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NORD is very grateful to Mark Denis P. Davis, MD, Professor of Dermatology at the Mayo Clinic, for assistance in the preparation of this report.
Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands (extremities). It is characterized by intense, burning pain of affected extremities, severe redness (erythema), and increased skin temperature that may be episodic or almost continuous in nature. (The prefix "erythro-" denotes redness, "mel-" is a combining form meaning limb or limbs, and the suffix "-algia" indicates pain.) Although erythromelalgia typically affects both sides of the body (bilateral), it may sometimes involve only one side (unilateral). In addition, the disease course may be extremely variable from case to case. For example, in some individuals, symptom onset may be gradual (insidious), with the condition potentially remaining relatively mild for years. However, in others, it may have a sudden (acute) onset, possibly spreading and becoming severe over weeks.
The specific underlying cause of erythromelalgia remains unknown. However, the condition is thought to result from vasomotor abnormalities or dysfunction in the normal narrowing (constriction) and widening (dilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities of blood flow to the extremities. Erythromelalgia may be an isolated, primary condition or occur secondary to various underlying disorders. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or may be familial, suggesting autosomal dominant inheritance.
Erythromelalgia is characterized by severe, burning pain, marked redness (erythema) of the skin, swelling, and increased skin temperature, particularly of the feet. However, in some affected individuals, the hands may be the primary sites of involvement. Although both sides of the body are usually affected (bilateral), involvement may sometimes be limited to one side (unilateral), particularly in cases in which erythromelalgia has occurred secondary to another underlying condition or disorder (secondary erythromelalgia).
As noted above, disorder onset may sometimes occur gradually and subtly, possibly remaining relatively mild and unchanged in nature or degree over years or decades. However, in others with the condition, symptoms may begin suddenly (acutely) and, in some cases, may rapidly spread, increase in severity, and possibly become disabling over weeks. Reports suggest that, in many affected individuals, the disorder has a chronic course that may gradually increase in severity over time. In some with severe erythromelalgia, involvement may spread (usually bilaterally), such as from the feet up the legs (lower limbs), from the hands up the arms (upper limbs), from the upper to the lower limbs, from the lower to the upper limbs, or to the ears or face.
Associated symptoms may occur intermittently or on an almost continuous basis. Episodes or intensification of symptoms are sometimes described as "flaring", during which there is sudden (acute) redness, pain, sensation of heat, and swelling. During a flare, some affected individuals may also experience tingling pain or other symptoms similar to those associated with peripheral neuropathy. (For further information on this condition, please see the "Related Disorders" section of this report below.) Evidence suggests that, in many cases, flaring occurs late in the day and may last throughout the night, thus potentially interfering with sleep.
"Hallmarks" or characteristics of erythromelalgia include triggering or worsening of symptoms with exposure to heat (heat intolerance) or exercise and relief with cooling. These symptoms are characteristic of erythromelalgia but may occur with other disorders. They are not unique to erythromelalgia. The temperature at which symptoms may be triggered or exacerbated varies from person to person. (Please see the "Standard Therapies" section below for further information).
In some cases, erythromelalgia is an apparently isolated, primary condition. Primary erythromelalgia may appear to occur randomly for unknown reasons (sporadically) or may be familial. For example, rarely, a number of families (kindreds) have been reported in which individuals in several generations have been affected. According to researchers, reported familial cases appear to suggest autosomal dominant inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Studies of families with autosomal dominant erythermalgia have now demonstrated mutations in sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons.
In others with erythromelalgia, the condition may occur secondary to various underlying disorders, particularly certain bone marrow disorders characterized by abnormally increased production of particular blood cells (myeloproliferative disorders); neuropathies; or certain autoimmune connective tissue diseases. Many additional disorders have also been reported in association with erythromelalgia. (For more information, please see the "Related Disorders" section of this report below.) In addition, evidence suggests that erythromelalgia may also occur as an adverse effect secondary to the administration of certain drugs (e.g., bromocriptine, nifedipine, nicardipine).
