- Author: Antoine N Saliba, MD; Chief Editor: Emmanuel C Besa, MD more...
Erythromelalgia is a rare disorder characterized by burning pain, warmth, and redness of the extremities. Despite the controversy regarding nomenclature and classification, a distinction is generally made between primary (idiopathic or genetic) and secondary erythromelalgia (most commonly associated with myeloproliferative disorders), as well as between early- and late-onset disease.
The name of this disorder is derived from three Greek words: erythros (“red”), melos (“limb”), and algos (“pain”). Mitchell first described erythromelalgia in the 1870s. Smith and Allen further categorized it in 1938, proposing the term erythermalgia to emphasize the characteristic warmth. They also suggested a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia (due to underlying neurologic, hematologic, or vascular problems).
Drenth and Michiels distinguished between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin.[1, 2] They established three categories: erythromelalgia (platelet-mediated and aspirin-sensitive), primary erythermalgia, and secondary erythermalgia.[1, 2]
Investigation into the pathophysiology of primary erythromelalgia indicates that this disorder may serve as a model for understanding common chronic pain conditions.
The first insights into the pathophysiology of erythromelalgia associated with thrombocythemia were gained when skin biopsy samples revealed arteriolar fibrosis and occlusion with platelet thrombi. In this setting, platelets may have abnormal hyperaggregability. Platelet kinetic studies show decreased platelet survival, predominantly due to consumption. Prostaglandins and cyclooxygenase apparently play an important pathogenetic role.
For erythromelalgia not associated with thrombocythemia, the pathophysiology is less clear, but it is known not to involve platelet-mediated inflammation and thrombosis. This is the major reason why Drenth and Michiels distinguished primary erythromelalgia (erythermalgia) from secondary erythromelalgia.[1, 2] Factors postulated to contribute to primary erythromelalgia include the following:
Postganglionic sympathetic dysfunction
Hypersensitivity of C-fibers 
Maldistribution of skin perfusion resulting from arteriovenous shunting, which leads to an imbalance between thermoregulatory and nutritive perfusion [5, 6]
Molecular biology may provide the key to understanding this disorder. Drenth et al examined 5 kindreds with familial erythermalgia and found a linkage to chromosomal arm 2q. Novel mutations of voltage-gated sodium channels that are selectively expressed in peripheral nerves have been discovered.[9, 10, 11, 12]
Han et al, in a study investigating whether a genotype-phenotype association exists in early- and late-onset inherited erythromelalgia, found a shift in the patient’s mutation hyperpolarization activation that was smaller than that seen in early-onset disease mutations but similar to another mutation associated with late-onset inherited erythromelalgia.
The test was done by conducting a voltage-clamp and current-clamp analysis of a new sodium channel Na(v)1.7 mutation, Q10R, in a patient who presented with erythromelalgia in the second decade. With current-clamp analysis, Q10r expression induced hyperexcitability in dorsal root ganglion neurons, but the increase in excitability was smaller than that produced by a mutation in early-onset disease.
Han et al suggested that their findings reflected a genotype-phenotype relation at the clinical, cellular, and molecular/ion channel levels in inherited erythromelalgia; mutations that produce smaller effects on sodium channel activation appear to correlate with smaller degrees of dorsal ganglion root neuron excitability and later onset of clinical signs.
Primary erythromelalgia may be idiopathic or genetic in origin. Early-onset erythromelalgia can show a familial occurrence. Adult-onset erythromelalgia is idiopathic in the majority of cases, although an inherited case has been reported. In the Mayo Clinic series, 3.6% of cases were familial.
Hereditary erythromelalgia is an autosomal dominant disorder caused by gain-of-function mutations in SCN9A, which encodes a voltage-gated sodium channel, subtype Nav1.7.[8, 9, 10, 11, 12] More than 20 SCN9A mutations have been reported in patients with primary erythromelalgia.
