I. What every physician needs to know.
Lambert-Eaton Myasthenic Syndrome (LEMS) is a relatively rare disease of the neuromuscular junction that typically presents with gradually progressive, symmetric, proximal muscle weakness, most commonly in the lower extremities. Patients frequently present with difficulty walking, climbing steps or arising from a seated position. Rarely patients present with isolated facial weakness (most commonly ptosis), or respiratory failure. Autonomic complaints such as dry mouth or erectile dysfunction are common. Notably, there are no sensory deficits.
LEMS is associated with autoantibodies against voltage-gated calcium channels (VGCC). Binding of these autoantibodies to the VGCC in the presynaptic nerve terminal results in a decreased amount of calcium influx, and consequently less acetylcholine release into the synaptic junction and a reduced compound muscle action potential (CMAP). Electromyography (EMG) demonstrates a characteristic improvement in CMAP amplitude with either high frequency repetitive nerve stimulation or sustained isometric muscle contraction.
In about half the cases, LEMS is associated with an underlying malignancy, most commonly small cell lung cancer (SCLC). An exhaustive search for an underlying malignancy is therefore a focus of treatment for LEMS. Other treatment modalities focus on either increasing the amount of acetylcholine in the neuromuscular junction, or eliminating the VGCC autoantibodies with a goal of improving weakness.
II. Diagnostic Confirmation: Are you sure your patient has Lambert-Eaton Myasthenic Syndrome?
Diagnosis is typically based on clinical suspicion in the setting of a positive autoantibody screen for VGCC antibodies and a characteristic EMG.
85%–95% of patients with LEMS have antibodies against VGCC. However, antibodies against VGCC may exist in the absence of LEMS.
Patients with LEMS typically have a reduced resting CMAP amplitude on EMG. The amplitude of the CMAP increases with high frequency (10–50 Hz) nerve stimulation and this response to high frequency nerve stimulation is called post-activation facilitation. Because patients frequently have a difficult time tolerating high frequency nerve stimulation, an alternative finding is an increase in the amplitude of the CMAP after sustained (10 seconds) isometric muscle contraction, called post-exercise facilitation.
A. History Part I: Pattern Recognition:
LEMS typically presents in adults over the age of 40 and is most commonly associated with SCLC.
The most common finding in patients with LEMS is gradually progressive, symmetric, lower extremity, proximal muscle weakness, which patients will describe as a difficulty walking, standing from a seated position, or climbing stairs. Upper extremity (although not as common as lower extremity) proximal muscle weakness may also be present and will be described by patients as difficulty brushing teeth or hair, or lifting heavy objects. About one third of patients will describe a feeling of muscle aching or soreness.
Autonomic dysfunction may also be present with the most common symptom being dry mouth. In men, about 50% experience erectile dysfunction. Other autonomic symptoms that may be present are constipation, blurry vision and orthostasis.
About two-thirds of patients will have some cranial nerve finding with the most common symptoms being diplopia, or ptosis. However, the severity of ocular symptoms is mild, compared with myasthenia gravis.
Very rarely, patients will present with isolated respiratory failure.
LEMS associated with SCLC tends to have more severe muscle weakness and a more rapid progression.
B. History Part 2: Prevalence:
There is limited data regarding incidence and prevalence of LEMS. One study, from the Netherlands, found a prevalence of 2.3 per million and an annual incidence rate of 0.5 per million.
About 60% of LEMS cases are associated with an underlying malignancy. SCLC is the most commonly associated malignancy with about 50% of LEMS cases being associated with SCLC. Among patients with SCLC about 0.5%–3% have LEMS.
Patients with non-paraneoplastic LEMS often have other autoimmune diseases such as thyroid disease and type I diabetes.
C. History Part 3: Competing diagnoses that can mimic Lambert-Eaton Myasthenic Syndrome.
The differential diagnosis for LEMS includes any other disease that affects the neuromuscular junction such as myopathies, inflammatory myositis, polyneuropathies, and myasthenia gravis (MG).
LEMS is characterized by depressed or absent deep tendon reflexes which helps to distinguish it from the myopathies and myositis diseases in which deep tendon reflexes are typically preserved. The absence of sensory complaints and deficits helps to differentiate LEMS from the polyneuropathies.
The primary differential diagnosis is therefore MG. Patients with LEMS usually present with limb weakness as their initial symptom, whereas patients with MG typically present with extraocular muscle weakness (ptosis and/or double vision). In addition, the ocular symptoms of LEMS, once they develop, are typically less severe than in MG. On physical exam, reflexes are typically preserved in MG, but weak or absent in LEMS (including the pupillary reflex to light). Autonomic dysfunction including dry mouth, constipation and orthostasis are common in LEMS, but not in MG.