The exact underlying cause of erythromelalgia is not known. However, evidence suggests that it results from abnormalities in the normal narrowing (vasoconstriction) and widening (vasodilation) of the diameter (caliber) of certain blood vessels, leading to abnormalities in blood flow to the extremities.
For example, investigators have found that, when some affected individuals are not flaring, they have skin temperatures lower than that of other study participants without the disorder (controls). (Body temperature is regulated by various complex mechanisms, including dilation and constriction of blood vessels in the skin to increase or decrease heat loss.) Researchers suggest that such findings indicate possible, undetected (subclinical) vasoconstriction during the day, with subsequent vasodilation and temporarily excessive blood flow to affected regions (reactive hyperemia) at night. (As noted above, erythromelalgia symptoms typically appear or worsen late in the day and may last throughout the night.) Some researchers indicate that similar abnormalities may underlie another blood vessel (vascular) condition known as Raynaud's disease or phenomenon. (For further information, please see the "Related Disorders" section of this report below.)
In erythromelalgia, additional evidence indicates that ring-shaped muscle regions (sphincters) of certain blood vessels that control blood flow from small arteries (arterioles) to capillaries (i.e., precapillary sphincters) may be abnormally narrowed while "arteriovenous shunts" are open. (According to researchers, blood flow through skin capillaries primarily provides necessary oxygen and nutrients to cells. Arteriovenous shunts, which are blood vessels that directly connect certain arteries and veins and thus bypass the capillary network, are thought to play a role in regulating temperature.) Constriction of some precapillary sphincters while arteriovenous shunts are open may lead to increased total blood flow yet decreased transport of oxygen and nutrients to cells, resulting in a simultaneous insufficient oxygen supply (hypoxia) to and excess of blood (hyperemia) in affected skin. The presence of hypoxia may in turn trigger increased, localized blood flow to skin regions, thus exacerbating pain, heat sensation, and redness.
In addition, some researchers indicate that there may be three different subtypes of erythromelalgia, with most individuals affected by vasoconstriction followed by reactive hyperemia (as described above); some with primarily vasodilation abnormalities; and others with erythromelalgia secondary to conditions characterized by increased numbers of certain cells in the blood, such as platelets (thrombocythemia), and associated, excessive viscosity of the blood (hyperviscosity). (For more information, please see the "Related Disorders" section below.)
Erythromelalgia is a rare disorder that was originally described in 1878. The overall age- and sex-adjusted incidence rate per 100 000 people per year in a population-based study in the US. Researchers in Norway have estimated an incidence of 0.25 per 100,000 and a prevalence of 2 per 100,000 in Norway. (Incidence refers to the number of new cases of a particular condition during a specific period, while prevalence indicates the total of new and old cases of a condition at any one time.)
Reports indicate that females are more affected than males Although disorder onset appears to occur most commonly in middle age, associated symptoms may develop at any age. For example, researchers have reported an extended family (kindred) in which affected members typically developed symptoms beginning between ages two to eight years.
Symptoms of the following disorders may be similar to those of erythromelalgia. Comparisons may be useful for a differential diagnosis:
Fabry's disease is a rare genetic disorder of lipid metabolism that is one of the more than 40 lysosomal storage diseases. Its early symptoms include severe burning pain in the hands and feet and sometimes in the arms and legs. These episodes may last only a few minutes or days, and are sometimes associated with exercise, fatigue, and/or fever. The disorder leads to kidney dysfunction in males and heart disease in females. An enzyme replacement therapy for Fabry's disease became available in 2003, so it is important to rule out Fabry disease in suspected cases of erythromelalgia (for further information, choose "Fabry's Disease" as your search term in the Rare Disease Database).
