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 (erythrothermalgia) provoked by heat and muscle work (OMIM:133020).
• Secondary erythromelalgia
  • Secondary erythromelalgia in various haematological diseases
  • Secondary erythromelalgia in inflammatory or degenerative vascular diseases (e.g., arterial occlusive disease, thrombophlebitis)

In Scandinavia, its incidence is estimated at 0.3-0.4/100,000 population.

Primary erythromelalgia (erythrothermalgia) has been shown to be caused by an autosomal dominantly inherited mutation in the sodium channel-encoding SCN9A gene (Sodium-channel, voltage-gated, type 9, alpha subunit) which is located on chromosome 2q24.3 (OMIM:133020).(Klein-Weigel PF et al. 2018). This gene defect leads to defective function of the voltage-gated sodium channel.

Evidence of"small-fiber" neuropathy with pathologic sudomotor axon reflex was found in a large proportion of patients. Some (about 25%) have impaired adrenergic function, others (also about 25%) have abnormal cardiovagal function.

In secondary variants, mostly idiopathic genesis, especially in polycythemia, leukemias (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 thrombocythemias, the disturbances of cutaneous microcirculation could be explained by formation of thrombi.

Associations with the application of drugs, e.g. 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, erythromelalgia-associated poxvirus (ERPV) has been isolated.

Associations with COVID-19 infections or COVID vaccinations are noteworthy (Gambichler T et al. 2022).

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).

Intermittent (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, skin temperature rises 7-8°C, blood flow is increased 10-fold. The seizures can be provoked by raising the temperature of the extremity to an individual "critical thermal point" which is between 32°C and 37°C, and by physical overload. Duration of seizures: minutes to hours. A large proportion of patients present with localized or generalized anhidrosis.

Clinical Outline:

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

Thrombocytosis (inconstant)

Burning-feet syndrome; Raynaud's syndrome; Fabry's disease

• 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.

Often chronic course. Individually very variable (remissions, progression, stable disease possible). Children have a more favorable prognosis according to individual case reports.

• 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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