Erythromelalgia

Disorder characterized by vasodilatation associated with paroxysmal, intense burning pain and episodic reddening of the extremities (mainly feet). The symptoms of redness, heat, pain, and swelling, when not associated with an organic disease, constitute the primary form, which has also been termed “erythermalgia” because of the significance of the heat. The secondary or acquired form is related to underlying medical conditions.

Acromelalgia; Erythermalgia; Gerhardt Disease; Weir-Mitchell Disease.

The first case was reported by the Irish physician Richard James Graves in 1834. The American physician Silas Weir Mitchell suggested the term “Erythromelalgia” in 1878, and the German physician Carl Jakob Gerhardt provided further insights into erythromelalgia in 1892.

Approximately 0.25:100,000 in the general population.

Autosomal dominant inheritance for primary erythromelalgia susceptibility, with the responsible gene located on chromosome 2q31-32.

Pathogenesis unknown. Proposed mechanisms involve abnormalities in platelet aggregation, with contributing factors such as vessel wall damage, changes in blood flow patterns, and disturbances in prostaglandin metabolism. Intravascular platelet aggregation appears to play a major role. Endothelial cells in affected areas appear swollen with enlarged nuclei. Smooth muscle cell proliferation and vacuolization of the cytoplasm in the tunica media of the vessels and deposition of interstitial collagen lead to narrowing of the vessels lumen. The internal elastic lamina seems to be split between the proliferated smooth muscle cells resulting in a picture of fibromuscular intimal proliferation, which is (with or without occlusive intravascular thrombosis) a specific erythromelalgia finding. Arterioles are frequently occluded by thrombi rich in platelets or which become completely fibrotic in the presence of peripheral necrosis. Immunofluorescence findings have failed to indicate a specific inflammatory process. It seems therefore that erythromelalgia is not a separate disease entity but rather a pathophysiologic response (microvascular arteriovenous shunting) of the skin microcirculation, with shunting induced by opening of anatomical arteriovenous anastomosis normally present in hands, feet, nose, and ears, or by angioneogenesis.

Primary and secondary/acquired types occurred. The primary type occurs in children, especially boys, whereas the secondary form is found almost entirely in adults who have an underlying disease (typically polycythemia vera, essential thrombocythemia, chronic myelogenous leukemia, and idiopathic myelofibrosis and other forms of myeloproliferative disorders) but may also include connective tissue disorders, autoimmune collagen vascular diseases (e.g., rheumatoid arthritis, Systemic Lupus Erythematosus (SLE)), infectious diseases (e.g., AIDS), neurologic diseases (e.g., multiple sclerosis, neuropathies), cardiovascular disorders (e.g., arterial hypertension, arteriosclerosis), diabetes mellitus, and drugs (e.g., iodine contrast injection, vaccinations, calcium antagonists). The clinical appearance of both primary and secondary forms is basically identical. The pathognomonic diagnostic criterion of secondary erythromelalgia is rapid pain relief that lasts a few days after one low dose of aspirin, which irreversibly inhibits platelet cyclooxygenase activity. Heat intolerance (and aggravation of symptoms with standing or exercise) and relief of symptoms with cooling (and elevation of the affected body part and rest) are hallmarks of erythromelalgia, whereas warmth exposure not only triggers flaring but also increases the severity of the episode. Pain relief from immersing the affected body parts in ice water is considered almost pathognomonic for the disease (similarly, immersing a limb in warm water may trigger an attack). In all cases of newly diagnosed erythromelalgia, polycythemia, thrombocythemia, and other diseases (neuropathies) must be excluded by appropriate laboratory and diagnostic studies. Regular followups are recommended.

Onset of erythromelalgia may be gradual, with some cases remaining mild and unchanged for decades but in other cases beginning acutely and spreading or becoming disabling within a few weeks. Episodes of erythromelalgia may occur spontaneously or are more commonly provoked by heat (in most patients, distress is triggered by ambient temperatures from 29-32°C), exercise, or dependency of limbs. A dusky red or cyanotic color change in the hands or feet is accompanied by intense pain and a sensation of heat. The episodes may be brief initially but with time may last longer. In primary erythromelalgia, the feet and lower legs are affected, with relative sparing of the toes. In contrast, in the secondary form, the burning pain and red congestion preferentially involve one or more toes or fingers or the sole of the forefoot. Typically the episodes are bilateral; however, unilateral occurrence has been described, particularly in secondary cases. In severe forms of erythromelalgia, the vasodilatation may be bilateral and spread proximally up the legs or arms, from the lower to upper limbs or vice versa, or to the face or ears. Some patients describe a diurnal cycle in their symptoms, which are most often worse in the evening or at night. The therapy is directed at reversal of the precipitating causes, applications of cold packs, and administration of indomethacin. Erythromelalgia vanishes with lowering of the platelet count to normal levels with chemotherapy in myeloproliferative disorders. A number of drugs have been used for treatment of erythromelalgia with varying success (e.g., vasoactive drugs [ephedrine, propranolol, calcium antagonists, α2-agonists], aspirin, serotonin-reuptake inhibitors [fluoxetine, sertraline], anticonvulsants [gabapentin], misoprostol). The same applies for epidural anesthetics and other forms of sympathetic blockade. Allodynia and paresthesias have been described by some patients.

Ask about precipitating causes of attacks and drug therapy. If secondary/acquired erythromelalgia is present, take steps to account for the primary disease process, such as phlebotomy and isovolemic hemodilution for polycythemia vera. Obtain a complete blood count and coagulation status, including bleeding time.

Avoid factors that precipitate an attack (e.g., aggressive warming techniques). In this instance, mild perioperative hypothermia is preferred. Careful positioning of the limbs to avoid dependency is recommended. Expose feet and hands outside of blankets or covers and try to maintain the patient below the critical temperature that triggers symptoms. When present, erythromelalgia pain is often resistant to a wide range of analgesic therapies, including high-dose narcotics.

Patients are often taking a number of different medications, so interactions with anesthetic drugs are possible.

Raynaud Syndrome: Disorder characterized by short-lasting vasospasms of the small arteries of the arms and legs, hands, and feet. Usually diagnosed before age 40 years.

Reflex Sympathetic Dystrophy Syndrome: Also known as CRPS. Progressive disease of the autonomic nervous system that can follow a simple trauma, heart problems, infections, surgery, spinal cord injuries, or major trauma.

Shoulder-Hand Syndrome: Variant of the reflex sympathetic dystrophy syndrome that affects the feet and the hands after an injury.