Description

• 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.

Epidemiology

• 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).

Incidence
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).

Genetics

• 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

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