a variety of approaches, often including an element of serendipity and deductive reasoning. © 2007 Elsevier Inc. All rights reserved.

Voltage-gated calcium channels (VGCC) are a family of multimeric transmembrane proteins involved in calcium homeostasis, gene expression, and neurotransmitter release. Multiple types of VGCCs have been described in both the central nervous system and peripheral tissue. Antibodies to various subtypes of VGCC have been implicated in a number of different neurological disorders, including the Lambert-Eaton myasthenic syndrome (LEMS), amyotrophic lateral sclerosis (ALS), and certain forms of cerebellar ataxia (CA). Although antibodies to the P-/Q-, N- and L-type VGCC have been described in LEMS, only the P-/Q-type antibodies have been shown experimentally to be pathogenic. These antibodies have also been described in the serum and CSF of some patients with CA and lung cancer, and therefore are diagnostic for LEMS and, at least, markers for paraneoplastic CA. Although antibodies to VGCC have been suggested as a possible cause in sporadic cases of ALS, evidence no longer supports this hypothesis, and the detection of anti-VGCC antibodies is not used diagnostically in ALS. Standard radioimmunoassay procedures can be used for the detection of VGCC antibodies. © 2007 Elsevier Inc. All rights reserved.

Diseases of the neuromuscular junction comprise a wide range of disorders. Antibodies, genetic mutations, specific drugs or toxins interfere with the number or function of one of the essential proteins that control signaling between the presynaptic nerve ending and the postsynaptic muscle membrane. Acquired autoimmune disorders of the neuromuscular junction are the most common and are described here. In myasthenia gravis, antibodies to acetylcholine receptors or to proteins involved in receptor clustering, particularly muscle-specific kinase, cause direct loss of acetylcholine receptors or interfere with the agrin-induced acetylcholine receptor clustering necessary for efficient neurotransmission. In the Lambert-Eaton myasthenic syndrome (LEMS), loss of the presynaptic voltage-gated calcium channels results in reduced release of the acetylcholine transmitter. The conditions are generally recognizable clinically and the diagnosis confirmed by serologic testing and electromyography. Screening for thymomas in myasthenia or small cell cancer in LEMS is important. Fortunately, a wide range of symptomatic treatments, immunosuppressive drugs, or other immunomodulating therapies is available. Future research is directed to understanding the pathogenesis, discovering new antigens, and trying to develop disease-specific treatments.

Two rare treatable acquired disorders of presynaptic neuromuscular junction are described. In infantile botulism, Clostridium botulinum toxin produced from intestinal colonization blocks docking proteins from releasing acetylcholine. Patients display bulbar signs and constipation, abnormal high-frequency repetitive nerve stimulation and positive stool toxin. However, treatment within 3 days of hospitalization with botulinum immunoglobulin results in reduced length of hospital stay by 3 weeks and ventilation by 2 weeks. Pediatric Lambert-Eaton Myasthenic Syndrome (LEMS) is a primary autoimmune disorder but less frequently paraneoplastic in less than half of patients. LEMS typically presents with leg weakness and areflexia. Supportive of LEMS diagnosis is a low amplitude compound muscle action potential facilitating >25% with 10–50 Hz stimulation or exercise. Patients respond well to 3,4-diaminopyridine as well as IVIg and immunosuppressive therapies. Although these are rare disorders, a high index of suspicion will lead to timely therapies and significant improvement in outcomes, and therefore they are well worth understanding.

Autoantibodies to different subtypes of the voltage-gated calcium channel (VGCC) have been described in two very different neurological syndromes, the Lambert-Eaton myasthenic syndrome (LEMS) and amyotrophic lateral sclerosis (ALS). In this chapter we discuss the evidence supporting the role of anti-P/Q-type VGCC autoantibodies in the pathogenesis of LEMS but challenging the role of any VGCC autoantibodies in ALS. © 2014 Elsevier B.V. All rights reserved.

Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies to voltage-gated calcium channels in the presynaptic terminal at the neuromuscular junction. In one-half of LEMS patients, the disease is paraneoplastic and the autoantibodies are directed against small cell lung carcinoma (SCLC) epitopes. LEMS patients with no SCLC have the same antibodies as LEMS patients with SCLC but with no apparent initiating event. Symptomatic and immunosuppressive therapy is given in accordance with pathogenetic knowledge.

The neuromuscular disorders comprise a variety of disease states that affect the lower motor and sensory neurons, the spinal (motor and sensory) roots, peripheral nerves, neuromuscular junctions, and muscles. The clinical manifestations associated with disorders affecting these elements of the peripheral nervous system and their underlying causes are described in this article.

