Erythromelalgia I73.82

Graves 1834; Mitchell 1872; Gerhardt 1892

Rare neuro-vascular skin disease and functional circulatory disorder characterized by burning, painful sensations in the acral area of the hands and feet (rare). Characteristic, paroxysmal, painful, seizure-like hyperemia of the acres after exposure to heat.

Three forms of erythromelalgia are described:

• Primary autosomal dominant inherited erythromelalgia (erythrothermal malalgia) provoked by heat and muscle work (OMIM:133020).
• Secondary erythromelalgia
  • Secondary erythromelalgia in various hematological diseases
  • Secondary erythromelalgia in inflammatory or degenerative vascular diseases (e.g. arterial occlusive disease, thrombophlebitis)

In Scandinavia their incidence is estimated at 0.3-04/100,000 inhabitants.

• In primary erythromelalgia (erythrothermal malgia) an autosomal dominant mutation in the sodium channel coding SCN9A gene (sodium channel, voltage-gated, type 9, alpha subunit) located on chromosome 2q24.3 (OMIM:133020) has been shown to be present (Klein-Weigel PF et al. 2018). This genetic defect leads to a defective function of the voltage-gated sodium channel.
• In the majority of patients a"small-fiber" neuropathy with pathological sudomotor axon reflex was detected. Some (about 25%) have impaired adrenergic function, others (also about 25%) have abnormal cardiovagal function.
• In secondary variants, mostly idiopathic etiology, especially in polycythemia, leukemia (chronic myeloid leukemia), diabetes mellitus, hypercholesterolemia, gout, rheumatoid arthritis, lupus erythematosus, mixed connective tissue disease, Sjögren's syndrome, AIDS, viral infections, syphilis, endangiitis obliterans, chronic perniosis, neurological diseases such as multiple sclerosis or neuropathies.
• In the case of thrombocythemia, the disorders of the cutaneous microcirculation could be explained by the formation of thrombi.
• Associations with the application of drugs such as nifedipine, bromocriptine, norephedrine and nicardipine have been described casuistically.
• Furthermore, in very rare cases, associations with carcinomas of the lung and gastrointestinal system have been described.
• In China, in an endemic form of erythromelalgia, an associated virus, the erythromelalgia-associated poxvirus (ERPV) has been isolated.

Equal for women and men; no gender preference. Age of manifestation: 5-6th decade; less frequently in children around 10 years of age (familial form of erythromelagia).

Leg feet (90%), hands (20-25%), nose (very rare).

Attacks (in larger series syncopal erythromelalgia occurs in 95% of patients. In 3-5% it is permanent), painful, hyperemic, reddened and swollen skin with increased sensitivity to heat. Often burning pain. During syncope the skin temperature rises by 7-8°C, the blood flow is increased 10 times. The seizures can be provoked by raising the temperature of the extremity to an individual "critical thermal point" between 32°C and 37°C and by physical overload. Duration of the seizures: minutes to hours. Most patients show localized or generalized anhidrosis.

Clinical profile:

• Seizure-like, uniform redness and swelling of the affected extremities
• Lesional hyperthermia
• burning pain in the extremities
• Pain is engraved by heat
• Pain is immediately relieved by cooling (Note: Many patients try to relieve the pain by permanent blow-drying or by ice water baths; this is successful as long as the cooling effect lasts. Prompt recurrence after rewarming).

Thrombocytosis (inconstant)

• Clomipramine (Anafranil) 100-200 mg/day can be tried.
• Alternatively, long-term therapy with small doses (100 mg/day) of acetylsalicylic acid or with indomethacin. In case of high platelet numbers or platelet dysfunction high doses of ASS.
• Alternative: experiment with high doses of magnesium (e.g. Magnesium Verla) p.o.
• Experimental: Prostaglandin-E1 (Alprostadil), e.g. Caverject i.v., followed by nitroprusside sodium (e.g. Nipruss).

In severe therapy-resistant cases a temporary borderline blockade with local anesthesia is recommended. If the treatment is successful and the autonomic dysregulation is permanently broken through, permanent sympathetic lysis (borderline blockade with alcohol) should then be discussed.

• Diagnosis based on the clinic.
• Typically, patients cool their extremities in cold water during a seizure. This results in sudden freedom from symptoms. Recurrence of symptoms when the body warms up. Exclusion of other functional or organic circulatory disorders.
• Possibly capillary microscopy. Search for causes of secondary erythromyalgia.

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2. da Costa AF et al (2014) Therapeutic success with local botulinum toxin in erythromelalgia. Pain Physician 17:E658-660
3. Davis M et al (2006) Thermoregulatory sweat testing in patients with erythromelalgia. Arch Dermatol 142: 1583-1588
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5. Gerhardt CA (1892) About erythromelalgia. Berl Klin weekday 29: 1125-1126
6. Graves RJ (1834) Clinical Lectures on the Practice of Medicine. Fannin, Dublin, Ireland
7. Han JH et al (2012) Paraneoplastic erythromelalgia associated with breast carcinoma. Int J Dermatol 51:878-880.
8. Harrison J et al (2003) The use of regional anaesthetic blockade in a child with recurrent erythromelalgia. Arch Dis Child 88: 65-66

9. Small whitefish PF et al (2018) Erythromelalgia. Vasa 47:91-97.

10. Michiels JJ et al (2015) Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera. Acta Haematol 133:56-63

11. Mitchell SW (1872) Clinical Lecture On Certain Painful Affections of the Feet. Philadelphia Medical Times 3: 81-82, 113-115
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17. Zambrano N et al (2012) Metanephric adenoma of the kidney associated with polycythemia and erythromelalgia: report of one case. Rev MedChil 140:629-632.