eMedicine Specialties > Hematology > Stem Cells and Disorders

Erythromelalgia

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
Andrea LM Silber, MD, Associate Clinical Professor of Medicine, Section of Hematology-Oncology, Yale University School of Medicine

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 (see image below).^{[1,2 ]}

Cardinal symptoms of erythromelalgia.

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 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 below).

Cardinal symptoms of erythromelalgia.

• 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.

Differential Diagnoses

Cellulitis
Frostbite
Reflex Sympathetic Dystrophy

Other Problems to Be Considered

Fabry disease
Peripheral neuropathy
Raynaud phenomenon
Vasculitis

Workup

Laboratory Studies

• On the CBC with differential, look for evidence of a myeloproliferative disorder. In particular, look for a platelet count greater than 600 X 10⁹/L (600 X 10³ mcg/L) but also a hematocrit greater than 0.50 (>50%) or an elevated granulocyte count (with all stages of maturation).
• Other laboratory results are nonspecific.

Imaging Studies

• No specific findings are present on plain radiography of the feet and hands.
• Triple-phase technetium bone scanning is warranted with patients with a history of trauma or stroke and when reflex sympathetic dystrophy is strongly considered (particularly if the symptoms are unilateral).

Other Tests

• Thermography reveals elevated skin temperatures in affected area, but this finding is not necessary to establish diagnosis.
• Striking differences in surface temperature can occur between involved and uninvolved areas.

Histologic Findings

In patients with thrombocythemia, skin biopsy results have shown arteriolar endothelial cell swelling, with sparing of venules, capillaries, and nerves. A thickening of the vessel wall and luminal narrowing due to smooth muscle cell proliferation occur. Thickened arterioles may contain occlusive thrombi and ultimately may become fibrosed. Biopsy specimens in patients with primary erythromelalgia show mild mononuclear perivascular infiltrates with edema, thickened vascular basement membranes, and moderate endothelial swelling; the intimal thickening and thrombi seen in secondary erythromelalgia are lacking.

Treatment

Medical Care

• Evaluation and treatment can be conducted in an outpatient setting.
• Local measures, such as cooling or elevating the extremity, may relieve symptoms.
• In patients with myeloproliferative disorders, chemotherapy to reduce the platelet count often alleviates symptoms, but it is not universally effective.
• Some patients with polycythemia vera have responded to phlebotomy.

Surgical Care

• Surgery probably has no role except to treat the rare complication of gangrene.
• Surgical sympathectomy has been attempted, with variable results.

Consultations

Hematologist, if an associated myeloproliferative disorder is present

Diet

No specific dietary restrictions are necessary.

Activity

Exercise may induce an acute episode.

Medication

Platelet inhibition is helpful in patients with thrombocytosis. Aspirin is most often used, but anagrelide may also be effective.^{[5 ]}

The optimal pharmacologic therapy in primary erythromelalgia is still unknown. Case reports of treatment with propranolol, epinephrine, biofeedback, sodium nitroprusside, gabapentin, and typhoid vaccine appear in the literature, as well as case series with high-dose magnesium, intravenous bupivacaine, the lidocaine patch, and lidocaine plus mexiletine. The present author knows of no randomized trial of therapy for erythromelalgia. In a pilot study of 12 patients, iloprost (a synthetic prostacyclin analog) improved symptoms.

Nonsteroidal anti-inflammatory agents

Aspirin is preferred because it provides relief lasting longer than that of indomethacin or other nonsteroidal anti-inflammatory drugs (NSAIDs), presumably because of irreversible platelet inhibition.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Dosing

Adult

500 mg PO; a single dose often relieves symptoms; maximum recommended dose 4 g/d (650 mg PO q4h)

Pediatric

10-15 mg/kg PO

Interactions

Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; due to association of aspirin with Reye syndrome, do not use in children ( <16 y) with flu

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in severe anemia, in history of blood coagulation defects, and in patients taking anticoagulants

Follow-up

Further Outpatient Care

• Monitor for complications, response to treatment, and development of a myeloproliferative disorder because erythromelalgia often precedes clinical appearance of polycythemia vera or essential thrombocythemia.

Inpatient & Outpatient Medications

• Primary erythromelalgia
  • The best therapy is unknown.
  • Medications that affect voltage-gated sodium channels (lidocaine, mexiletine) show promise.
  • Prostacyclin may be of benefit; some patients achieve relief with gabapentin or high-dose magnesium.
• Erythromelalgia related to thrombocytosis
  • Aspirin is usually the treatment of choice.
  • Other NSAIDs provide relief of short duration.
  • Anagrelide may be an alternative.
  • Other platelet-inhibiting agents, such as ticlopidine or dipyridamole, have no effect.

