Lambert-Eaton Myasthenic Syndrome (LEMS)

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Background

Lambert-Eaton myasthenic syndrome (LEMS) is a rare presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired, 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.

LEMS disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca2+ channels involved with neurotransmitter release.[1]

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.[1]

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:

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 50-70% 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 SCLC-LEMS 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.

History

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%).[2] 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.[2]

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.

Cancer and LEMS

Cancer is present or subsequently discovered in 50-70% of patients with LEMS. In the case of lung cancer, the clinical symptoms of LEMS may precede detection of the underlying disease. Symptoms of the underlying cancer, as well as the “B” symptoms of cancer, may be present.

Smoking and age at onset are major risk factors for cancer in patients with LEMS. Duration of symptoms is also a factor. If a tumor is not found within the first 2 years after symptom onset, cancer is unlikely. For example, a patient younger than 50 years at onset who does not have a tumor discovered after 2 years of close follow-up is unlikely to have an underlying cancer. On the other hand, a long-term smoker with LEMS onset after age 50 years probably has underlying lung cancer.

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.

Approach Considerations

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:

Other, more specific tests are ordered as indicated (see below).

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.[3]

Acetylcholine receptor antibodies

ACh receptor (AChR) antibodies are most commonly associated with myasthenia gravis (MG) and are occasionally found in low titers in LEMS. The only true methods of differentiating MG from LEMS are the detection of AChR antibodies and the presence of underlying malignancy.

Imaging Studies and Bronchoscopy

SCLC is the malignancy most frequently associated with LEMS. In all adult patients with LEMS, diagnostic imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest for cancer detection should be performed. Screening strategies may help to detect SCLC in patients with newly diagnosed LEMS and therefore offer a better approach to treatment.

If imaging findings are negative in a patient with a substantial risk of having lung cancer, bronchoscopy should be performed. If both imaging and bronchoscopy results are initially negative and risk factors for lung cancer are present, positron emission tomography (PET) scanning should be considered. If all imaging study results are negative in such patients, periodic reassessment thereafter is indicated.

In a large cohort study, Titulaer et al screened for tumors using various methods (CT, radiography,18 F-fluorodeoxyglucose PET (FDG-PET), bronchoscopy, or mediastinoscopy) and found that CT of the thorax detected 93% of the tumors.[4]

Repetitive Nerve Stimulation Studies

Repetitive nerve stimulation (RNS) studies confirm the diagnosis of LEMS by demonstrating characteristic findings (see the image below). Compound muscle action potentials (CMAPs) recorded with surface electrodes are usually small, often less than 10% of normal, and fall during 1- to 5-Hz RNS.


View Image

Characteristic responses to repetitive nerve stimulation in patient with Lambert-Eaton myasthenic syndrome. (A) Responses elicited from hand muscle by....

During stimulation at 20-50 Hz, the CMAP increases in size (ie, facilitation) and characteristically becomes at least twice the size of the initial response. A similar increase in CMAP size is seen immediately after the patient voluntarily contracts the muscle maximally for several seconds (see the image below).


View Image

Compound muscle action potentials elicited from hand muscle before and immediately after maximal voluntary activation of muscle for 10 seconds. Amplit....

In virtually all patients with LEMS, a decremental response to low-frequency nerve stimulation is observed in the hand muscles. This finding is not specific to LEMS and can be seen in MG and other neuromuscular diseases.

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.

Edrophonium (Tensilon) Test

Testing with edrophonium (Tensilon) may be performed to help differentiate LEMS from MG. However, such testing is highly subjective, and it is of little value in the diagnosis of LEMS in the ED.

The test may produce an improvement in strength, but rarely is the response in patients with LEMS as noticeable as the typical response in patients with MG.

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).

Avoidance of weakness-exacerbating drugs

Drugs that compromise neuromuscular transmission frequently exacerbate weakness in LEMS. Competitive neuromuscular blocking agents, such as d-tubocurarine and pancuronium, have an exaggerated and prolonged effect in patients with LEMS.

Initial signs of possible LEMS include prolonged weakness or apnea following administration of neuromuscular blocking agents during anesthesia.

Some antibiotics, particularly aminoglycosides, fluoroquinolones (eg, ciprofloxacin), and erythromycin, have significant neuromuscular blocking effects. Some antiarrhythmics (eg, quinine, quinidine, procainamide) and beta-adrenergic blocking drugs also worsen myasthenic weakness.

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.

Treatment of Underlying Malignancy

In patients with cancer, LEMS is usually not the major therapeutic concern: the primary concern is the cancer. Accordingly, when the diagnosis of LEMS is confirmed, perform an extensive search for an underlying malignancy with radiography and computed tomography (CT) of the chest, bronchoscopy, and possibly positron emission tomography (PET) scanning.

If no tumor is found, periodically search again for occult malignancy. Frequency of these evaluations is determined by the patient’s risk of cancer.

Patients younger than 50 years without history of long-term smoking have a low risk of associated malignancy, especially if evidence of coexisting autoimmune disease is present. Extensive surveillance for cancer may not be necessary for such patients. Patients older than 50 years with a history of long-term smoking almost certainly have underlying 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.

