What causes erythromelalgia?

Causes of Erythromelalgia

Erythromelalgia is primarily caused by genetic mutations in the SCN9A gene that encodes the Nav1.7 sodium channel in primary forms, while secondary forms are associated with underlying conditions such as myeloproliferative disorders, autoimmune diseases, and certain medications. 1

Primary Erythromelalgia

• Genetic mutations: Approximately 5% of patients have a family history of erythromelalgia with autosomal dominant inheritance pattern. Most cases involve mutations in the SCN9A gene that encodes neuronal Nav1.7 sodium channels 1
• Gain-of-function variants: These mutations cause Nav1.7 sodium channels to open more easily and stay open longer, resulting in multiple and prolonged neuronal activation in sensory neurons, explaining the disproportionate pain experienced during episodes 1
• Non-SCN9A variants: Some familial cases have been documented in which SCN9A variants were not detected, suggesting other genes may also be linked with this disorder 1
• Small fiber neuropathy: Evidence of small fiber neuropathy is strongly associated with erythromelalgia, with marked abnormalities on thermoregulatory sweat testing present in approximately 90% of patients 1

Secondary Erythromelalgia

• Myeloproliferative disorders: Present in approximately 5% of erythromelalgia cases, particularly essential thrombocythemia and polycythemia vera 1

  • The syndrome is often associated with thrombocythemia, with an estimated incidence of approximately 3% in polycythemia vera 1
  • The pathogenesis involves platelet-mediated endothelial cell injury resulting in inflammation and transient thrombotic occlusion by platelet aggregates 1

• Autoimmune conditions: Secondary erythromelalgia can be associated with various autoimmune diseases including systemic lupus erythematosus 1, 2

• Medication-induced: Several medications can trigger erythromelalgia, including:

  • Calcium channel blockers 1, 2
  • Bromocriptine 2
  • Ergot derivatives 1

• Other associated conditions:

  • Diabetes mellitus 1, 3
  • Peripheral neuropathy 3
  • Viral infections 2

Pathophysiological Mechanisms

• Platelet-mediated mechanisms: In myeloproliferative disorders, thromboxane-mediated platelet activation plays a pathogenetic role, consistent with the efficacy of low-dose aspirin treatment 1

• Neurogenic mechanisms: Primary erythromelalgia may involve sensitized skin polymodal C-fiber receptors with lowered threshold to heat activation (32-36°C), causing vasodilation via axon reflexes with resultant redness, heat, and swelling 3

• Large and small fiber neuropathy: Large fiber neuropathy is found on electromyography and nerve conduction studies in almost 50% of patients with erythromelalgia 1

• Bidirectional relationship with neuropathy: Whether neuropathy leads to erythromelalgia or vice versa remains unclear. Small fiber neuropathies could precipitate erythromelalgia, or conversely, underlying disease (including hyperexcitable Nav1.7) and cold water treatment may lead to small fiber neuropathy 1

Clinical Pearls and Pitfalls

• Early recognition is crucial: Symptoms of erythromelalgia may precede the diagnosis of myeloproliferative disorders by a median of 2½ years, making regular monitoring with periodic blood counts essential for all patients with erythromelalgia 4

• Diagnostic challenges: There are no specific diagnostic tests for erythromelalgia. Diagnosis is based on history, physical examination during symptomatic episodes, and exclusion of other probable causes 5

• Treatment response as diagnostic clue: Prompt and lasting relief of burning pain by low-dose aspirin is considered a prerequisite for diagnosing thrombocythemic erythromelalgia 6

• Avoid excessive cooling: Patients often try to cool their extremities with ice or cold water, which may increase risk for tissue damage and ulcerations. Water and ice immersion should be limited (e.g., 10 minutes, 4 times daily) to prevent complications like immersion foot or trench foot 1