D. Physical Examination Findings.
Weakness of the proximal muscles is the most common physical exam finding, although the degree of weakness on exam may seem less than expected given the degree of functional impairment.
Hyporeflexia or areflexia is almost always present. Reflexes may temporarily improve after 10–15 seconds of sustained isometric contraction of the involved muscle (called post-exercise facilitation).
In the absence of a secondary polyneuropathy, sensation is intact in LEMS.
E. What diagnostic tests should be performed?
The diagnosis of LEMS requires a high index of suspicion, and is primarily supported by the clinical picture of proximal muscle weakness, autonomic dysfunction and hyporeflexia. The diagnosis is confirmed by serologic testing for antibodies to VGCC and by neurophysiologic testing.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
All patients with suspected LEMS should have testing for antibodies against the P/Q-type VGCC. These antibodies are present in 85%–95% of patients with LEMS and less than 5% of patients with MG. However, it is important to note that these antibodies may be present in the absence of LEMS. VGCC antibody titers do not correlate with disease severity, but the levels of these antibodies may decrease substantially in patients being treated with immunotherapy. Therefore, the possibility of LEMS should not be excluded if a patient has a negative VGCC antibody screen, but is, for example, taking steroids.
Electrodiagnostic studies are also an important part of confirming the diagnosis of LEMS. In LEMS, the CMAP amplitude is reduced and with low frequency repetitive nerve stimulation (1–5 Hz) there is a further decrement in the amplitude of the CMAP. High frequency repetitive nerve stimulation at 20–50 Hz results in an increase in the CMAP amplitude usually by more than 100%. This finding is called post-activation facilitation.
Because patients do not tolerate high frequency nerve stimulation well, an alternative finding is a similar increase in the CMAP amplitude after 10–15 seconds of voluntary sustained isometric muscle contraction, called post-exercise facilitation. Because not all muscles will have an increase in CMAP amplitude of more than 100%, several muscles may need to be examined.
In patients with LEMS, additional testing for sex determining region Y-box protein 1 (SOX1) antibodies may help to determine if there is underlying SCLC. It is important to recognize that the sensitivity of SOX1 antibody testing is low (67%), meaning many LEMS patients with SCLC will not have SOX1 antibodies. However, the specificity of SOX1 antibodies for underlying SCLC is high (95%), and therefore LEMS patients with a positive SOX1 antibody screen are much more likely to have underlying SCLC.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
The primary goal of imaging in LEMS is to detect underlying malignancy, most commonly SCLC. Computed tomography (CT) scan of the chest followed by a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, if the initial CT of the chest is negative, is recommended. These tests should be repeated every 3–6 months for 2 years after the diagnosis of LEMS.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
III. Default Management.
Initial management of LEMS should focus on the search for an underlying malignancy using the screening imaging tests mentioned above. If an underlying malignancy is found, then treatment of LEMS depends on treatment of the underlying malignancy. Both the weakness and the EMG findings associated with LEMS often improve with treatment of the underlying cancer, and in some patients no further treatment is needed.
If no underlying malignancy is found, or if symptoms are persistent or severe despite management of an underlying cancer, then treatment is focused on improving weakness by increasing the amount of acetylcholine available at the neuromuscular junction, or by decreasing the concentration of VGCC antibodies using immunotherapy.
Since the goal of treatment is improvement in weakness, the initial choice of treatment depends on the severity of the underlying weakness. If the weakness is mild, then pyridostigmine at a dose of 30–120 mg every 3–6 hours may be tried initially. Pyridostigmine is an acetylcholinesterase inhibitor, which increases the amount of acetylcholine available to bind at the postsynaptic membrane. The primary side effects of pyridostigmine include nausea, abdominal cramping and diarrhea.
Acetylcholinesterase inhibitors used as monotherapy have rarely had significant effect on the symptoms of LEMS. Therefore, if the weakness persists despite a trial of pyridostigmine then a second agent may be added.
Guanidine, which increases the concentration of intracellular calcium in the presynaptic terminal and therefore augments the release of acetylcholine, was the first agent studied in the treatment of LEMS. It has been shown to improve weakness and the EMG findings of LEMS in multiple case reports. However, because of significant toxicity including bone marrow suppression and renal failure, guanidine has not been studied in a controlled trial. Guanidine may still be considered as an addition to pyridostigmine, but at a low total daily dose (maximum of 1000 mg/day).
