What is the etiology of paraneoplastic (related to cancer) muscle weakness?

From the Guidelines

Paraneoplastic muscle weakness is primarily caused by antibody-mediated autoimmunity, where the body produces antibodies against tumor antigens that cross-react with similar proteins in muscle tissue, particularly at neuromuscular junctions, as seen in Lambert-Eaton myasthenic syndrome and myasthenia gravis 1. The etiology of paraneoplastic muscle weakness can be broken down into several key points:

• Antibody-mediated autoimmunity is a primary mechanism, where antibodies against tumor antigens cross-react with proteins in muscle tissue, leading to conditions such as Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis 1.
• LEMS is characterized by the presence of antibodies against voltage-gated calcium channels (VGCCs), which block ion channel function and decrease calcium influx into the presynaptic nerve terminal, resulting in decreased synaptic transmission at the neuromuscular junction 1.
• The prevalence of LEMS in small cell lung cancer (SCLC) is 1% to 1.6%, and diagnosis is generally made by clinical characteristics, electromyography, and anti-VGCC antibodies 1.
• Other paraneoplastic syndromes, such as paraneoplastic neuromyotonia (Isaacs syndrome), are associated with antibodies against voltage-gated potassium channels, leading to increased release of acetylcholine and prolonged muscle fiber action potential 1.
• Treatment of paraneoplastic muscle weakness focuses on addressing the underlying malignancy, as well as managing the autoimmune component with immunosuppressive therapies like corticosteroids, intravenous immunoglobulin, or plasma exchange 1.
• Prompt recognition and treatment of paraneoplastic syndromes is crucial to prevent delayed diagnosis and treatment of the underlying cancer, and to minimize complications that may limit or delay cancer treatment 1.

From the Research

Etiology of Paraneoplastic Muscle Weakness

The etiology of paraneoplastic muscle weakness is complex and multifactorial. Some key points to consider include:

• Paraneoplastic syndromes are rare, but well-defined neuromuscular paraneoplastic syndromes have been described, with small-cell lung cancer being the most common malignancy associated with these syndromes 2
• Cancer-associated muscle weakness can result from loss of muscle mass (i.e., muscle atrophy, cachexia) and occur independently of muscle atrophy or cachexia, with multiple cancer-specific triggers that can initiate the progression of muscle weakness 3
• The mechanisms underlying cancer-associated muscle weakness involve a complex interplay of inflammation, autophagy, disrupted protein synthesis/degradation, and mitochondrial dysfunction 3
• Paraneoplastic necrotizing myopathy is a rare entity characterized by rapidly progressive, symmetrical, predominantly proximal muscle weakness with severe disability, and is associated with a marked increase in serum muscle enzyme levels 4
• The diagnosis of paraneoplastic neuromuscular disorders requires prompt detection and treatment of the underlying tumor, as this has been shown to offer the best chance for neurologic stabilization or improvement 5

Key Factors Contributing to Paraneoplastic Muscle Weakness

Some key factors contributing to paraneoplastic muscle weakness include:

• Impaired intrinsic capacity (i.e., contractile dysfunction and intramuscular impairments in excitation-contraction coupling or crossbridge cycling) 3
• Neuromuscular disconnection 3
• Muscle atrophy 3
• Inflammation 3
• Autophagy 3
• Disrupted protein synthesis/degradation 3
• Mitochondrial dysfunction 3

Associated Cancers and Syndromes

Paraneoplastic muscle weakness has been associated with various cancers and syndromes, including:

• Small-cell lung cancer 6, 2
• Adenocarcinoma of the lung 4
• Lambert-Eaton myasthenic syndrome 2
• Motor neuron disorders 2
• Peripheral neuropathies 2
• Stiffman syndrome 2
• Paraneoplastic necrotizing myopathy 4