Erythromelagia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Erythromelalgia (erythro – red, melos – limb, algos – pain), also called erythermalgia, is a rare disorder characterized by intense burning pain in an extremity associated with erythema and increased skin temperature, which worsens with skin warming and improves with skin cooling. The condition was first described by Wilson in the 1870s.

Pathophysiology & Etiology

• Limited data has been obtained in this rare disease, and reports of histology and pathophysiology are limited by small samples, and have not been reproducible in all groups. Given the heterogeneity of clinical findings and response to treatment in different individuals, caution should be used in drawing too many conclusions or generalizing too many findings to all patients.
• Histology in patients with thrombocythemia-associated erythromelalgia has been reported to show fibromuscular proliferation of arterioles, resulting in lumen narrowing, with occasional thrombotic occlusion. Fibrosis of this lesion is seen in patients who have progressed on to necrosis. Venules, capillaries and nerves are unaffected.
• Intravascular platelet activation and aggregation with associated arteriolar plugging appears to occur, and appears to be particularly important in patients that respond to aspirin (ASA) treatment.

  • Platelet hyperaggregability has been demonstrated in affected patients
  • ASA effectively treats erythromelalgia in many patients

    • ASA effects lasts for days, while indomethacin effects lasts for <24 hours. Since ASA irreversibly inhibits cyclooxygenase, and indomethacin reversibly does so, cyclooxygenase is likely an important mediator in this disease.

      • Other non-cyclooxygenase platelet and coagulation inhibitors (ticlopidine, anticoagulation, etc) do not appear to be effective.

  • Platelet consumption is increased in patients with erythromelalgia
  • Mediators released from platelets, such as platelet-derived growth factor, could mediate some of the other manifestations, such as intimal thickening.

• Increased local temperature, hyperemia and hypoxia occur in affected tissue. Maldistributed skin perfusion with increased arteriovenous (AV) shunting has been hypothesized to contribute to the increased warmth and redness and insufficient tissue perfusion, particularly in childhood, early onset disease.

Classification

• Erythromelalgia may be classified as primary and secondary, or childhood and adult onset.
• Primary versus Secondary

  • Primary forms are idiopathic

    • These are more likely to develop in childhood, although up to 40% of adult-onset disease is also idiopathic.

  • Secondary forms are associated with a number of conditions listed below, and are more likely to develop in adulthood.

    • Erythromelalgia may proceed associated conditions such as malignancy and systemic rheumatic diseases.
    • Chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, myelofibrosis and chronic myelogenous leukemia (CML) are common associations, developing an average of 2.5 years after erythromelalgia develops. Only 10% of patients present with both myeloproliferative disease and erythromelalgia at the same time, and 5% develop erythromelalgia after diagnosis of the myeloproliferative disorder.

      • These variants are often in association with thrombocytosis and disturbed platelet function.

    • Improvement of erythromelalgia with treatment of the underlying condition is variable.

• Childhood Onset versus Adult Onset

  • Childhood onset erythromelalgia is characteristically a persistent condition

    • Less likely to respond to ASA treatment
    • Familial associations have been described

  • Adult onset erythromelalgia is more likely to respond to ASA treatment

    • Adult onset erythromelalgia is more common in women.
    • Adult onset is more commonly associated with predisposing associated conditions

History and Symptoms

• Burning pain in hands or feet
• Increased skin temperature
• Increased skin erythema, usually with swelling
• Relieved by cooling; also may be relieved by elevation
• Aggravated by warmth; also may be aggravated by exercise or standing
• The ends of extremities, including the fingertips and ends of the toes, are often involved. Lower extremity involvement is most common. Upper extremity or unilateral disease is more commonly associated with secondary erythromelalgia. Face involvement is less common.
• Severity is variable.

  • Disease may become very severe in some patients, with progression to ischemic acrocyanosis, ulceration, and even gangrene, sometimes requiring amputation. Necrosis developed in nine of one group of 26 patients studied.

• Symptoms may come and go over time. Attacks may last hours or days or become chronic. Some patients suffer from Raynaud’s between episodes of erythromelalgia.
• Peripheral pulses are generally normal in erythromelalgia patients.
• Time from onset of symptoms to diagnosis is often prolonged, averaging >5 years in one study.

Laboratory Findings

• Platelet counts >400,000 are common.
• Antinuclear antibody (ANA), cryoglobins, cold agglutinins, and immune complexes are not usually found. Erythrocyte sedimentation rate (ESR) and coagulation markers are usually normal.
• Blood counts may be abnormal in patients with associated myeloproliferative disorders.

Differential Diagnosis

• Cellulitis
• Recovery phase of frostbite
• Reflex sympathetic dystrophy
• Peripheral neuropathy
• Fabry’s disease – inborn error of metabolism with deficiency of alpha-glactosidase A activity. May have episodes of painful crises in palms and soles associated with exercise or temperature change.
• Chemotherapy associated acral drug toxicity

  • Distal extremity drug toxicity associated with rash, edema, blistering and desquamation
  • Involvement characteristically includes the palms
  • Associated with high dose chemotherapeutic regimens
  • Commonly develops during leucocyte recovery
  • Differential diagnosis includes graft versus host disease
  • Self-limited with conservative treatment.

Treatment

Acute Pharmacotherapies

• Aspirin may be beneficial in some patients, particularly patients with adult-onset disease. In these patients low doses (~500 mg) appear to be beneficial for about 4 days.

  • In particular, adults tend to respond well to ASA, while children, particularly those with familial variants, tend to be resistant.

• Blood cell indices should be followed periodically in patients with primary erythromelalgia given their increased risk for hematologic malignancy.
• Improvement is variable with treatment of the underlying condition in secondary erythromelalgia.

Future or Investigational Therapies

• Trials of prostoglandin E1 infusions, methysergide, selective serotonin reuptake inhibitors (SSRIs) and nitroprusside have had variable success in ASA-resistant patients. A variety of other treatments have been tried with mediocre response, including beta-blockers, gabapentin, biofeedback, and sympathectomy. The efficacy of prednisone in patients with SLE associated erythromelalgia is also variable.
• Some have advocated maintenance of platelet counts below 400-550K in patients with myeloproliferative associated erythromelalgia, though this does not help all patients.

References

1. kalgaard pmid=9350163 Kalgaard, OM, et al. Erythromelalgia: a clinical study of 87 cases. J Int Med 1997;242:191.
2. hart pmid=8843870 Hart, JJ. Painful, swollen and erythematous hands and feet. A & R 1996;39:1761.
3. kurzrock pmid=1951386 Kurzrock, R, et al. Erythromelalgia: Review of clinical characteristics and pathophysiology. Amer J Med 1991;91:416.
4. paulson Paulson, Family Service. Erythromelalgia: A case report and a review of the literature. Int Med 1983;9:112.
5. thompson pmid=535232 Thompson, GH,et al. Erythromelalgia 1979;144:249.

Acknowledgements

The content on this page was first contributed by: ELLISON L. SMITH, M.D.

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