The aminopyridines work in a similar manner to guanidine by increasing intracellular calcium in the presynaptic terminal and therefore leading to increased acetylcholine release. The most commonly studied aminopyridine is 3,4-diaminopyridine (3,4-DAP). Four placebo-controlled trials (with a total of less than 100 patients) have now demonstrated improvement in muscle strength and resting EMG findings in patients with LEMS treated with 3,4-DAP. It is recommended to start 3,4-DAP at 5 mg three times per day, and the dose may be increased up to 60 mg/day in 3–4 daily doses.
The side effects of 3,4-DAP are usually mild and most commonly consist of paresthesias of the perioral area and extremities, nausea and vomiting, and difficulty with sleep. However, serious side effects including seizures, myoclonus, chorea, and cardiovascular disorders have been reported, and the likelihood of serious adverse events appears to be dose-related. Because seizure is the most common serious adverse event, 3,4-DAP is contraindicated in patients with epilepsy. Due to concern for prolongation of the QTc, 3,4-DAP is also contraindicated in patients with congenital QT syndromes, and those taking other drugs known to prolong the QTc interval. Unfortunately, 3,4-DAP has limited availability in the United States.
For patients with more severe symptoms or who fail to respond to a combination of pyridostigmine and either 3,4-DAP or low-dose guanidine, immunosuppressive therapy should be initiated. Unfortunately, there have been no randomized controlled trials of oral immunosuppressant drugs. So, the following recommendations are based on limited data. A typical starting regimen consists of oral prednisone at a dose of 1 mg/kg daily either alone or in combination with azathioprine at a starting dose of 50 mg twice per day.
Mycophenolate mofetil or cyclosporin may be substituted for azathrioprine in patients who are unable to tolerate azathioprine or do not have an adequate response. Rituximab has recently been reported to have some benefit in several patients with LEMS, but has not been more extensively studied.
In patients with the most severe presentation, such as respiratory failure, or who do not respond to the above treatment regimens, plasma exchange or intravenous immunoglobulin (IVIG) should be used. Plasma exchange has been shown to have benefit in several case series but only in the short term. IVIG has been shown in a single randomized controlled trial of 9 patients with LEMS to improve muscle strength, although the effect waned at 8 weeks. Therefore, both plasma exchange and IVIG should be used in combination with oral immunosuppressant therapy.
A. Immediate management.
In the absence of respiratory failure or severe weakness, no emergent therapy for LEMS is required. As mentioned above, with a severe LEMS flare, either IVIG or plasma exchange in combination with oral immunosuppressant therapy should be initiated.
B. Physical Examination Tips to Guide Management.
The need to alter therapy is dependent on symptomatic response and side effects. If a patient with LEMS continues to have weakness on physical exam, then additional therapy should be considered.
However, patients should be given an adequate trial of therapy prior to either increasing the dosage or changing therapy. In the case of pyridostigmine, guanidine, and 3,4-DAP the patient should be treated for several days prior to assessing for adequate response. In the case of oral immunosuppressants the patient may not see a benefit for several months.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
For patients taking 3,4-DAP, periodic electrocardiograms should be obtained to monitor the QTc.
Due to its significant toxicity, patients taking guanidine should have serial blood counts to monitor for bone marrrow suppression, as well as renal and hepatic monitoring.
Measurement of VGCC titer is not recommended for following response to any therapy.
D. Long-term management.
The long-term management of LEMS is dependent on whether there is an underlying malignancy. In the presence of cancer, the prognosis of LEMS depends on the patient’s response to cancer treatment. In the absence of underlying malignancy, most patients with LEMS require continued immunosuppressive medications.
E. Common Pitfalls and Side-Effects of Management.
In terms of side effects, patients taking pyridostigmine especially in combination with 3,4-DAP may experience nausea, vomiting, abdominal cramping and diarrhea. These symptoms may be lessened by decreasing the dose of pyridostigmine.
The most common serious adverse event with 3,4-DAP is seizure and the risk of seizure appears to be dose-dependent. Other common side effects with 3,4-DAP include insomnia, oral and extremity paresthesias, and gastrointestinal upset.
Patients taking guanidine may experience bone marrow toxicity, renal and hepatic failure.
