What is Lambert-Eaton Syndrome (LES)?

From the Guidelines

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder that affects the neuromuscular junction, causing muscle weakness primarily in the proximal muscles of the limbs, and is associated with small cell lung cancer in about 60% of cases, as noted in studies such as 1.

Definition and Pathophysiology

LEMS occurs when antibodies attack voltage-gated calcium channels at nerve terminals, reducing acetylcholine release and impairing muscle contraction, as described in 1. This leads to symptoms such as progressive weakness in the legs and hips, dry mouth, erectile dysfunction, and autonomic dysfunction. Unlike myasthenia gravis, LEMS patients often show temporary strength improvement with repeated muscle use.

Diagnosis and Treatment

Diagnosis involves electromyography showing characteristic incremental response to repetitive nerve stimulation, blood tests for voltage-gated calcium channel antibodies, and screening for underlying malignancies, as outlined in 1. Treatment focuses on addressing any underlying cancer and managing symptoms with medications like 3,4-diaminopyridine (Firdapse), which blocks potassium channels and prolongs nerve action potentials, as well as immunosuppressants and physical therapy to maintain muscle strength and function.

Prognosis and Associated Conditions

Prognosis varies depending on whether LEMS is associated with cancer, with cancer-related cases generally having poorer outcomes tied to the underlying malignancy, as discussed in 1. LEMS is also associated with other paraneoplastic syndromes, including encephalomyelitis and sensory neuropathy, and can be a presenting feature of small cell lung cancer, highlighting the importance of early diagnosis and treatment, as noted in 1.

Key points to consider in the management of LEMS include:

• Early recognition and diagnosis of the condition
• Screening for underlying malignancies, particularly small cell lung cancer
• Treatment with medications such as 3,4-diaminopyridine and immunosuppressants
• Physical therapy to maintain muscle strength and function
• Regular monitoring and follow-up to adjust treatment as needed and manage any associated conditions.

From the FDA Drug Label

The efficacy of FIRDAPSE for the treatment of LEMS was demonstrated in two randomized, double-blind, placebo-controlled discontinuation studies. A total of 64 adults (age 21 to 88 years) with LEMS were enrolled (Study 1 and Study 2) The studies enrolled patients with a confirmed diagnosis of LEMS based on either neurophysiology studies or a positive anti-P/Q type voltage-gated calcium channel antibody test.

Lambert-Eaton Syndrome (LES), also known as Lambert-Eaton Myasthenic Syndrome (LEMS), is a rare autoimmune disorder characterized by muscle weakness. The exact definition of LES is not directly provided in the drug label, but it is mentioned that patients with a confirmed diagnosis of LEMS were enrolled in the studies based on either neurophysiology studies or a positive anti-P/Q type voltage-gated calcium channel antibody test. The drug label does provide information on the diagnosis of LEMS, including:

• Neurophysiology studies
• Positive anti-P/Q type voltage-gated calcium channel antibody test It also provides information on the types of LEMS, including:
• Autoimmune LEMS: 84% of patients had a diagnosis of autoimmune LEMS
• Paraneoplastic LEMS: 16% of patients had a diagnosis of paraneoplastic LEMS 2

From the Research

Definition and Characteristics of Lambert-Eaton Syndrome (LES)

• Lambert-Eaton Syndrome (LES) is a rare pre-synaptic auto-immune disorder of neuromuscular transmission characterized by proximal muscle weakness, depressed tendon reflexes, and autonomic dysfunction 3.
• It is an immune-mediated disorder that can be associated with small-cell lung cancer in 50-60% of cases, whereas the remaining cases are found in younger adults with a higher likelihood of coexisting autoimmune disease 4.
• LES is clinically characterized by proximal muscle weakness, autonomic dysfunction, and areflexia, with approximately 90% of patients presenting antibodies against presynaptic membrane P/Q-type voltage-gated calcium channels (VGCC) 5.

Forms of LES

• There are two forms of LES: the paraneoplastic (P-LEMS) form, which is associated with a malignant tumor, most frequently a small cell lung carcinoma (SCLC), and the autoimmune (A-LEMS) form, which is often related to other dysimmune diseases 5, 6.
• The paraneoplastic form is associated with cancer, while the autoimmune form is associated with underlying autoimmune disease 6.

Diagnosis and Treatment

• Diagnosis of LES requires a high level of awareness and necessitates the initiation of a prompt screening and surveillance process to detect and treat malignant tumors 5.
• The detection of P/Q-type VGCC antibodies is supportive when there is clinical suspicion, but should be carefully interpreted in the absence of characteristic clinical or electrodiagnostic features 5.
• Symptomatic treatment of LES typically involves medications that improve neurotransmission, such as the potassium channel blocker 3,4-diaminopyridine, with addition of immunosuppressants/modulators in individuals with persistent symptoms 3, 7, 6.
• Where a tumor is identified, oncological treatment should take priority, but LES has a significant impact on a patient's quality of life and ability to perform daily activities, and therefore warrants timely diagnosis and appropriate treatment in and of itself 6.