Causes of secondary erythromelalgia include the following:
Most reported cases of secondary erythromelalgia are due to myeloproliferative disorders with thrombocytosis (most commonly polycythemia vera or essential thrombocytosis). The actual prevalence of erythromelalgia in myeloproliferative disorders is uncertain. Erythromelalgia manifests before the appearance of a myeloproliferative disorder in 85% of cases.
Medications implicated in erythromelalgia include the following:
The calcium channel blockers nifedipine, felodipine, and nicardipine
Pergolide (withdrawn from the US market in 2007)
A Chinese epidemic of erythromelalgia (see Epidemiology) was determined to be associated with poxvirus infection.
Other disorders reported to be associated with erythromelalgia include the following:
Systemic lupus erythematosus (SLE)
Whether the above associations are coincidental is not clear. In one patient with SLE, biopsy results showed vasculitis, and symptoms resolved with immunosuppressive therapy.
Reports in Europe and Japan describe cases due to the ingestion of different species of Clitocybe mushrooms.[20, 21]
United States statistics
Brown reported an incidence of one case per 40,000 patients at the Mayo Clinic in the 1930s. This rate overestimates the incidence in the general population; however, underrecognition of mild cases may cause underestimation of the frequency of these conditions. Early-onset erythromelalgia (primary erythermalgia in the Drenth-Michiels classification) is rare, with fewer than 30 cases reported in the literature. In patients with myeloproliferative disorders, the reported prevalence of erythromelalgia is 3-65%.
A case series from Norway appears to reveal data similar to that from the Mayo Clinic series. In China, more than 70 outbreaks of epidemic erythromelalgia, with over 80,000 cases reported, have occurred since the mid-20th century; most have been reported between February and March and have coincided with a sharp temperature decline followed by a rapid temperature rise within a few days.[22, 18] A retrospective study in Sweden reported an incidence of 0.36 cases per 100,000 population.
In early reports, the median age of onset of the early-onset form was 10 years. Adult-onset erythromelalgia has a wide age distribution, with most cases occurring in the fifth and sixth decades.
After an analysis of 32 pediatric cases treated over a 37-year period at the Mayo Clinic, researchers concluded that the majority of cases are not inherited and that progress of the disease is variable. No safe or reliable treatment has been established, and the erythromelalgia in the pediatric population is associated with substantial morbidity and, sometimes, death.
In the Norwegian case series, patients were classified as having primary or secondary erythromelalgia. The age range in the primary group (which could include patients with early-onset and idiopathic adult-onset disease) was 7-76 years, and the age range in the secondary group was 18-81 years. In the Mayo Clinic series, the median age was 60 years, and the age range was 5-91 years.
The early-onset (primary) form is reported to have a male-to-female ratio of 1:2.5. Secondary erythromelalgia was reported to have a male-to-female ratio of 3:2 in a review of 60 cases of erythromelalgia due to myeloproliferative disorders.
The 1997 case series from Norway showed a female predominance (male-to-female ratio of 1:2), which included a variety of causative factors (only 19% were myeloproliferative disorders). The Mayo Clinic series of 168 patients showed a male-to-female ratio of 1:3.
A retrospective review of 168 patients with erythromelalgia examined at the Mayo Clinic between 1970 and 1994 showed a significant decrease in survival compared with that expected for age- and sex-matched control subjects. However, a recent Swedish study that collected data retrospectively for a period of 10.5 years reported no mortality directly related to erythromelalgia, although three patients developed intra-abdominal malignancies on follow-up.
Patients who respond to aspirin have little morbidity. Spontaneous remissions may occur. Early-onset disease is relatively unresponsive to treatment and generally is unremitting. Complications appear to be more frequent in patients who clearly have platelet-mediated disease.
Ulceration, necrosis, and gangrene of affected extremities are possible. Digital necrosis or skin ulceration with secondary infection can lead to amputation. At least one patient had near-fatal hypothermia related to constant cooling required to control symptoms.
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