Deterrence/Prevention

• Avoid excessive warming or dependency of the extremity.
• Avoid vigorous exercise.

Complications

• Ulceration, necrosis, and gangrene of affected extremities are possible.

Prognosis

• 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.

Patient Education

• Elevate the legs when possible.
• Modify the environment so that it is not too hot.

Miscellaneous

Medicolegal Pitfalls

• Failure to make the diagnosis
• Failure to recognize associated myeloproliferative disorder

Special Concerns

• With no diagnostic test, maintaining a high index of suspicion is necessary to make the diagnosis.

Multimedia

Media file 1: Cardinal symptoms of erythromelalgia.

References

1. Drenth JP, van Genderen PJ, Michiels JJ. Thrombocythemic erythromelalgia, primary erythermalgia, and secondary erythermalgia: three distinct clinicopathologic entities. Angiology. Jun 1994;45(6):451-3. [Medline].

2. Michiels JJ, Drenth JP, Van Genderen PJ. Classification and diagnosis of erythromelalgia and erythermalgia. Int J Dermatol. Feb 1995;34(2):97-100. [Medline].

3. Kalgaard OM, Seem E, Kvernebo K. Erythromelalgia: a clinical study of 87 cases. J Intern Med. Sep 1997;242(3):191-7. [Medline].

4. Davis MD, O'Fallon WM, Rogers RS 3rd, Rooke TW. Natural history of erythromelalgia: presentation and outcome in 168 patients. Arch Dermatol. Mar 2000;136(3):330-6. [Medline].

5. Cacciola RR, Cipolla A, Di Francesco E, et al. Treatment of symptomatic patients with essential thrombocythemia: effectiveness of anagrelide. Am J Hematol. Sep 2005;80(1):81-3.

6. Alarcon-Segovia D, Babb RR, Fairbairn JF, Hagedorn AB. Erythermalgia. A clue to the early diagnosis of myeloproliferative disorders. Arch Intern Med. Apr 1966;117(4):511-5. [Medline].

7. Charkoudian N. Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Mayo Clin Proc. May 2003;78(5):603-12. [Medline].

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9. Davis MD, Sandroni P. Lidocaine patch for pain of erythromelalgia: follow-up of 34 patients. Arch Dermatol. Oct 2005;141(10):1320-1.

10. Davis MD, Sandroni P, Rooke TW, Low PA. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol. Oct 2003;139(10):1337-43. [Medline].

11. Drenth JP, te Morsche RH, Guillet G, et al. SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol. Jun 2005;124(6):1333-8.

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14. Kalgaard OM, Mork C, Kvernebo K. Prostacyclin reduces symptoms and sympathetic dysfunction in erythromelalgia in a double-blind randomized pilot study. Acta Derm Venereol. 2003;83(6):442-4. [Medline].

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24. Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. Mar 2004;41(3):171-4. [Medline]. [Full Text].

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Keywords

erythromelalgia, erythermalgia, primary erythromelalgia, secondary erythromelalgia, myeloproliferative disorder, arteriolar fibrosis, idiopathic erythromelalgia, platelet-mediated erythromelalgia, aspirin-sensitive erythromelalgia, primary erythermalgia, secondary erythermalgia, polycythemia vera, essential thrombocytosis, peripheral vascular disease

Contributor Information and Disclosures

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
Robert J Nardino, MD is a member of the following medical societies: American College of Physicians, Association of Program Directors in Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Andrea LM Silber, MD, Associate Clinical Professor of Medicine, Section of Hematology-Oncology, Yale University School of Medicine
Andrea LM Silber, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Society of Preventive Oncology
Disclosure: sanofi Aventis Honoraria Speaking and teaching; novartis Honoraria Speaking and teaching; gsk Honoraria Speaking and teaching

Medical Editor

Rodger L Bick, MD, PhD, FACP, Clinical Professor of Medicine, University of Texas Southwestern Medical Center; Director, Dallas and Pacific Thrombosis Hemostasis and Vascular Medicine Clinical Center
Rodger L Bick, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Blood Banks, American Cancer Society, American College of Angiology, American College of Physicians, American Geriatrics Society, American Heart Association, American Medical Association, American Society for Clinical Pathology, American Society of Hematology, Association of Clinical Scientists, California Medical Association, California Thoracic Society, International College of Angiology, International Society of Hematology, International Society on Thrombosis and Haemostasis, New York Academy of Sciences, and Southwest Oncology Group
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Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
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CME Editor

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Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
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Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
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