Raynaud's disease and Raynaud's phenomenon are blood vessel (vascular) conditions characterized by sudden contraction (vasoconstriction) of small arteries (arterioles) supplying the fingers and toes (digits) and, less commonly, the nose or ears, causing a temporarily decreased blood supply. Episodes are typically triggered by exposure to the cold, while warming relieves symptoms. Due to such responses to heat and cold, these conditions were often considered "opposite" to that of erythromelalgia. However, according to researchers, evidence currently suggests that the conditions may share more similarities than differences.
Episodes of Raynaud's are typically characterized by whitening of affected regions followed by bluish (cyanotic) discoloration and are often accompanied by tingling and numbness. Subsequent restoration of blood supply is associated with widening of the diameter of blood vessels (vasodilation) and temporarily excessive blood flow to affected regions (reactive hyperemia). Symptoms that may occur in association with this "hyperemia phase" include reddening of affected regions, intense heat, and throbbing or burning pain, findings that are similar to those associated with erythromelalgia. Some researchers suggest that Raynaud's and erythromelalgia may result from similar vasomotor abnormalities, with the vasoconstriction phase more prominent in Raynaud's and the hyperemia phase more apparent in erythromelalgia. (For further information, please see the "Causes" section above.)
The term Raynaud's disease is used when such episodes appear to occur as an isolated, primary condition. However, the term Raynaud's phenomenon indicates that the condition occurs secondary to another underlying disorder or condition, such as certain autoimmune connective tissue disorders, nerve diseases, injury, adverse reactions to certain drugs, or other abnormalities. There have also been some reports in which Raynaud's phenomenon has occurred in some individuals with erythromelalgia. (For further information, choose "Raynaud*" as your search term in the Rare Disease Database.)
Reflex sympathetic dystrophy syndrome (RSDS) refers to various disorders characterized by severe pain, particularly of an arm or a leg. Some experts currently advise that the term RSDS should be substituted with the designation "complex regional pain syndrome" (CRPS). CRPS is described as a regional pain syndrome that usually develops following injury to tissue or to nerves outside the brain and spinal cord (i.e., peripheral nerves). Associated symptoms may include severe, burning, aching, or throbbing pain that may extend to involve an area beyond the original injury site. Affected individuals may also have additional symptoms, such as abnormal warmth of the affected region; redness (erythema); swelling; changes in blood flow; localized, increased sweating; wasting (atrophy) of affected skin and underlying (subcutaneous) tissues; and/or abnormal bending (flexion) and fixation of affected joints (contractures). (For more information on this disorder, choose "reflex sympathetic dystrophy" as your search term in the Rare Disease Database.)
As noted above, erythromelalgia may sometimes occur secondary to certain disorders, including the following. They may be useful in identifying an underlying cause in some cases:
Essential thrombocythemia (thrombocytosis) is considered a myeloproliferative disorder, meaning that it is characterized by abnormalities of certain bone marrow (i.e., precursor) cells that produce particular blood cells. In essential thrombocythemia, there is abnormally increased production of platelets (thrombocytes), which are essential in blood clotting. Associated findings may include the abnormal, spontaneous development of blood clots (thrombi) within intact blood vessels, blocking proper blood flow; bleeding episodes that may be characterized by nose bleeds, easy bruising, and/or bleeding into the gastrointestinal tract; abnormal enlargement of the liver and spleen (hepatosplenomegaly); and/or other symptoms and findings. (For more information on this disorder, choose "essential thrombocythemia" as your search term in the Rare Disease Database.)
Polycythemia vera is a myeloproliferative disorder characterized by abnormally increased production of red cells by the bone marrow, resulting in high numbers of circulating red blood cells (erythrocytes) and a rise in the concentration of the oxygen-carrying component (hemoglobin) of the blood. Associated symptoms and findings may include fatigue, weakness, headaches, shortness of breath, and/or blurred vision. Affected individuals may also develop abnormal redness (erythema) of the skin and severe, widespread itching (pruritus), particularly after hot baths. Additional findings may include platelet abnormalities, leading to the development of blood clots and bleeding episodes; abnormal enlargement of the liver and spleen (hepatosplenomegaly); and/or other complications. (For more information on this disorder, choose "polycythemia vera" as your search term in the Rare Disease Database.)