IV. Management with Co-Morbidities.
Some antimicrobials should be used with caution in patients with LEMS as they can further impair neuromuscular transmission and therefore increase weakness. These include quinine and aminoglycoside antibiotics, particularly gentamicin, kanamycin, neomycin, and streptomycin. If it is necessary to use one of the aforementioned antibiotics, then a patient with LEMS should be carefully monitored for increased weakness.
Similarly, anesthetic agents should be used with caution in patients with LEMS. These include succinylcholine, d-tubocurarine, and other neuromuscular-blocking agents.
A. Renal Insufficiency.
Guanidine should be used with caution in cases of renal insufficiency.
B. Liver Insufficiency.
Guanidine should be used with caution in cases of hepatic disease.
C. Systolic and Diastolic Heart Failure.
Beta blockers, calcium channel blockers and certain antiarrhythmics including quinidine and procainamide affect neuromuscular transmission and therefore should be used with caution in patients with LEMS as they may significantly exacerbate weakness.
IVIG should be used with caution in the treatment of patients with LEMS and concurrent heart failure due to the large amount of volume required for administration.
D. Coronary Artery Disease or Peripheral Vascular Disease.
Similar caution applies as previously mentioned for the use of beta blockers and antiarrhythmics.
E. Diabetes or other Endocrine issues.
For patients with underlying diabetes, steroids should be used with caution as they may exacerbate hyperglycemia.
As mentioned previously, symptoms of LEMS often improve with treatment of the underlying malignancy, and therefore effective treatment of the underlying malignancy is central to management of malignancy-associated LEMS.
G. Immunosuppression (HIV, chronic steroids, etc).
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD).
Due to reports of bronchial hypersensitivity, 3,4-DAP is contraindicated in patients with uncontrolled asthma.
I. Gastrointestinal or Nutrition Issues.
Patients treated with pyridostigmine and 3,4-DAP commonly experience gastrointestinal upset including nausea, vomiting, abdominal cramping and diarrhea. Patients with other coexistent gastrointestinal disease, may therefore have worsening symptoms if treated with pyridostigmine or 3,4-DAP.
J. Hematologic or Coagulation Issues.
Patients treated with guanidine must be monitored for bone marrow toxicity.
K. Dementia or Psychiatric Illness/Treatment.
No change in standard management.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
The weakness of LEMS may worsen if the patient is febrile, or takes a hot shower or bath. Additionally, any coexisting illness may acutely exacerbate the symptoms of LEMS and should be treated aggressively.
In the setting of severe worsening of weakness including respiratory failure, immediate treatment would include plasma exchange and/or IVIG.
B. Anticipated Length of Stay.
In the absence of severe weakness or respiratory failure, patients with LEMS do not require hospitalization, and much of the evaluation and treatment of these patients can be performed in the outpatient setting.
C. When is the Patient Ready for Discharge.
In the absence of severe weakness or respiratory failure, patients with LEMS may be discharged home to complete much of their evaluation and treatment in the outpatient setting.
D. Arranging for Clinic Follow-up.
For patients with malignancy-associated LEMS, the most important follow up should be with oncology. Similarly, patients with underlying autoimmune disease should have follow up arranged with rheumatology. For management of symptoms related to LEMS, patients should be followed regularly by a neurologist.
1. When should clinic follow up be arranged and with whom.
Follow up with neurology should be arranged within 1–2 weeks of discharge depending on the severity of the underlying weakness. If malignancy was found during the hospitalization then follow up with oncology should ideally be arranged within 1 week.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
For patients with newly diagnosed LEMS, it is helpful to have a CT of the chest and FDG-PET prior to discharge in order to determine appropriate follow up. A baseline EMG and serum titer of VGCC antibodies would also be useful.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
If a patient with suspected LEMS did not undergo the above mentioned testing (CT chest, EMG, VGCC antibody screen), then these should be completed in the outpatient setting prior to the first clinic appointment.
If a patient was started on treatment during the hospitalization, then repeat EMG could be considered prior to clinic follow up to document response to treatment, although a decision to change treatment is primarily based on symptomatic response.
Any patient treated with guanidine should have a blood count, hepatic function panel and renal function panel on the day of clinic follow up.
E. Placement Considerations.
For patients who have severe weakness during their hospitalization, an assessment of their functional status by physical and occupational therapy should be obtained as soon as possible in order to assist with placement. Since many of the treatment options for LEMS are not effective immediately, patients with severe impairments are likely to require skilled nursing placement.
