Erythromelalgia

What is erythromelalgia?

Erythromelalgia is a “zebra” diagnosis occurring in 1 : 100,000 people that also happens to the first chronic neuropathic pain disorder associated with a discovered ion channel mutation, specifically in the Na v 1.7 channel. A subset of erythromelalgia has this mutation. Erythromelalgia can be familial (hereditary, more likely associated with the Na v 1.7 mutation) or spontaneous. It is primarily a vascular peripheral pain disorder in which peripheral blood vessels (typically in the lower extremities or hands) periodically spasm, causing skin redness and severe burning pain via small sensory fibers. Attacks can be precipitated by heat exertion (even mild), pressure, dependent position, or stress. Differential diagnosis includes polycythemia and SFPN.

Erythromelalgia is a neurovascular peripheral pain disorder in which blood vessels are episodically blocked and then become hyperemic and inflamed. The attacks are episodic and characterized by red, warm, swollen, and painful (burning) extremities. Feet are affected more than hands. Attacks are triggered by exertion, heat, pressure, caffeine, and alcohol. Symptoms are bilateral but not necessarily symmetric. Rarely symptoms may progress to gangrene. Other diseases such as Fabry disease, peripheral neuropathy, complex regional pain syndrome, and vasculitis can mimic erythromelalgia and need to be excluded. Erythromelalgia is categorized as primary or secondary.

  • • Primary erythromelalgia: may be genetic or idiopathic in origin. Early-onset erythromelalgia is usually familial with an autosomal dominant inheritance. It is associated with a gain-of-function mutation of the voltage-gated sodium channel α subunit gene (SCN9A) located on chromosome 2. This mutation causes hyperexcitability of dorsal root ganglion leading to symptoms similar to chronic regional pain syndrome. The severity of the mutation determines if the clinical symptoms start at puberty or later in adulthood. Elevation and cold exposure including emersion of feet in ice water give relief. There is no consistently effective therapy. It does not respond to aspirin therapy. Mexiletine may be helpful. Prostacyclin and gabapentin have also been used. Most of the patients presenting with adult-onset erythromelalgia do not have an identifiable genetic mutation or an associated disease and are considered to have primary idiopathic erythromelalgia.
  • • Secondary erythromelalgia: is similar to primary erythromelalgia clinically, has its onset during adulthood, and is associated with various diseases or medications. Treatment of the underlying disease or withdrawal of the offending medication is helpful. There are two types of secondary erythromelalgia: aspirin-sensitive and aspirin-insensitive.
    • • Aspirin-sensitive erythromelalgia is associated with polycythemia vera, essential thrombocytosis, and other chronic myeloproliferative disorders. In 85% of patients, the cutaneous symptoms precede the myelodysplastic syndrome by months to years (median 2.5 years). Erythromelalgia is diagnosed on the basis of platelet counts exceeding 400,000/mm , relief of symptoms lasting for days with low-dose aspirin, and histopathologic evidence of arterioles with fibromuscular proliferation. The response to aspirin suggests that platelet-derived prostaglandins cause the symptoms.
    • • Aspirin-insensitive erythromelalgia is typically attributable to a medication (calcium channel blockers, bromocriptine) or another disease (small fiber neuropathy, autoimmune disease, mushroom poisoning).

Erythromelalgia is a very specific syndrome of severe burning pain in both feet that is reproducibly precipitated by skin warming, alleviated by cooling, and associated with striking erythema and swelling. All of these features should be present for the diagnosis to be made with confidence, as many patients with painful distal symmetric polyneuropathy will note some changes in the severity of their pain with skin warming or cooling but do not demonstrate the dramatic erythema, warmth, and temperature sensitivity seen in this condition.

Erythromelalgia has been described in the presence of hematologic malignancies and chronic inflammatory states, and therefore a careful investigation for both is important. In these circumstances, exquisite responsiveness to treatment with aspirin or nonsteroidal antiinflammatory medications has been reported. When it does not respond to these simple measures, erythromelalgia is usually treated with medications used for distal symmetric painful sensory polyneuropathy, but can be refractory to treatment.

Erythromelalgia also occurs in a familial form, which has been shown to be due to a mutation in the SCN9A gene encoding for a sodium channel in nociceptors. The causative mutation results in a lowered firing threshold in affected neurons, essentially resulting in a neuropathic pain state with thermal allodynia and hyperalgesia, whereby skin warming into the normally innocuous range is perceived as painful. Familial erythromelalgia is allelic to paroxysmal extreme pain disorder, which presents with episodic facial or rectal pain.

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