CASE #2: Erythromelalgia
Erythromelalgia manifests as red inflammation of the limbs (almost always lower) that is accompanied by severe burning and is associated with paroxysmal blood vessel pathology and vasodilation. The ears and face are affected rarely.
The symptoms and signs of erythromelalgia have a broad range and include painful red, mauve, or purple patches and plaques on the toes, fingers, hands, feet, and limbs. These lesions are accompanied by swelling, dysesthesia, burning, and increased temperature. Necrosis and ulceration of fingers and toes may occur with secondary infection and can result in amputation. Paroxysmal attacks unleashed by such triggers as heat, alcohol consumption, or exertion usually underlie erythromelalgia. Exercise can trigger an episode.
The incidence of erythromelalgia in a population-based study in Olmsted County, Minn., was 1.3 per 100,000 people per year,1 an incidence much greater than reported elsewhere at two to three per million persons. Among patients with myeloproliferative diseases, the prevalence of erythromelalgia has been reported at 3%-65%.1 Erythromelalgia is more common in women than men by a 2.5-to-1 ratio.
Also referred to as acromelalgia, Weir Mitchell disease, erythremomalgia, or red neuralgia, erythromelalgia is divided into primary and secondary types. Primary erythromelalgia is a genetic disease that can be inherited or occur sporadically. Inheritance is in an autosomal dominant manner. Primary erythromelalgia can be further divided into juvenile- and adult-onset variants. Juvenile-onset erythromelalgia usually affects patients prior to age 10 years and almost always before age 20 years.
The juvenile-onset and sporadic adult-onset forms of primary erythromelalgia are caused by genetic mutations that have been defined, but the genetic basis for the adult-onset inherited type has yet to be defined. A mutation in chromosome 2q on the SCN9A gene, which encodes a voltage-gated sodium channel alpha subunit (Nav1.7) expressed in both sensory and sympathetic neurons, has been reported as a basis of the genetically related types of erythromelalgia. The human body expresses the SCN9A-encoded Nav1.7 mostly in nociceptors of the dorsal root ganglion and in the sympathetic ganglion neurons.2 Defective nerve conduction in C fibers (symphathetic peripheral fibers) results specifically in hyperexcitability of C fibers in the dorsal root ganglion. The mechanics of how the defect causes disease require further definition. As of 2007, 10 known mutations in SCN9A had been defined.
The secondary forms of erythromelalgia can be related to hematologic/circulatory or neurologic toxins or metabolic problems. Hematologic problems include myeloproliferative disorder, autoimmune-related hematologic disorders, PV, and essential thrombocytosis. Circulatory problems linked to erythromelalgia include arteriolar fibrosis, hypercholesterolemia, and hypertension. Erythromelalgia can be associated with neurologic (e.g., small-fiber peripheral neuropathy, sciatica syringomyelia) and psychological disturbances.
The disorder has been linked to use of such medications as bromocriptine (Parlodel), pergolide (Permax), verapamil (Calan, Covera, Verelan), and ticlopidine (Ticlid) as well as topical exposure to isopropyl alcohol. Causative poisons include lead and mercury and certain mushrooms (Clitocybe acromelalga and Clitocybe amoenolens). Interestingly, Fabry disease (angiokeratoma corporis diffusum), an X-linked lysosomal storage disease that is caused by deficient activity of the lysosomal enzyme alpha-galactosidase, is associated with acral pain which resembles that of erythromelalgia. Sometimes the reason for secondary erythromelalgia is not known.
Treatment of primary erythromelalgia is difficult and focuses around avoidance of inciting triggers. Secondary erythromelalgia related to thrombocytosis can be ameliorated by aspirin. The painful symptoms associated with erythromelalgia can occasionally be eased by immersion in cold water and use of cold compresses.
In some patients, serotonin antagonists have been effective. One small double-blind study found iloprost (Ventavis), a synthetic prostacyclin analog, was beneficial, and another study reported that misoprostol (Cytotec) 0.4-0.8 mg daily led to disease abatement.3 Another study found lidocaine or oral mexiletine (Mexitil) useful. Antihistamines, tricyclic antidepressants, gabapentin (Neurontin), venlafaxine (Effexor), and oral magnesium have been anecdotally reported to be beneficial.3 Surgically, lumbar ganglionectomy and peripheral nerve block have been reported useful.3 In patients with increased platelet counts related to myeloproliferative disorders and PV, phlebotomy and chemotherapy to reduce the platelet count have provided some benefit.
This patient was given gabapentin 400 mg orally three times a day and aspirin 325 mg daily. He was also advised to use ice packs. This seemed to alleviate his symptoms before he was lost to follow-up.
Dr. Scheinfeld is assistant clinical professor of dermatology at Columbia University in New York City, where he has a private practice.
1. Reed KB, Davis MD. Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota. J Eur Acad Dermatol Venereol. 2009;23:13-15.
2. Nassar MA, Stirling LC, Forlani G, et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci USA. 2004;101:12706-12711 (accessed June 12, 2009).
3. Mork C, Kvernedo K. Erythromelalgia. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease. 2nd ed. London, England: Mosby; 2006.