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causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes. The initial presentation can be similar to that of myasthenia gravis (MG), but the progressions of the 2 diseases have some important differences. In 40% of patients with LEMS, cancer is present when the weakness begins or is found later. This is usually a small cell lung cancer (SCLC), although LEMS has also been associated with non-SCLC, lymphosarcoma, malignant thymoma, or carcinoma of the breast, stomach, colon, prostate, bladder, kidney, or gallbladder. Clinical manifestations frequently precede cancer identification. In most cases, the cancer is discovered within the first 2 years after onset of LEMS and, in virtually all cases, within 4 years. Pathophysiology Physiologic studies of neuromuscular transmission demonstrate that ACh release from the motor nerve terminal is impaired in the LEMS muscle. An autoimmune attack directed against the voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal results in a loss of functional VGCCs at the motor nerve terminals. The number of quanta released by a nerve impulse is diminished. However, because presynaptic stores of ACh and the postsynaptic response to ACh remain intact, rapid repetitive stimulation or voluntary activation that aids in the release of quanta will raise the endplate potential above threshold and permit generation of muscle action potential. As neuromuscular transmission is completed at additional neuromuscular junctions, a transient increase will occur in the strength of the muscle. Parasympathetic, sympathetic, and enteric neurons are all affected. Clinically, this phenomenon is noted by the appearance of previously absent tendon reflexes following a short period of strong muscle contraction by the patient. Etiology For many years, clinical observations suggested an autoimmune etiology for LEMS. Such observations included the following:
LEMS is frequently associated with known autoimmune diseases Prednisone, plasma exchange (PEX), and intravenous immunoglobulin (IVIg) are effective treatments Patients with LEMS but without cancer frequently have elevated serum levels of organspecific autoantibodies
More direct evidence has been accumulated supporting the autoimmune etiology of LEMS. Active zone particles (AZPs), which represent the VGCCs, are normally arranged in regular parallel arrays on the presynaptic muscle membrane. In patients with LEMS and in mice injected with LEMS immunoglobulin G (IgG), divalent antibodies against the VGCC cross-link the
calcium channels, disrupting the parallel arrays. Ultimately, the AZPs cluster and decrease in number. SCLC cells originate from neuroectoderm, share a number of antigens with peripheral nervous system tissue, and contain high concentrations of VGCCs. Calcium influx into these cells is inhibited by LEMS IgG. Antibodies to VGCCs are found in the serum of most LEMS patients. These observations suggest that VGCC antibodies downregulate VGCCs in LEMS. In patients with LEMS who have SCLC or other cancer, cancer cells presumably contain antigens that mimic VGCCs and induce production of VGCC antibodies. In patients with LEMS but no cancer, VGCC antibodies are probably produced as part of a more general autoimmune state. In patients who have LEMS without cancer, an antibody response to domain IV of the 1A subunit of P/Q-type VGCCs is more common than in patients who have LEMS with cancer. VGCC antibody levels do not correlate with disease severity among patients with LEMS. However, antibody levels do fall in individual patients if the disease improves after cancer therapy or immunosuppression. All patients with LEMS who have associated SCLC have a history of long-term smoking. Only half of patients with autoimmune LEMS are long-term smokers. Epidemiology United States statistics The true incidence of LEMS is unknown. An estimated 3% of patients with SCLC have LEMS. The prevalence of SCLC is 5 cases per million population in the United States. Because only 5070% of patients with LEMS have an identifiable cancer and because LEMS goes undiagnosed in many patients, the true total prevalence of LEMS may be considerably higher. The overwhelming majority of cancers associated with LEMS are SCLC. However, many different malignancies may be involved. A partial list includes non-SCLC; neuroendocrine carcinomas; lymphosarcoma; malignant thymoma; cancers of the breast, stomach, colon, prostate, bladder, kidney, gallbladder, and rectum; basal cell carcinoma; leukemia; lymphoproliferative disorders such as Castleman syndrome; and Hodgkin lymphoma. According to one estimate, there are approximately 400 cases in the United States at any given time. However, this estimate does not take into account the number of patients with LEMS who do not have SCLC or any other identifiable malignancy. Age- and sex-related demographics LEMS usually begins in later adulthood and is primarily a disease of middle-aged and older people. The most common age for the appearance of symptoms is 60 years. It is rare in children; however, at least 7 children younger than 17 years are reported to have had LEMS.
