Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Presentation includes proximal muscle weakness and symptoms of autonomic dysfunction such as dry mouth and sluggish pupillary reflexes. Diagnosis includes nerve conduction studies/electromyography (EMG) and serum detection of antibodies. Management is mainly symptomatic with the use of potassium channel blockers and immunosuppressants. Prognosis is good for nonparaneoplastic LEMS but usually poor for paraneoplastic LEMS secondary to underlying malignancy.

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Overview

Definition

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma.

Epidemiology

  • Rare disorder with an estimated prevalence of 2.8 per million
  • Approximately 3% of patients with small cell lung carcinoma develop LEMS.
  • Extremely rare in the pediatric population; the typical age of onset is around 35 years old.
  • Current reports suggest the incidence of LEMS is almost equal in both men and women (previously 2:1 men:women ratio).
  • About 50% of cases are associated with malignancy (small cell lung carcinoma or lymphoproliferative disorders).

Etiology

  • Autoimmune disease:
    • Antibodies to voltage-gated calcium channels (VGCCs)
    • Decreased release of acetylcholine (ACh) from presynaptic nerve terminals
  • Risk factors:
    • Malignancies (mostly small cell lung carcinoma and lymphoma)
    • Other autoimmune disorders (notably diabetes mellitus type 1 and thyroid disorders)
    • Smoking

Pathophysiology and Clinical Presentation

Pathophysiology

  • In LEMS, antibodies are formed against VGCCs, which mediate the release of ACh.
  • Due to a block in the VGCCs, the normal calcium flux leading to the release of ACh vesicles is blocked.
  • Due to little or no ACh release, muscle contraction is minimal or none, which presents as muscle weakness.
  • Chronic postsynaptic ACh deficiency leads to increased “folding” of the postsynaptic membrane (greater surface area) and a greater density of available ACh receptors.
  • On initial presynaptic stimulation, limited ACh is available in the synaptic cleft.
  • With repetitive stimulation, more ACh is released and binds to the increased population of available ACh receptors.
  • Paraneoplastic LEMS:
    • Small cell lung carcinoma cells express surface VGCCs.
    • Antibodies form against surface VGCCs, causing cross-reaction with presynaptic VGCCs.
  • Nonparaneoplastic LEMS: the specific trigger for the development of VGCC antibodies is unknown.
Lambert-Eaton Myasthenic Syndrome pathophysiology

Illustrations showing normal activity at the neuromuscular junction, pathogenesis of LEMS, and activity at the neuromuscular junction after LEMS treatment

Image by Lecturio.

Clinical presentation

Muscle weakness:

  • Slow, progressive proximal muscle weakness
  • Paraneoplastic LEMS may have more rapid progression.
  • Achy, stiff muscles
  • Muscle fatigue and cramping
  • Lower extremities more commonly involved
  • Alteration in gait (presents as difficulty rising from a chair)
  • Deep tendon reflexes (DTRs) are decreased (hyporeflexia) or, more rarely, absent (areflexia).
  • Post-exercise facilitation: 
    • DTRs and muscle strength improve with brief, vigorous muscle activation.
    • Lambert’s sign: Grip becomes more powerful on repeated evaluation of muscle strength.
  • Important note: absence of sensory symptoms/findings

Bulbar involvement:

  • Not as common or severe as in myasthenia gravis
  • Ptosis and ophthalmoplegia
  • Diplopia
  • Dysphagia
  • Dysarthria
  • Difficulty chewing

Autonomic dysfunction:

  • Dry mouth
  • Sluggish pupillary response (symmetrical)
  • Blurred vision
  • Impaired sweating
  • Erectile dysfunction in men
  • Orthostatic hypertension
  • Constipation

Respiratory failure:

  • Respiratory weakness is mild to moderate in LEMS.
  • Respiratory failure is rare and only occurs in progressed disease.
  • Associated with increased mortality

Diagnosis

History and physical exam

  • Known malignancy (especially small cell lung carcinoma)
  • Personal or family history of autoimmune disorder
  • Triad of symptoms:
    • Muscle weakness (proximal to distal)
    • Hyporeflexia or areflexia
    • Autonomic dysfunction

Electrodiagnostic studies

  • Repetitive nerve stimulation (RNS) during nerve conduction velocity testing is the study of choice for LEMS diagnosis.
  • Nerve conduction velocity shows 3 primary test findings:
    • Reduced compound muscle action potential
    • Low-frequency RNS gives a decremental response > 10% at 3 Hz
    • High-frequency RNS gives an incremental response > 100% at 3 Hz (diagnostic due to increased release of Ca2+ with repeated stimulation)
  • Single fiber electromyography (EMG) examination is the most sensitive, but not specific, test for LEMS.

Antibody tests

  • Antibodies against P/Q type VGCCs:
    • 85%–90% of patients with LEMS associated with small cell lung carcinoma test positive for the antibodies.
    • 50%–90% of patients with LEMS not associated with small cell lung carcinoma test positive for the antibodies.
  • SOX antibodies are commonly associated with small cell lung carcinoma and help to determine the cause of LEMS.
  • ACh receptor antibodies: 
    • Present at a low titer level in patients with LEMS
    • Aids in LEMS and myasthenia gravis differentiation

Cancer screening

  • Perform an aggressive search for underlying malignancy (especially small cell lung carcinoma).
  • CT
  • MRI
  • Chest X-ray
  • Biopsy suspicious radiographic findings for pathologic analysis.
CT scan showing SCLC

CT scan of the thorax showing central (A) and peripheral (B) small cell lung carcinoma (black arrow)

Image: “Distinct Characteristics of Small Cell Lung Cancer Correlate With Central or Peripheral Origin: Subtyping Based on Location and Expression of Transcription Factor TTF-1” by Miyauchi, E. et al. License: CC BY 4.0

Management

Management

General:

  • No curative treatment
  • Mild cases not significantly affecting everyday life do not require treatment.
  • A few options are available for moderate to severe cases.