Myasthenia gravis (MG) and the Lambert-Eaton myasthenic syndrome (LEMS) are the prototypical autoimmune channelopathies of the peripheral nervous system. The predominant neuromuscular junction antigenic targets are either postsynaptic (MG; nicotinic acetylcholine receptor (AChR)) or presynaptic (LEMS; voltage-gated calcium channels (VGCCs)). Over the last 35 years the development of active immunization, passive transfer models, and use of transgenic animals has greatly enhanced our understanding of the biology of these disorders. The search for other antibodies in previously "seronegative" MG cases has led to the recognition of antibodies against clustered AChRs, muscle-specific kinase (MuSK) and low density lipoprotein receptor-related protein 4 (Lrp4). The pathogenic mechanisms that underlie these newer serological subclasses of MG are not yet fully understood, but are likely to be different from AChR antibody-mediated disease. While many still would consider MG an antibody-mediated disorder, it is well recognized that AChR-specific T lymphocytes and the thymus are critical to the autoimmune pathogenesis. In LEMS, new antibodies have been found including those against the intracellular protein SOX-1, which may help better predict those patients with a paraneoplastic disorder. This chapter aims to summarize the important clinical, immunological, and therapeutic aspects of both MG and LEMS, as well as highlighting recent developments in the field. © 2014 Elsevier Inc. All rights reserved.

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of neuromuscular transmission characterized clinically by muscle weakness, hyporeflexia or areflexia, and autonomic dysfunction. LEMS can occur as a remote effect of a neoplasm, in the paraneoplastic form (PLEMS), usually in association with small cell lung cancer (SCLC), or in the non-paraneoplastic form (NPLEMS). To denote a case as a patient with non-paraneoplastic LEMS needs a long-term follow up as in paraneoplastic cases where neurological symptoms can precede the diagnosis of primary neoplasm. Brain metastases from small cell lung cancer (SCLC) are found in approximately 10–14% of cases at presentation, with 65–95% of these cases also having disease outside the central nervous system (CNS) on diagnosis or shortly after. A solitary brain metastasis with an undetected primary is a rare presentation in cases of SCLC. Sometimes combinations of paraneoplastic syndromes (PS) and metastatic features might be the only presentation of the underlying occult primary SCLC. Certain clinical features together with relevant investigation help to clinch the diagnosis which has significant therapeutic implications in patients with occult primary SCLC. This chapter presents varied clinical features, diagnostic modalities, and therapeutic options in patients with LEMS and brain metastasis arising from occult primary SCLC. The authors also share their experience of a case of PLEMS and solitary cerebellar metastasis occurring simultaneously in the absence of a florid picture of SCLC.

Publisher Summary The Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune condition where weakness results from a presynaptic abnormality of acetylcholine (ACh) release at the neuromuscular junction. LEMS begins in later life. LEMS may be first discovered when prolonged paralysis follows the use of neuromuscular blocking agents during surgery. Small cell lung cancer (SCLC) is the most common associated cancer. The classical clinical findings of LEMS are weakness, particularly of proximal muscles, reduced or absent muscle stretch reflexes, and dry mouth. The diagnosis can be confirmed by demonstrating characteristic abnormalities on electrodiagnostic studies. Autonomic function tests are abnormal in most LEMS patients, even when there are no clinical signs of autonomic dysfunction. These tests show evidence of sympathetic or parasympathetic dysfunction. LEMS patients with SCLC may have other paraneoplastic syndromes, such as inappropriate ADH secretion (SIADH), sensorimotor neuropathy, or cerebellar degeneration. Clinical features for MG are ocular muscle weakness, limb weakness (predominating in arms), and normal muscle stretch reflexes. Therapy must be tailored for each patient, based on the severity of weakness, underlying disease(s), life expectancy and response to previous treatment. The prognosis in LEMS patients is determined by presence and type of any underlying cancer, presence and severity of any associated autoimmune disease, and severity and distribution of weakness. Overlapping features of MG and LEMS include: clinical features of one condition but facilitation, or lack thereof, typical of the other; clinical and electrodiagnostic patterns typical of one condition initially, but changing to the other later; or electrodiagnostic patterns typical of MG in one muscle, and of LEMS in another. The ultimate diagnosis in patients with mixed features of MG and LEMS may be moot because many treatments are the same for both conditions.

Publisher Summary This chapter discusses the features of the antibodymediated disorders that affect neuromuscular transmission that include myasthenia gravis (MG), seronegative myasthenia gravis (SNMG), Lambert–Eaton myasthenic syndrome (LEMS), and acquired neuromyotonia (NMT). Electron microscopy shows an essentially normal motor nerve terminal, but the postsynaptic membrane lacks junctional folds, and there are reduced areas of contact between the presynaptic nerve terminal and the muscle membrane. About 10%–15% of all MG patients with generalized symptoms do not have detectable acetylcholine receptor (AChR) antibodies by current laboratory methods, and these patients are termed as “seronegative.” Seronegative patients respond well to plasma exchange, and their immunoglobulins passively transfer a defect in neuromuscular transmission to mice. LEMS is electrophysiologically distinct from MG. The compound muscle action potential (CMAP) is reduced in amplitude following supramaximal nerve stimulation with decrement at low rates of repetitive nerve stimulation, and increment at higher rates, or following a few seconds of voluntary contraction. LEMS is often associated with small cell lung cancer (SCLC) and is also sometimes found with paraneoplastic cerebellar degeneration and paraneoplastic encephalomyelitis.