In earlier reports, LEMS occurred in males more frequently than females, by a ratio of almost 2:1. However, current reports note almost equal frequency in men and women. Prognosis The prognosis is often difficult to assess. It is largely determined by the presence and type of any underlying cancer, the presence and severity of any associated autoimmune disease, and the severity and distribution of weakness. In addition, patients with rapidly progressive symptoms usually have more severe disease. The main problem created by LEMS is the progressive weakness that affects everyday activities and general quality of life. LEMS does not seem to affect the respiratory system as significantly as MG does. In most patients, weakness does not severely affect vital muscles. Maximum severity usually becomes established within several months of symptom onset. In most cases, therapy with agents such as 3,4-diaminopyridine (DAP) may help to relieve symptoms partially, but usually symptoms progress over time. Without treatment, weakness and dysfunction do not usually vary. Exceptions are during periods of exacerbation induced by intercurrent illness or by medications that impair neuromuscular transmission. Eventually, the weakness caused by LEMS can have profound consequences. However, death often results from the underlying malignancy. The diagnosis of LEMS frequently heralds cancer. This association is important in overall morbidity, since there is a very short survival time with SCLC. Because LEMS may lead to early detection of SCLC, prognosis of SCLC in patients with SCLCLEMS is better than in SCLC without LEMS. Patients with SCLC who develop LEMS possibly have a more effective immunologic response to the cancer, which results in improved survival. A more rapid clinical course is more frequent in patients with SCLC-LEMS. When LEMS has been symptomatic for at least 2 years and no underlying cancer has been demonstrated, the LEMS was probably caused by an autoimmune process. At that point, prognosis is determined by severity of dysfunction and the presence and severity of other autoimmune conditions. Symptoms of Lambert-Eaton myasthenic syndrome (LEMS) usually begin insidiously and progress slowly. Many patients have symptoms for months or years before the diagnosis is made. Weakness is the major symptom. Weak muscles may ache and are occasionally tender. Proximal muscles are more affected than distal muscles; lower extremity muscles are affected predominantly. Patients typically have difficulty rising from a chair, climbing stairs, and walking. Increased temperatures from fever or the environment may worsen the weakness. Patients may experience transient worsening after hot baths and showers or during systemic illnesses.
The oropharyngeal and ocular muscles are mildly affected in about one quarter of cases of LEMS, with symptoms that may include ptosis, diplopia, and dysarthria, but they are usually not affected to the same extent or severity as in myasthenia gravis (MG). Differentiation between the 2 diseases may be difficult. A study examining the localization of the initial muscle weakness and at the time of maximum severity in MG and LEMS patients found that patients with MG had initial muscle weakness involving the extraocular muscles (59%) and bulbar muscles (29%).[1] Conversely, LEMS patients never presented initially with ocular weakness; 5% presented with bulbar weakness, and 95% presented with limb weakness. In fact, almost all LEMS patients with oculobulbar or proximal upper extremity weakness also have proximal lower extremity weakness. In contrast, a significant portion of patients with MG never progress past weakness in the extraocular muscles. At the point of maximum weakness, 25% of patients with MG had purely ocular involvement, and there were no patients with LEMS who had only ocular involvement.[1] Respiratory muscles are not usually affected. When respiratory muscle function often is involved, the involvement is usually not as severe as with MG. However, rare cases of severe respiratory compromise or respiratory failure have been reported in patients with LEMS. Acute respiratory compromise is the most significant complication of LEMS and the only one that is relevant in the emergency setting. It is usually of iatrogenic origin. Most patients have a dry mouth, which frequently precedes other symptoms of LEMS. (Many do not mention this unless specifically questioned.) Many patients report an unpleasant metallic taste. Some patients have other manifestations of autonomic dysfunction, including impotence in males and postural hypotension. LEMS may be discovered first when prolonged paralysis follows the use of neuromuscular blocking agents during surgery. Exacerbation of weakness has been described after administration of aminoglycoside or fluoroquinolone antibiotics, magnesium, calcium channel blockers, and iodinated intravenous contrast agents.
