Excerpt from Erythromelalgia

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Background

Erythromelalgia is a rare disorder characterized by burning pain and warmth and redness of the extremities. Confusion exists in the literature concerning 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 (extremities), 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 (1994) and Michiels (1995) make a distinction between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin. 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.

Pathophysiology

First insight into the pathophysiology of erythromelalgia associated with thrombocythemia was 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.

In cases not associated with thrombocythemia, the pathophysiology has been less clear, but it does not involve platelet-mediated inflammation and thrombosis. This is the major reason that Drenth and Michiels distinguish primary erythromelalgia (erythermalgia) from secondary erythromelalgia. Several factors postulated to contribute to primary erythromelalgia are postganglionic sympathetic dysfunction; hypersensitivity of C-fibers; and maldistribution of skin perfusion resulting from arteriovenous shunting, which leads to an imbalance between thermoregulatory and nutritive perfusion.

Molecular biology may provide the key to understanding this disorder. Drenth and colleagues 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 were recently discovered.

Frequency

United States

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 (or primary erythermalgia by 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

A case series from Norway (1997) appears to reveal data similar to that from the Mayo Clinic series. In China, an epidemic of erythromelalgia occurred in the late 1980s, affecting hundreds to thousands of individuals³.

Mortality/Morbidity

• 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.


• 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.⁴

Sex

• The early-onset, or 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).³


• The Mayo Clinic series of 168 patients showed a male-to-female ratio of 1:3.⁴

Age

• In early reports, the median age of onset of the early-onset form was 10 years.


• Adult-onset erythromelalgia has 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. 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.³


• In the Mayo Clinic series, the median age was 60 years, with a range of 5-91 years.

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