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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. Management is mainly symptomatic with the use of potassium channel blockers and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. 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 Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus type 1 and thyroid disorders)
    • Smoking

Pathophysiology and Clinical Presentation

Pathophysiology

  • In LEMS, antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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 Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis
  • Ptosis and ophthalmoplegia
  • Diplopia
  • Dysphagia
  • Dysarthria
  • Difficulty chewing

Autonomic dysfunction:

  • Dry mouth
  • Sluggish pupillary response (symmetrical)
  • Blurred vision
  • Impaired sweating
  • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction in men
  • Orthostatic hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation

Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure:

  • Respiratory weakness is mild to moderate in LEMS.
  • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.
    • 50%–90% of patients with LEMS not associated with small cell lung carcinoma test positive for the antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.
  • SOX antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are commonly associated with small cell lung carcinoma and help to determine the cause of LEMS.
  • ACh receptor antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
    • Present at a low titer level in patients with LEMS
    • Aids in LEMS and myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer Correlate With Central or Peripheral Origin: Subtyping Based on Location and Expression of Transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
      • Elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. 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 Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the 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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. 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 Botulism Botulism is a rare, neuroparalytic syndrome caused by Clostridium botulinum (C. botulinum). A fatal neurotoxin (botulinum toxin) is released causing varying degrees of muscle paralysis and distinct clinical syndromes. The most common types of botulism are foodborne and infant. Botulism: foodborne disease caused by the organism Clostridium botulinum. Clinical presentation includes ptosis, abdominal cramps, symmetric neurological deficits, diplopia, and blurred vision. Botulism Botulism Botulism is a rare, neuroparalytic syndrome caused by Clostridium botulinum (C. botulinum). A fatal neurotoxin (botulinum toxin) is released causing varying degrees of muscle paralysis and distinct clinical syndromes. The most common types of botulism are foodborne and infant. 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 Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, fatigue, and breathlessness. Myasthenia gravis is diagnosed by edrophonium test, conduction studies, and specific antibody detection. Medical management includes acetylcholinesterase inhibitors and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. 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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