F. Prognosis and Patient Counseling.
Prognosis in the case of malignancy-associated LEMS is entirely dependent on the prognosis of the underlying cancer. In the case of non-paraneoplastic LEMS prognosis is quite good, although patients may require long term treatment with immunosuppressant medications.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
For patients in whom long term steroid use is planned, patients should be started on calcium plus vitamin D and trimethoprim/sulfamethoxazole for PCP prophylaxis. Bisphosphonate may be considered.
VII. What's the Evidence?
Bain, PG, Motomura, M, Newsom-Davis, J, Misbah, SA, Chapel, HM, Lee, ML, Vincent, A, Lang, B. “Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome”. Neurology. vol. 47. 1996. pp. 678-683.
Elmqvist, D, Lambert, EH. “Detailed analysis of neuromuscular transmission in a patient with the myasthenic syndrome sometimes associated with bronchogenic carcinoma”. Mayo Clin Proc. vol. 43. 1968. pp. 689-713.
Gilhus, NE. “Lambert-Eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy”. Autoimmune Dis. vol. 2011. 2011. pp. 973808
Karam, C, Scelsa, SN. “Clinical reasoning: a 48-year-old woman with generalized weakness.”. Neurology. vol. 74. 2010. pp. e76-e80.
Keogh, M, Sedehizadeh, S, Maddison, P. “Treatment for Lambert-Eaton myasthenic syndrome”. Cochrane Database of Systematic Reviews. vol. 2. 2011. pp. CD003279
Lambert, EH, Eaton, LM, Rooke, ED. “Defect of neuromuscular conduction associated with malignant neoplasms”. Am J Physiol. vol. 87. 1956. pp. 612-613.
Lambert, EH, Elmqvist, D. “Quantal components of end-plate potentials in the myasthenic syndrome. Ann N Y Acad Sci 183: 183-199, 1971Lang B, Pinto A, Giovannini F, Newsom-Davis J, Vincent A: Pathogenic autoantibodies in the Lambert-Eaton myasthenic syndrome”. Ann N Y Acad Sci. vol. 998. 2003. pp. 187-195.
Lindquist, S, Stangel, M. “Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine”. Neuropsychiatr Dis Treat. vol. 7. 2011. pp. 341-349.
Lorenzoni, PJ, Scola, RH, Kay, CS, Parolin, SF, Werneck, LC. “Non-paraneoplastic Lambert-Eaton myasthenic syndrome: a brief review of 10 cases”. Arq Neuropsiquiatr. vol. 68. 2010. pp. 849-854.
Pellkofer, HL, Armbruster, L, Linke, R, Schumm, F, Voltz, R. “Managing non-paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics in 25 German patients”. J Neuroimmunol. vol. 217. 2009. pp. 90-94.
Prommer, E. “Neuromuscular paraneoplastic syndromes: the Lambert-Eaton myasthenic syndrome”. J Palliat Med. vol. 13. 2010. pp. 1159-1162.
Simon, JI, Herbison, GJ, Levy, G. “Case report: a case review of Lambert-Eaton myasthenic syndrome and low back pain”. Curr Rev Musculoskelet Med. vol. 4. 2011. pp. 1-5.
Titulaer, MJ, Maddison, P, Sont, JK, Wirtz, PW, Hilton-Jones, D, Klooster, R, Willcox, N, Potman, M, Sillevis Smitt, PA, Kuks, JB, Roep, BO, Vincent, A, van der Maarel, SM, van Dijk, JG, Lang, B, Verschuuren, JJ. “Clinical Dutch-English Lambert-Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS”. J Clin Oncol. vol. 29. 2011. pp. 902-908.
Titulaer, MJ, Verschuuren, JJ. “Lambert-Eaton myasthenic syndrome: tumor versus nontumor forms”. Ann N Y Acad Sci. vol. 1132. 2008. pp. 129-134.
Wirtz, PW, Nijnuis, MG, Sotodeh, M, Willems, LN, Brahim, JJ, Putter, H, Wintzen, AR, Verschuuren, JJ. “The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland”. J Neurol. vol. 250. 2003. pp. 698-701.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Lambert-Eaton Myasthenic Syndrome?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Lambert-Eaton Myasthenic Syndrome.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management.
- IV. Management with Co-Morbidities.
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure.
- D. Coronary Artery Disease or Peripheral Vascular Disease.
- E. Diabetes or other Endocrine issues.
- F. Malignancy.
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD).
- I. Gastrointestinal or Nutrition Issues.
- J. Hematologic or Coagulation Issues.
- K. Dementia or Psychiatric Illness/Treatment.
- V. Transitions of Care.
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up.
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures.
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
- VII. What's the Evidence?