• Also known as “erythermalgia” and “Mitchell disease,” erythromelalgia (EM) is a clinical syndrome best described as chronic in nature that entails the hallmark symptoms of pain, erythema, and increased temperature of the extremities.
  • Symptoms affect the feet more commonly than the hands and have also been reported to affect the face and ears in rare occurrences.
  • Thought to be either a microvascular syndrome, a neurologic syndrome, or both
  • There are two major subtypes of the syndrome: primary and secondary.
  • Primary EM can further be divided into hereditary and idiopathic subsets. Secondary EM is associated with myeloproliferative disorders, essential thrombocythemia and polycythemia vera, certain medications, rheumatologic diseases, neuropathies, and infections.


  • Primary hereditary EM is most common in patients <30 years of age (median age is 10 years) with a male-to-female ratio of 1:2.5 (1).
  • Secondary EM most commonly occurs in the 5th and 6th decades (median age of 61) and a 3:1 ratio of females to males (2).

Estimates range from 0.4 to 15.0/100,000.

Etiology and Pathophysiology

  • Primary EM has two subcategories: idiopathic and inherited.
  • Secondary EM is acquired and associated with systemic diseases or other external causes.
  • Two major etiologic theories, vascular and neurologic, which may not be mutually exclusive:
    • Microvascular shunting: Increased thermoregulatory perfusion with inadequate capillary perfusion in the affected skin causes tissue hypoxia, leading to reactive arteriole dilation and hyperemia (3).
    • Neurologic: Primary hereditary EM has a component of small fiber involving cutaneous sympathetic and sensory fibers (1). A defect in NaV1.7 sodium channels causes nerve hyperexcitability and pain. This hyperexcitability may also cause a secondary vascular maldistribution and induce hypoxia (3).


  • Most patients with EM have either the idiopathic form or the secondary form, neither of which have a known genetic component.
  • The inherited form of primary EM is rare and has the following characteristics:
    • A mutation of a voltage-gated sodium channel α-subunit NaV1.7 expressed on nociceptive dorsal root ganglion and sympathetic ganglion neurons
    • Autosomal dominant, linked to chromosomal arm 2q
    • Results in a lowered threshold for action potentials and high-frequency firing in dorsal root ganglia (4)
    • Often symptomatic in childhood (1)

Risk Factors

  • Family history of EM
  • Smoking history
  • History of myeloproliferative disease
  • History of systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus
EM may precede myeloproliferative diseases.

General Prevention

Primary EM cannot be prevented. If due to a known condition, secondary EM improves and recurrences prevented with adequate disease management.

Commonly Associated Conditions

  • Myeloproliferative diseases (polycythemia vera and essential thrombocythemia)
  • Connective tissue disorders (lupus)
  • Insulin-dependent diabetes mellitus
  • Neuropathies and spinal cord diseases
  • Rheumatologic diseases (rheumatoid arthritis)
  • Tobacco abuse
  • Possible link with colon cancer, thyroid cancers and astrocytomas, pernicious anemia, TTP, vasculitis (5,6)
  • Possible link with pregnancy
  • Mercury poisoning
  • Infectious associations include mononucleosis and poxvirus.
  • Calcium channel blockers (verapamil, nicardipine)
  • Dopamine receptor agonists (bromocriptine, pergolide)
  • Topical isopropanol

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