Erythromelalgia 

Erythromelalgia is a rare disorder that is characterized by burning pain and warmth and redness of the extremities. There is some confusion in the literature regarding nomenclature and classification; however, in general, a distinction is made between primary (idiopathic) and secondary erythromelalgia (most commonly associated with myeloproliferative disorders), as well as between early- and late-onset disease.

The name is derived from 3 Greek words: erythros (“red”), melos (“limb”), and algos (“pain”). Mitchell first described erythromelalgia in the 1870s, and Smith and Allen further categorized it in 1938, proposing the term erythermalgia to emphasize the characteristic warmth. They also proposed a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia (due to underlying neurologic, hematologic, or vascular problems).

Drenth and Michiels made a distinction between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin.^{[1, 2]} They established 3 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.^[3] 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^[4]
• 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.^[7] Drenth et al examined 5 kindreds with familial erythermalgia and found a linkage to chromosomal arm 2q.^[8] Novel mutations of voltage-gated sodium channels that are selectively expressed in peripheral nerves have been discovered.^{[9, 10, 11]}

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.^[12]

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.^[12] 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.^[12]

Causes of erythromelalgia include the following:

• Myeloproliferative disorders
• Idiopathic origin
• Medications
• Infection
• Other associated disorders
• Genetic mutation
• Mushroom poisoning

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.

Adult-onset erythromelalgia is idiopathic in the majority of cases. Most early-onset cases are idiopathic. In the Mayo Clinic series, 3.6% of cases were familial, and only 9% were associated with myeloproliferative disorders.^[13] In the Norwegian series, 19% of cases were due to myeloproliferative disorders.^[14]

Medications implicated in erythromelalgia include pergolide, which was withdrawn from the US market on March 29, 2007; bromocriptine^[15] ; the calcium channel blockers nifedipine, felodipine, and nicardipine; and topical isopropanol.

The Chinese epidemic of erythromelalgia (see Epidemiology) was determined to be associated with poxvirus infection.^[16]

Other disorders reported to be associated with erythromelalgia include systemic lupus erythematosus (SLE), HIV infection, diabetes mellitus, venous insufficiency, astrocytoma, rheumatoid arthritis, and gout. Whether the associations are coincidental is not clear. In the case of the patient with SLE, biopsy results showed vasculitis, and symptoms resolved with immunosuppressive therapy.

Early-onset erythromelalgia can show a familial occurrence; evidence suggests that a mutation on chromosome arm 2q is responsible.

Reports in Europe and Japan describe cases due to the ingestion of different species of Clitocybe mushrooms.

United States statistics

Brown reported an incidence of 1 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%.

International statistics

A case series from Norway appears to reveal data similar to that from the Mayo Clinic series.^[14] In China, an epidemic of erythromelalgia occurred in the late 1980s, affecting hundreds to thousands of individuals.^[16]

Age-related demographics

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.

In the Norwegian case series, patients were classified as having primary or secondary erythromelalgia.^[14] 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.

Sex-related demographics

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).^[14] The Mayo Clinic series of 168 patients showed a male-to-female ratio of 1:3.^[13]

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.^[13]

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 1 patient had near-fatal hypothermia related to constant cooling required to control symptoms.