Physical Examination
Strength is usually reduced in proximal muscles of the legs and arms, producing a waddling gait and difficulty elevating the arms. The degree of weakness is usually mild, compared with that reported by the patient. Sensory examination is normal unless a coincident peripheral neuropathy is present, which is not uncommon in patients with underlying cancer. Some degree of eyelid ptosis or diplopia, usually mild, is found in 25% of patients. Occasionally, difficulty chewing, dysphagia, or dysarthria is present. Most patients have a dry mouth, eyes, or skin. Constipation, urinary retention, pupillary constriction, sweating, postural hypotension, or respiratory muscle weakness may be present. Clinical manifestations of underlying malignancy (eg, cachexia) may be present. Fasciculations, common in diseases of the anterior horn cell, such as amyotrophic lateral sclerosis (ALS), are absent. In some patients, strength may improve after exercise and then weaken as activity is sustained. This phenomenon is demonstrable in approximately half of all patients with LEMS. It can also occur in the proximal muscles of patients with MG; however, repeated testing of many separate muscle groups may differentiate the 2 diseases. Reflexes usually are reduced or absent in LEMS. They can frequently be provoked or increased by having the patient actively contract the muscle group in question for 10 seconds prior to reflex testing or by repeatedly tapping the muscles. An increase in reflex activity after contraction is a hallmark of LEMS
Diagnostic Considerations
Other conditions to be considered in the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) include the following:
Anemia Botulism Cachexia Hypocalcemia Hypokalemia Hypomagnesemia Hyponatremia Hypothyroidism and myxedema coma Paraneoplastic neuropathy Tick paralysis
Differential Diagnoses
Amyotrophic Lateral Sclerosis (ALS) in Physical Medicine and Rehabilitation Chronic Inflammatory Demyelinating Polyradiculoneuropathy Dermatomyositis Inclusion Body Myositis Multiple Sclerosis Myasthenia Gravis Polymyalgia Rheumatica in Emergency Medicine Polymyositis Spinal Muscular Atrophy
In the emergency setting, very few tests are of importance in regard to Lambert-Eaton myasthenic syndrome (LEMS), because the diagnosis is not made in the emergency department (ED). It would be reasonable, however, to consider basic tests in any patient with cancer who reports weakness and dry mouth. These basic tests would include the following:
Antibody Assays
Voltage-gated calcium channel antibodies
Antibodies to voltage-gated calcium channels (VGCCs) have been reported in 75-100% of LEMS patients who have small cell lung cancer (SCLC) and in 50-90% of LEMS patients who do not have underlying cancer. They are also found in fewer than 5% of patients with myasthenia gravis (MG), in up to 25% of patients with lung cancer without LEMS, and in some patients who do not have LEMS but have high levels of circulating immunoglobulins (eg, those with systemic lupus erythematosus or rheumatoid arthritis). The sensitivity and specificity of the VGCC antibody assay are affected by the source of the antigen and the specific laboratory measuring the antibody. Reports suggest that SOX1, an immunogenic tumor antigen in SCLC, may play a role in identifying LEMS patients with lung cancer.[2]
In LEMS, the CMAP amplitude is low in most muscles tested. This finding is also nonspecific and is commonly observed in other neuromuscular diseases. Facilitation greater than 100% is seen in some but not all muscles (or in all patients) with LEMS. Facilitation greater than 50% in any muscle suggests LEMS. However, these findings might also be observed in MG. If facilitation is greater than 100% in most muscles tested or greater than 400% in any muscle, the patient almost certainly has LEMS. If facilitation is less than 50% in all muscles tested, the patient still may have LEMS, especially if weakness has been present for only a short time or the patient has been partially treated. When LEMS is mild, the electromyography (EMG) findings may resemble those of MG, including normal CMAP amplitudes, decremental response to RNS at low rates, and little facilitation. One helpful feature is that in LEMS, the EMG findings are usually more severe than the clinical findings would suggest. The opposite is frequently true in MG.
Electromyography
Needle electromyography
Conventional needle EMG in LEMS demonstrates markedly unstable motor unit action potentials, which vary in shape during voluntary activation.
Single-fiber electromyography
The jitter and blocking measured by single-fiber EMG is increased markedly in LEMS, frequently out of proportion to the severity of weakness. In many endplates, jitter and blocking decrease as the firing rate increases. This pattern is not seen in all endplates or in all patients with LEMS. Because jitter and blocking may also decrease at higher firing rates in some endplates of patients with MG, this pattern does not confirm an LEMS diagnosis unless it is dramatic and seen in most muscles.