Pharmacotherapy:

  • Potassium channel blockers (3,4-diaminopyridine and guanidine): 
    • Potassium channel blockers prolong membrane depolarization at the presynaptic terminal membrane.
    • Entry of calcium is increased, releasing ACh from the vesicles.
    • Adverse effects include:
      • Headache
      • Nausea
      • Abdominal pain
      • Diarrhea
      • Elevated liver enzymes
  • Acetylcholinesterase inhibitors (pyridostigmine): 
    • Only marginally effective in the management of LEMS; considered in patients who cannot tolerate 3,4-diaminopyridine
    • When combined, pyridostigmine and guanidine can produce a positive effect and also reduce the toxic effect of guanidine.
  • Use chemotherapeutic agents to target underlying carcinoma.

Immunotherapy:

  • Immunosuppressive drugs:
    • Corticosteroids (prednisone)
    • Nonsteroidal immunosuppressants: 
      • Methotrexate
      • Cyclosporine
  • IV immunoglobulin for severe/refractory cases
  • Plasmapheresis for severe/refractory cases

Surgery: Where possible, tumor resection can be considered and produce positive results (small number of cases).

Prognosis

Paraneoplastic LEMS:

  • Survival is determined by the underlying malignancy.
  • Short life span is associated with small cell lung carcinoma.
  • Rapid disease progression
  • At least partial remission of LEMS can be achieved with treatment/resection of the tumor.

Nonparaneoplastic LEMS:

  • LEMS patients with no associated small cell lung carcinoma have a normal or a near-normal lifespan.
  • Slow disease progression
  • Managed better than paraneoplastic LEMS with proper therapy

Differential Diagnosis

  • Guillain-Barre syndromé: disorder of the peripheral nervous system triggered by an acute bacterial or viral infection, which presents with initial paresthesia in the feet/legs and progresses to ascending paralysis. Additional symptoms include walking abnormalities, fatigue, tachycardia, hypertension, and urinary retention. Diagnosis is made by CSF analysis, EMG, and nerve conduction studies. Management includes plasmapheresis and immunoglobulin therapy, analgesics, blood thinners, and physiotherapy.
  • Amyotrophic lateral sclerosis: a group of neurological disorders involving neurons associated with voluntary movement. Clinical presentation includes fasciculations, muscle cramps, spasticity, and dysarthria, which are progressive over time. A definitive test is not available; diagnosis relies heavily on history and physical examination. Treatment includes supportive care as no cure has been found yet.
  • Botulism: foodborne disease caused by the organism Clostridium botulinum. Clinical presentation includes ptosis, abdominal cramps, symmetric neurological deficits, diplopia, and blurred vision. Botulism is diagnosed by isolation of the organism and toxin detection in the serum or food source. Treatment includes botulinum antitoxin, immunoglobulin, and physiotherapy.
  • Tick paralysis: occurs due to injection of toxin by a tick bite. Symptoms occur within 2–7 days. Clinical presentation includes initial numbness and weakness in both legs, which progresses to ascending paralysis and respiratory distress within hours. Deep tendon reflexes are decreased or absent. Diagnosis is based on symptoms and finding an embedded tick, usually on the scalp. Management includes detecting/removing the tick, cleaning the bite location, and monitoring for respiratory distress.
  • Myasthenia gravis: an autoimmune neuromuscular junction disorder characterized by varying degrees of muscle weakness of the arms and legs. Presentation also includes ptosis, dysphagia, fatigue, and breathlessness. Myasthenia gravis is diagnosed by edrophonium test, conduction studies, and specific antibody detection. Medical management includes acetylcholinesterase inhibitors and immunosuppressants; surgical management includes thymectomy.
  • Stroke: A medical emergency causing damage to the brain due to interrupted blood supply. Presentation includes headache, dysarthria, blurred vision, facial paralysis, and numbness of the face, arms, and/or legs. A stroke is diagnosed by physical examination, CT, MRI, cerebral angiogram, or carotid ultrasound. Management depends on the type of stroke (ischemic or hemorrhagic).

References

  1. Tarr, T.B., Wipf, P., Meriney, S.D. (2015). Synaptic pathophysiology and treatment of Lambert-Eaton myasthenic syndrome. Mol Neurobiol. 52(1),456–463. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362862/
  2. Stickler, D.E. (2019). Lambert-Eaton myasthenic syndrome (LEMS). Medscape. https://emedicine.medscape.com/article/1170810-overview#a4
  3. Physiopedia. (2021). Lambert-Eaton myasthenic syndrome (LEMS). https://www.physio-pedia.com/Lambert-Eaton_Myasthenic_Syndrome
  4. Weinberg, D.H. (2021). Lambert-Eaton myasthenic syndrome: Clinical features and diagnosis. UpToDate. https://www.uptodate.com/contents/lambert-eaton-myasthenic-syndrome-clinical-features-and-diagnosis
  5. Weinberg, D.H. (2021). Lambert-Eaton myasthenic syndrome: Treatment and prognosis. UpToDate. https://www.uptodate.com/contents/lambert-eaton-myasthenic-syndrome-treatment-and-prognosis
  6. Longo, Fauci, Kasper, Hauser, Jameson, Loscalzo. (2011). Myasthenia gravis and other diseases of the neuromuscular junction. Harrison’s Principles of Internal medicine. 18th edition. p. 6817.

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