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