Immunotherapy of LEMS without effective treatment of the underlying cancer usually produces little or no improvement in strength. A theoretical concern is that the immunosuppression may reduce immunologic suppression of tumor growth.

In patients with LEMS who do not have cancer, aggressive immunotherapy should be considered (see Pharmacologic Therapy and Plasma Exchange).

Pharmacologic Therapy and Plasma Exchange

Limited data from randomized controlled trials examining different interventions for LEMS are available. A Cochrane review identified only 4 controlled trials of 3,4-diaminopyridine (DAP) and a single cross-over study that examined the use of IV immunoglobulin (IVIg) and concluded that there was limited but moderate-to-high-quality evidence to suggest improved muscle strength with these interventions.[5] All other potential interventions have not been examined in controlled trials.

Recent studies have introduced a Ca2+ channel agonist (GV-58) as a potential therapeutic alternative for LEMS. In addition, in a mouse model, GV-58 and 3,4-DAP were shown to interact in a supra-additive manner to restore the magnitude of neurotransmitter release at the neuromuscular junctions.[1, 6]

The initial pharmacotherapy for LEMS is with agents that increase the transmission of acetylcholine (ACh) across the neuromuscular junction, either by increasing the release of ACh (eg, DAP[7] ) 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.[8] 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.[8]

Other appropriate consultations may include an oncologist and a physical medicine specialist.

Long-Term Monitoring

Ideally, the patient’s 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.

Pyridostigmine bromide (Mestinon, Regonol)

Clinical Context:  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)

Clinical Context:  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

Clinical Context:  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.

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 3,4-diaminopyridine (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.

Prednisone

Clinical Context:  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.

Azathioprine (Imuran, Azasan)

Clinical Context:  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.

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.

Intravenous immunoglobulin (IVIg) (Gamunex, Gammagard, Carimune NF)

Clinical Context:  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).

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.

Author

David E Stickler, MD, Assistant Professor, Department of Neurosciences, Director of Electromyography Laboratory, Director of MDA Clinic, Director of Neuromuscular Service, Director of ALS Clinic, Medical University of South Carolina

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, CPE, Chairman and CEO, Neurology Specialists and Consultants; Former Senior Vice President, Founding Executive Director, Continuing Medical Education, Gannett Education (Division Gannett Healthcare Group)

Disclosure: Nothing to disclose.

Additional Contributors

Paul E Barkhaus, MD Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Affairs Medical Center

Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association

Disclosure: Nothing to disclose.

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center

Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Paul Kleinschmidt, MD Consulting Staff, Department of Emergency Medicine, Womack Army Medical Center

Paul Kleinschmidt, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: ScrubCast, INC Ownership interest Other

Donald B Sanders, MD EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

  1. Tarr TB, Wipf P, Meriney SD. Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome. Mol Neurobiol. Sep 9 2014;[View Abstract]
  2. Wirtz PW, Sotodeh M, Nijnuis M, Van Doorn PA, Van Engelen BG, Hintzen RQ, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. Dec 2002;73(6):766-8. [View Abstract]
  3. Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. Mar 18 2008;70(12):924-8. [View Abstract]
  4. Titulaer MJ, Wirtz PW, Willems LN, van Kralingen KW, Smitt PA, Verschuuren JJ. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol. Sep 10 2008;26(26):4276-81. [View Abstract]
  5. Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. Feb 16 2011;2:CD003279. [View Abstract]
  6. Tarr TB, Lacomis D, Reddel SW, Liang M, Valdomir G, Frasso M, et al. Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist. J Physiol. Aug 15 2014;592:3687-96. [View Abstract]
  7. [Best Evidence] Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. Apr 18 2005;CD003279. [View Abstract]
  8. Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. May 2005;252 Suppl 1:I14-8. [View Abstract]

Characteristic responses to repetitive nerve stimulation in patient with Lambert-Eaton myasthenic syndrome. (A) Responses elicited from hand muscle by stimulation of nerve at 3 Hz. Amplitude of initial response is less than normal, and response is decremental. (B) Responses as in A, immediately after voluntary activation of muscle for 10 seconds. Amplitude has increased. (C) Responses in hand muscle elicited by 20-Hz stimulation of nerve for 10 seconds. Response amplitude is less than normal initially, falls further during first few stimuli, then increases and ultimately becomes more than twice initial value.

Compound muscle action potentials elicited from hand muscle before and immediately after maximal voluntary activation of muscle for 10 seconds. Amplitude is small initially, increasing almost 10 times after activation.

Characteristic responses to repetitive nerve stimulation in patient with Lambert-Eaton myasthenic syndrome. (A) Responses elicited from hand muscle by stimulation of nerve at 3 Hz. Amplitude of initial response is less than normal, and response is decremental. (B) Responses as in A, immediately after voluntary activation of muscle for 10 seconds. Amplitude has increased. (C) Responses in hand muscle elicited by 20-Hz stimulation of nerve for 10 seconds. Response amplitude is less than normal initially, falls further during first few stimuli, then increases and ultimately becomes more than twice initial value.

Compound muscle action potentials elicited from hand muscle before and immediately after maximal voluntary activation of muscle for 10 seconds. Amplitude is small initially, increasing almost 10 times after activation.