Approach Considerations
Individually tailor therapy for Lambert-Eaton myasthenic syndrome (LEMS) on the basis of severity of weakness, underlying disease(s), life expectancy, and response to previous treatment. Therapy is best coordinated with the primary care physician and appropriate consultants. If an underlying neoplasm is present (eg, small cell lung cancer [SCLC]), initial treatment should be aimed at the neoplasm because weakness frequently improves with effective cancer therapy. No further LEMS treatment may be necessary in some patients. Typical treatments for patients with SCLC as the cause of their LEMS would include combination therapy with cisplatin and etoposide. Through both tumor modulation and its direct immunosuppressive properties, chemotherapy does seem to improve the symptoms of LEMS. In patients with LEMS who do not have cancer, aggressive immunotherapy should be considered.
Initial Management
Therapy seldom is started in the emergency department (ED). In general, before medical therapy begins, myasthenia gravis (MG) must be excluded. If the diagnosis is in any doubt, further workup or therapy for MG should be considered. In the ED setting, the most serious threat to life in these patients is the rare cases of respiratory failure. In such cases, treat as in any other patient: initiate supplemental oxygen; secure intravenous (IV) access; and intubate, if indicated. If intubation proves necessary, the use of neuromuscular blocking agents may further exacerbate the weakness and have prolonged effects (see Avoidance of weakness-exacerbating drugs). Patients experiencing acute exacerbations of weakness should be admitted for further testing and therapy that is best completed on an in-patient basis. Medical therapy, to include immunosuppression and plasmapheresis, may be indicated (see Pharmacologic Therapy and Plasma Exchange).
Exacerbation of LEMS after administration of any of several other agents, including magnesium and IV iodinated radiographic contrast agents, has been reported in isolated cases. In general, patients with LEMS should be observed for clinical worsening after initiating any new medication. Unless absolutely necessary, avoid drugs that are known to impair neuromuscular transmission. In such cases, a thorough knowledge of their potential deleterious effects is required.
(eg, DAP[5] ) or by decreasing the action of acetylcholinesterase (eg, pyridostigmine). Treatment of the associated cancer may also decrease the weakness and other symptoms. If these treatments are not effective and the patient has relatively mild weakness, determine if aggressive immunotherapy is justified. When such therapy is warranted, plasma exchange (PEX) or high-dose IVIg may be used initially to induce rapid, albeit transitory, improvement. Immunosuppressants should be added for more sustained improvement, although a theoretical concern exists that immunologic suppression of tumor growth may thereby be reduced in paraneoplastic LEMS. Prednisone and azathioprine, the most frequently used immunosuppressants, can be used alone or in combination. Cyclosporine may benefit patients with LEMS who are candidates for immunosuppression but cannot take or do not respond well to azathioprine. Improvement may be seen within 1-2 month after initiation of cyclosporine, with the maximum response usually observed in 3-4 months. PEX produces improvement in many patients with LEMS. Improvement is temporary unless the patient is also receiving immunosuppression. Response to PEX is often more gradual in patients with LEMS than in those with MG. Maximal response may take several weeks. Repeated courses of PEX may be necessary to maintain improvement. PEX may be performed 4-6 times over 7-10 days, as described in standard protocols. Potential complications include autonomic instability, hypercalcemia, and bleeding due to depletion of clotting factors. IVIg, given in a course of 2 g/kg over 2-5 days, also induces clinically significant temporary improvement in many patients.[6] The frequency of improvement in response to repeated courses of treatment has not been determined.
Consultations
In patients with chronic weakness, consultation with a neurologist may be indicated for electromyography (EMG), further workup, and initiation of pharmacotherapy. The diagnosis of LEMS may be suspected clinically but must be confirmed by electrodiagnostic testing. In addition, many of the medications and therapies that have been shown to produce clinical improvement are not appropriate for the ED. Most notably, in addition to pharmacotherapy, IVIG has been shown to have significant results.[6] Other appropriate consultations may include an oncologist and a physical medicine specialist.
Long-Term Monitoring
Ideally, the patients neurologist or primary care physician should coordinate all tests and procedures ordered on an outpatient basis. Physical therapy and exercise are important parts of the outpatient regimen to help maintain muscle tone and strength. Weakness of LEMS may be worse when the ambient temperature
increases or when the patient is febrile. Patients should avoid hot showers or baths. Systemic illness of any sort may cause transient worsening of weakness.
