Erythromelalgia

Philip R Effraim MD PhD (Dr. Effraim of Yale University has no relevant financial relationships to disclose.)
Stephen G Waxman MD PhD (Dr. Waxman of Yale University has no relevant financial relationships to disclose.)
James G Greene MD PhD, editor. (Dr. Greene of Emory University School of Medicine has no relevant financial relationships to disclose.)
Originally released December 28, 2007; last updated April 26, 2017; expires April 26, 2020

This article includes discussion of erythromelalgia, erythermalgia, and Mitchell disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

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 juvenile (onset before age 20) 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 most 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. Wier Mitchell in 1878 (Mitchell 1878). 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 (Davis 2004; Waxman and Dib-Hajj 2005a; Waxman and Dib-Hajj 2005b). 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 1 case per 40,000 patients (Brown 1932). 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 (Zheng et al 1988). 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 (Kvernebo and Seem 1987; Kalgaard et al 1997).

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 (Toledo-Aral et al 1997; Rush et al 2006), plays a major role in inflammatory pain (Black et al 2004; Nassar et al 2004), 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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