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Lambert-Eaton Myasthenic Syndrome (LEMS) Treatment & Management

  • Author: David E Stickler, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: May 06, 2016
 

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.

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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.

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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).

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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.[6] 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, 7]

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[8] ) 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.[9] The frequency of improvement in response to repeated courses of treatment has not been determined.

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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.[9]

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

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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.

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Contributor Information and Disclosures
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

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

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Acknowledgements

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. 2014 Sep 9. [Medline].

  2. Young JD, Leavitt JA. Lambert-Eaton Myasthenic Syndrome: Ocular Signs and Symptoms. J Neuroophthalmol. 2016 Mar. 36 (1):20-2. [Medline].

  3. 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. 2002 Dec. 73(6):766-8. [Medline]. [Full Text].

  4. Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2008 Mar 18. 70(12):924-8. [Medline].

  5. 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. 2008 Sep 10. 26(26):4276-81. [Medline].

  6. Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011 Feb 16. 2:CD003279. [Medline].

  7. 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. 2014 Aug 15. 592:3687-96. [Medline].

  8. Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2005 Apr 18. CD003279. [Medline].

  9. Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. 2005 May. 252 Suppl 1:I14-8. [Medline].

 
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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.
 
 
 
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