eMedicine Specialties > Hematology > Stem Cells and Disorders

Erythromelalgia

Author: Robert J Nardino, MD, Director, Internal Medicine Residency Program, Assistant Clinical Professor, Department of Internal Medicine, Hospital of Saint Raphael, Yale University School of Medicine
Coauthor(s): Andrea LM Silber, MD, Associate Clinical Professor of Medicine, Section of Hematology-Oncology, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Aug 13, 2009

Introduction

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 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

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 distinguished primary erythromelalgia (erythermalgia) from secondary erythromelalgia.^1,2 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.¹¹ Novel mutations of voltage-gated sodium channels that are selectively expressed in peripheral nerves have been discovered.

Han et al investigated whether a genotype-phenotype association exists in early- and late-onset inherited erythromelalgia by conducting a voltage-clamp and current-clamp analysis of a new sodium channel Na(v)1.7 mutation, Q10R, in a patient presented with erythromelalgia in the second decade.²⁸ The investigators found a smaller shift in the patient's mutation hyperpolarization activation relative that seen in early-onset disease mutations but similar to another mutation associated with late-onset inherited erythromelalgia. 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.²⁸

Han et al suggested their findings indicate a genotype-phenotype relationship 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.²⁸

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 individuals.³

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.

Clinical

History

The classic description is that of red, painful, warm extremities brought on by warming or dependency and relieved by cooling (see Image 1).

• Character: Episodes may last minutes to days.
• Severity: Episodes often begin with an itching sensation, progressing to a more severe pain with a burning quality. Pain may be so intense that the patient cannot walk; some must even keep their feet immersed in ice water.
• Location: The lower extremities are affected more often than the upper extremities. The soles of feet and toes are most commonly involved. Involvement as high as the knees is observed but rare. Involvement is usually bilateral though not necessarily symmetric.
• Exacerbating factors: Warming the extremity or placing and maintaining the extremity in a dependent position can exacerbate symptoms.
• Relieving factors: Cooling and elevating the extremity can relieve symptoms.
• Associated symptoms: Occurrence of Raynaud phenomenon between episodes of erythromelalgia is reported, but this is possibly coincidental.
• In cases associated with a myeloproliferative disorder, erythromelalgia usually precedes diagnosis of the myeloproliferative disorder by a median of 2.5 years. Dramatic relief with aspirin is typical of this type and can be used as an aid to diagnosis.

Physical

• Examination findings may be normal between episodes.
• During an episode, the affected extremity becomes warm, tender, and appears dusky, red, and sometimes mottled.
• Peripheral pulses may be normal or bounding.
• Acrocyanosis may be observed and rarely progresses to necrosis of the distal ends of digits.
• Ischemic ulcers may be observed and may become infected secondarily.

Causes

• Myeloproliferative disorders: Most reported cases of secondary erythromelalgia are due to myeloproliferative disorders with thrombocytosis (most commonly polycythemia vera or essential thrombocythemia).
  • The actual prevalence of erythromelalgia in myeloproliferative disorders is uncertain.
  • Erythromelalgia manifests before the appearance of a myeloproliferative disorder in 85% of cases.
• Idiopathic erythromelalgia: 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.⁴
  • In the Norwegian series, 19% of cases were due to myeloproliferative disorders.³
• Medications: Implicated medications include pergolide (withdrawn from US market March 29, 2007), bromocriptine, calcium channel blockers nifedipine, felodipine, and nicardipine, and topical isopropanol.
• Infection: The Chinese epidemic was determined to be associated with poxvirus infection.
• Other disorders: Other reported associated disorders include systemic lupus erythematosus, HIV infection, diabetes mellitus, venous insufficiency, astrocytoma, rheumatoid arthritis, and gout.
  • Whether the occurrence is coincidental is not clear.
  • In the case of the patient with systemic lupus erythematosus, biopsy results showed vasculitis, and symptoms resolved with immunosuppressive therapy.
• Genetic evidence: Early-onset erythromelalgia can show a familial occurrence; evidence suggests that a mutation on chromosome arm 2q is responsible.
• Mushroom poisoning: Reports in Europe and Japan describe cases due to the ingestion of different species of Clitocybe mushrooms.

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