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  • Updated 06.03.2022
  • Released 12.28.2007
  • Expires For CME 06.03.2025

Erythromelalgia

Introduction

Overview

The authors have summarized erythromelalgia in this article. Discoveries of sodium channel mutations help our understanding of a variety of pain syndromes, including erythromelalgia. The authors further elaborate on its differential diagnosis, pathophysiology, and the current management options. Importantly, the role of aspirin in the diagnosis and management of secondary erythromelalgia has been emphasized.

Key points

• Erythromelalgia is characterized by episodic vasodilation associated with severe burning pain in the extremities.

• Primary erythromelalgia can be either familial or sporadic.

• Gain-of-function mutations of gene SCN9A (which encodes the Nav1.7 sodium channel) are present in many patients with primary erythromelalgia.

• Secondary erythromelalgia often presents as a symptom of underlying disease. It is often associated with myeloproliferative diseases; in these cases, it can be remarkably responsive to treatment with aspirin.

• Although many medications have been used for the treatment of erythromelalgia, the cornerstone of treatment is genetic counseling and avoidance of triggers.

Historical note and terminology

Erythromelalgia, or “Mitchell disease,” was first described by Dr. Silas Wier Mitchell in 1878 (61). Erythromelalgia, which literally means red, painful extremities, describes an exceedingly rare, chronic condition that is characterized by the clinical triad of pronounced erythema, painful burning, and elevated skin temperature usually around the extremities (12; 83; 84). Clinically, erythromelalgia presents as intense redness (erythros) and severe pain (algia) in the extremities (melos). Erythermalgia, the alternative name of the condition, describes the elevated temperature (thermos) that is often noticed in the affected areas.

Although first described in 1878, the first major study reporting the incidence of erythromelalgia was conducted in 1932 at the Mayo Clinic. The study estimated the incidence of the disease to be in the range of one case per 40,000 patients (04). In the mid-1980s, an epidemic outbreak of erythromelalgia occurred among rural inhabitants in China, prompting medical professionals to investigate the characteristic distribution of the disorder (90). A comprehensive study undertaken in Norway in 1997 estimated the incidence of erythromelalgia to be 0.25/100,000 and prevalence 2/100,000, further strengthening the notion that the original Mayo Clinic study may have overreported the overall incidence of the disease (46; 43).

The genetic and molecular basis underlying primary erythromelalgia was not uncovered until the early 2000s; the inherited erythromelalgia susceptibility gene was first localized to the long arm of chromosome 2 based on a genomic analysis of one large kindred from the United States (20). Three years later, in 2004, linkage analysis identified mutations in the SCN9A gene, encoding the voltage-gated sodium channel NaV1.7, in a family with primary erythromelalgia. Studies in experimental animals have shown that the Nav1.7 sodium channel, which is preferentially expressed with dorsal root ganglion neurons and sympathetic ganglion neurons (77; 69), plays a major role in inflammatory pain (03; 64), but until the demonstration of mutations of Nav1.7 in patients with erythromelalgia, there was no definitive evidence for a role of this channel in pain in humans. Erythromelalgia is the first known human pain syndrome to be examined at a molecular level. Interestingly, primary erythromelalgia is also the first known human disease that involves the Nav1.7 sodium channel.

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