A high index of suspicion is essential in arriving at the correct diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). LEMS should be considered in the differential in any patient who has proximal weakness, reduced or absent muscle stretch reflexes, and dry mouth. Weakness predominates in hip and shoulder muscles, but may also affect ocular and oropharyngeal muscles to a lesser extent. The diagnosis is confirmed by demonstrating characteristic electromyographic findings-low-amplitude muscle responses that increase dramatically after activation. Most patients also have circulating antibodies to the voltage-gated calcium channel. Half the patients with LEMS have a malignancy, usually small-cell lung cancer. The diagnosis should trigger an intensive search for malignancy, especially in older patients with a history of smoking. Younger, nonsmoking patients are likely to have LEMS as part of a more general autoimmune state. Successful treatment of the underlying cancer leads to improvement in many patients. More than 85% of patients have clinically significant benefit from 3,4-diaminopyridine (DAP). In over half of these, the improvement is marked. If severe weakness persists despite DAP, immunotherapy should be considered. Plasma exchange and high-dose immunoglobulin induce transient improvement in many patients, but function rarely becomes normal. Combinations of prednisone, azathioprine, or cyclosporine have been used with variable success. Improvement, if any, occurs only after many months and requires chronic administration of immunosuppressive medications at significant doses. The long-term prognosis in LEMS is determined by the presence of cancer or other autoimmune disease.

The Lambert-Eaton myasthenic syndrome (LEMS) is the most common neurologic paraneoplastic syndrome. Although very rare, LEMS is the prototype presynaptic neuromuscular transmission disorder in adults. Most patients with LEMS are symptomatic less than a year; however, diagnostic recognition rarely is delayed as much as 8 to 25 years after initial symptoms. Clinical manifestations of LEMS usually precede pulmonary or radiographic definition of small cell lung cancer (SCLC) by a number of months to years. In most instances when a cancer is not already identified at the time of the LEMS presentation, the likelihood of developing a SCLC or other malignancy becomes significantly less after 4 years. In that instance one then presumes that LEMS has a primary immunologic basis similar to myasthenia gravis.

Publisher Summary This chapter discusses the current therapy of the Lambert-Eaton myasthenic syndrome (LEMS). In the human disease, generally called the “LEMS,” nearly all symptoms can be explained by peripheral blockade of somatic motor nerves and the parasympathetics, such as the cholinergic portions of the peripheral nervous system. LEMS seems to be caused by an autoimmune reaction against nerve terminal active zones mediated by plasma IgG. Electron microscopy using the technique of freeze-fracturing show reduction and disorganization of presynaptic active zone particles in LEMS and that type of lesion can be transferred to mice by LEMS IgG like the electrophysiological features of LEMS. The active zone particles represent the calcium ionophore triggering transmitter release by permitting calcium into the nerve terminal; LEMS appears to be caused by an autoimmune attack on these calcium channels. Guanidine has good therapeutic efficacy in LEMS and has long been the standard drug. The administration intravenously of 4-aminopyridine (4-AP) or 3,4-diaminopyridine (3,4-DAP) to a patient with LEMS often produces a “Lazarus effect.”

The role of antibodies against the P/Q type voltage-gated calcium channels (VGCC-ab) in the pathogenesis of paraneoplastic cerebellar degeneration (PCD) and lung cancer is unclear. We evaluated in mice the effect of intrathecal injection of IgG purified from serum of a patient with both PCD and Lambert-Eaton myasthenic syndrome (LEMS), and from another patient with isolated LEMS. Mice injected with PCD/LEMS IgG developed marked, reversible ataxia compared with those injected with LEMS or control IgG. These findings suggest that P/Q-type VGCC-ab may play a role in the pathogenesis of ataxia in patients with PCD and SCLC. This study was supported in part by grants PS09/0193 (FG) and PS11/01780 (JD) from Fondo de Investigaciones Sanitarias, Madrid; grant from Fundació la Marató de TV3 (JD), Barcelona; and grants from the “Ministerio de Ciencia e Innovación” (SAF2007-64062), and “Instituto de Salud Carlos III” (RETICS-Red de Trastornos Adictivos-Redes Temáticas de Investigación Cooperativa en Salud: RD06/0001/0001, RD06/0001/1004) (RM), Spain.The partial support of FEDER funds (EU) is also acknowledged