Lambert–Eaton myasthenic syndrome

Overview

Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder that affects the communication between nerves and muscles, resulting in muscle weakness. It is caused by the disruption of voltage-gated calcium channels at the neuromuscular junction, which leads to impaired release of acetylcholine, a neurotransmitter necessary for muscle contraction. LEMS is often associated with an underlying malignancy, particularly small cell lung cancer (SCLC), but it can also occur independently (non-paraneoplastic). It primarily affects adults and typically begins with weakness in the limbs and autonomic dysfunction.

Causes

LEMS is caused by autoantibodies that target presynaptic voltage-gated P/Q-type calcium channels at the neuromuscular junction. This disrupts calcium influx and impairs the release of acetylcholine, which is needed to stimulate muscle fibers. The two main types of LEMS include:

• Paraneoplastic LEMS – Occurs as a paraneoplastic syndrome, most commonly associated with small cell lung cancer (SCLC).

• Idiopathic LEMS – Not associated with any cancer; arises from a primary autoimmune process.

Risk factors include smoking (which increases the risk of SCLC) and existing autoimmune diseases in idiopathic cases.

Symptoms

The symptoms of Lambert–Eaton myasthenic syndrome typically develop gradually and may vary in severity. Common clinical features include:

• Muscle weakness – Especially in the proximal muscles of the legs and arms, causing difficulty climbing stairs or rising from a chair.

• Autonomic dysfunction – Dry mouth, constipation, blurred vision, erectile dysfunction, and decreased sweating.

• Fatigue – Exacerbated by activity and improves temporarily with rest.

• Hyporeflexia or areflexia – Diminished or absent deep tendon reflexes, which may temporarily improve after exercise.

• Oculobulbar involvement – Less common than in myasthenia gravis, but may include drooping eyelids (ptosis) and difficulty speaking or swallowing.

Diagnosis

Diagnosing LEMS requires a combination of clinical evaluation, electrophysiological testing, and laboratory analysis. Common diagnostic steps include:

• Clinical examination – Reveals proximal muscle weakness, autonomic symptoms, and absent reflexes.

• Electromyography (EMG) – Shows a characteristic increase in compound muscle action potential (CMAP) amplitude after exercise or high-frequency stimulation.

• Antibody testing – Detection of anti-P/Q-type voltage-gated calcium channel antibodies supports the diagnosis.

• Cancer screening – Especially chest CT or PET scan to evaluate for underlying small cell lung cancer.

Treatment

The treatment of LEMS depends on whether the syndrome is paraneoplastic or idiopathic. Management strategies include:

• Treating the underlying cancer – In paraneoplastic LEMS, treating small cell lung cancer often improves neurological symptoms.

• 3,4-Diaminopyridine (3,4-DAP) – Enhances acetylcholine release by blocking potassium channels and prolonging depolarization.

• Pyridostigmine – A cholinesterase inhibitor that increases acetylcholine levels at the neuromuscular junction.

• Immunosuppressive therapy – Includes corticosteroids, azathioprine, or IV immunoglobulin (IVIG) in severe or refractory cases.

• Plasmapheresis – May provide temporary relief by removing circulating autoantibodies.

Prognosis

The prognosis of Lambert–Eaton myasthenic syndrome varies based on its cause and response to treatment. In idiopathic cases, patients may experience significant improvement or remission with immunotherapy and symptomatic management. In paraneoplastic LEMS, the neurological outcome depends largely on the control of the underlying cancer. Early detection and treatment of the malignancy can improve both survival and muscle strength. Long-term monitoring is necessary due to the risk of cancer development even after initial diagnosis of LEMS.