What is Lambert-Eaton syndrome?

Lambert-Eaton Myasthenic Syndrome (LEMS)

Lambert-Eaton myasthenic syndrome is an autoimmune disorder characterized by antibodies targeting voltage-gated calcium channels at the presynaptic nerve terminal, causing reduced acetylcholine release and resulting in distinctive proximal muscle weakness, autonomic dysfunction, and areflexia. 1, 2

Pathophysiology

Lambert-Eaton myasthenic syndrome (LEMS) is caused by autoantibodies directed against P/Q-type voltage-gated calcium channels (VGCCs) located at the presynaptic nerve terminal. These antibodies:

• Are present in approximately 90% of LEMS patients 2
• Directly block ion channel function
• Decrease calcium influx into the presynaptic nerve terminal
• Prevent release of acetylcholine secretory vesicles
• Result in decreased synaptic transmission at the neuromuscular junction 1

Clinical Presentation

The classic triad of LEMS symptoms includes:

1. Proximal muscle weakness:

   • Craniocaudally progressive
   • Predominantly affects hip girdle 1
   • Often accompanied by general fatigue

2. Autonomic dysfunction:

   • Dry mouth
   • Impotence
   • Orthostatic hypotension
   • Cardiac arrhythmia 1

3. Areflexia (reduced or absent reflexes) 2

Etiology and Classification

LEMS occurs in two forms:

1. Paraneoplastic LEMS (P-LEMS):

   • Associated with malignancy in 40-60% of cases
   • Small cell lung carcinoma (SCLC) is the most common associated cancer 2, 3
   • Neurological symptoms typically precede cancer diagnosis 3

2. Autoimmune LEMS (A-LEMS):

   • Not associated with cancer
   • Often related to other autoimmune diseases 2

Diagnosis

Diagnosis of LEMS follows a three-pronged approach:

1. Clinical features:

   • Proximal muscle weakness
   • Autonomic dysfunction
   • Areflexia

2. Electrophysiological testing:

   • Reduced compound motor action potentials (CMAPs)
   • Significant decrements in responses to low-frequency stimulation
   • Incremental responses after brief exercise or high-frequency stimulation 2

3. Serological testing:

   • Anti-VGCC antibodies (P/Q type)
   • Present in approximately 90% of LEMS patients 2

Treatment

Treatment of LEMS involves:

1. Symptomatic treatment:

   • 3,4-diaminopyridine (amifampridine/FIRDAPSE) - FDA-approved for LEMS in adults and children 6 years and older 4
   • Acts as a potassium channel blocker to improve neuromuscular transmission 4, 5

2. Immunomodulatory therapy:

   • Intravenous immunoglobulin (IVIg)
   • Plasma exchange
   • Immunosuppressants (prednisone, azathioprine) for persistent symptoms 5, 6

3. Cancer treatment (if P-LEMS):

   • Oncological treatment should take priority when cancer is identified
   • Treating the underlying malignancy often improves LEMS symptoms 5

Prognosis

• P-LEMS: Prognosis primarily determined by the underlying cancer; death typically results from tumor progression
• A-LEMS: Generally does not reduce life expectancy 5

Clinical Pearls and Pitfalls

1. Early diagnosis is critical:

   • LEMS can be an early indicator of cancer, particularly SCLC
   • Prompt diagnosis should trigger immediate oncological screening 2, 5

2. Differential diagnosis:

   • LEMS can be misdiagnosed as myasthenia gravis due to overlapping symptoms
   • Key differences include distribution of weakness (proximal in LEMS) and presence of autonomic symptoms 5

3. Medication considerations:

   • Monitor for seizures with 3,4-diaminopyridine treatment
   • Avoid medications that may worsen neuromuscular transmission 4

4. Cancer surveillance:

   • All newly diagnosed LEMS patients require thorough cancer screening
   • Continued surveillance is necessary, particularly in the first few years after diagnosis 3

Lambert-Eaton myasthenic syndrome significantly impacts quality of life and requires prompt diagnosis and appropriate treatment to improve outcomes, particularly when associated with underlying malignancy.