Medication Summary
Medical therapy is tailored for each patient and might include various combinations of the drugs listed below. Therapy is best coordinated with the primary care physician and appropriate consultants. The initial pharmacotherapy for Lambert-Eaton myasthenic syndrome (LEMS) is with agents that increase the transmission of acetylcholine (ACh) across the neuromuscular junction, either by increasing the release of ACh or by decreasing the action of acetylcholinesterase. Treatment of the associated cancer may also decrease the weakness and other symptoms. If these treatments are not effective and the patient has relatively mild weakness, aggressive immunotherapy may be warranted. In such cases, plasma exchange (PEX) or high-dose intravenous immunoglobulin (IVIg) may be used initially to induce rapid, albeit transitory, improvement. Immunosuppressants should be added for more sustained improvement. Prednisone and azathioprine, the most frequently used immunosuppressants, can be used alone or in combination. Cyclosporine may benefit patients with LEMS who are candidates for immunosuppression but cannot take or do not respond well to azathioprine. IVIg, given in a course of 2 g/kg over 2-5 days, also induces clinically significant temporary improvement in many patients. The frequency of improvement in response to repeated courses of treatment has not been determined.
Neuromuscular agents
Class Summary
Neuromuscular agents produce symptomatic improvement in strength, autonomic symptoms, or both in some patients with LEMS. They act by inhibiting the breakdown of ACh, which is intended to help compensate for the relative lack of ACh quanta release in LEMS. They usually do not provide a significant improvement; however, a few patients with mild disease may note some difference. Aminopyridines block potassium channels in membranes and facilitate chemical synaptic transmission at autonomic, neuromuscular, and central synapses. Both 4-aminopyridine and 3,4diaminopyridine (DAP) have been used, but 4-aminopyridine is thought to be less effective and is almost twice as toxic, with many neurologic effects reported.
Acetylcholinesterase inhibitors do not usually produce dramatic improvement in LEMS, but they may provide relief from weakness or dry mouth in some patients. Pyridostigmine is the preferred agent and should be administered for several days before assessing response. View full drug information
Pyridostigmine blocks ACh hydrolysis by cholinesterase, resulting in ACh accumulation at synapses and increasing stimulation of cholinergic receptors at myoneural junction. In most of the literature, the consensus seems to be that monotherapy with a cholinesterase inhibitor is ineffective. It is in combination with drugs such as 3,4-diaminopyridine that cholinesterase inhibitors may have some slight benefit.
3,4-Diaminopyridine (DAP)
For more than 20 years, DAP has been used to improve strength and autonomic function in patients with LEMS. Effect begins about 20 minutes after an oral dose. Each dose lasts about 4 hours, and maximum effect of a given dosage may not be observed for 2-3 days. Patients with or without underlying cancer benefit from DAP. In the authors' experience, >80% of patients with LEMS have significant clinical benefit; in over half of these, improvement is marked. This agent is not approved for clinical use in the United States, but it is available on a compassionate-use basis for individual patients. In most patients, pyridostigmine enhances and prolongs DAP's duration of action, permitting lower doses. Obtain application process information from Jacobus Pharmaceutical Co., Inc., Princeton, NJ, 609-799-1176 (fax).
Guanidine HCl
Guanidine is thought to act by increasing free intracellular calcium concentrations through inhibition of mitochondrial respiration. It inhibits respiration by blocking potassium channels and thus prolonging the nerve terminal action potential. This increases release of ACh after nerve impulses and may decrease rates of repolarization and depolarization of muscle cell membranes. It temporarily improves strength in many patients with LEMS. Maximal effect may take 2-3 days. This agent is primarily cited in case reports and has not been studied in randomized trials.
Immunosuppressants
Class Summary
If the therapies already described are ineffective, more aggressive immunotherapy may be indicated. Therapy can take the form of plasma exchange or high-dose IVIg, with the potential for more long-term immunosuppression, usually with prednisone or azathioprine. View full drug information
Prednisone
Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders. The combination of corticosteroid therapy with azathioprine may be more effective than steroid monotherapy. View full drug information
Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may inhibit formation of immune cells, possibly reducing activity of immune system.
Blood products
Class Summary
Agents in this category may be used to improve clinical and immunologic aspects of LEMS. They may decrease autoantibody production and increase solubilization and removal of immune complexes. IVIg can be an effective treatment for LEMS. View full drug information
Features of IVIg that may be relevant to efficacy include neutralization of circulating antibodies through anti-idiotypic antibodies; downregulation of proinflammatory cytokines, including interferon gamma; blockade of Fc receptors on macrophages; suppression of inducer T and B
cells and augmentation of suppressor T cells; blockade of the complement cascade; promotion of remyelination; and a possible increase in cerebrospinal fluid (CSF) immunoglobulin (IgG).