Peripheral neuropathy is a general term used to describe a group of neurological conditions that affect nerves known as peripheral nerves, which extend from the brain or spinal cord (central nervous system) to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary functions, including regulating blood pressure, temperature, and heart rate. In individuals with peripheral neuropathy, a single nerve (mononeuropathy) or many nerves (polyneuropathy) may be affected. Depending upon the nerve(s) involved and other factors, peripheral neuropathy may produce symptoms that relate to motor, sensory, and/or autonomic malfunction. Damage to motor nerve fibers may lead to muscle weakness and wasting (atrophy). Symptoms associated with sensory nerve involvement may include pain or abnormal sensations, such as numbness, burning, sensations of cold, or tingling. Involvement of autonomic nerves may lead to various symptoms and findings, such as high or low blood pressure, impaired sweating, inability to control urination or defecation (incontinence), impotence, and/or other abnormalities. Peripheral neuropathy may result from many underlying causes, including injury, exposure to certain toxic agents, nutritional deficiencies, alcohol abuse, viral infections, autoimmune diseases, diabetes mellitus, or other underlying disorders or conditions. (For more information, choose "peripheral neuropathy" as your search term in the Rare Disease Database.)
Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease of connective tissue that may affect multiple organ systems and tissues, such as the skin, joints, membranes lining the walls of certain body cavities, the kidneys, and/or the nervous system. The disorder is thought to result from an abnormal immune response against the body's own cells and tissues (autoimmune disease), leading to inflammation and malfunction of various organ systems. The range and severity of associated symptoms and findings may vary from case to case. However, many affected individuals may initially develop generalized symptoms, such as excessive fatigue, fever, a general feeling of ill health (malaise), loss of appetite (anorexia), weight loss, and joint swelling, inflammation, and pain. The disorder may also be associated with skin abnormalities, such as a scaling, reddish rash in a "butterfly" pattern across the cheeks and the nasal bridge; increased sensitivity to light (photosensitivity); reddish swelling around the nails; tender, reddish-purplish skin swellings; or other findings. Additional abnormalities may include muscle inflammation (myositis); Raynaud's phenomenon (see above); inflammation of the filtering units of the kidneys; neurologic symptoms, such as headaches and seizures; and/or inflammatory changes of the membranes lining the chest cavity and lungs, lining the abdominal wall and organs, and/or surrounding the heart. Disease progression may also affect other tissues, leading to additional symptoms and findings. (For more information, choose "lupus" as your search term in the Rare Disease Database.)
As mentioned above, erythromelalgia has also been reported in association with a number of other underlying conditions and disorders. These have included other myeloproliferative and blood (hematologic), connective tissue, and neurologic disorders as well as certain disorders of the heart and blood vessels (cardiovascular disorders), musculoskeletal disorders, infectious diseases, underlying benign tumors or malignancies, and/or other disorders and conditions.
The diagnosis of erythromelalgia is established by a thorough evaluation of the characteristic symptoms and signs of the disease. Patient and family history can be helpful, and specialized tests may help to exclude certain disorders with similar symptoms. It is also helpful to confirm or rule out underlying diseases or conditions that may occur in association with erythromelalgia (i.e., to help differentiate primary and secondary erythromelalgia). For example, because erythromelalgia may be an early sign of certain conditions (e.g., thrombocythemia, polycythemia vera), certain laboratory tests, such as regular blood cell counts, and other specialized tests may be periodically conducted to help ensure prompt diagnosis and treatment of such underlying disorders.
Experts indicate that the intermittent nature of erythromelalgia in some cases may potentially lead to difficulties or delays in its diagnosis. Therefore, because symptoms may be reduced or absent until late in the day, for example, physicians may recommend that affected individuals take pictures of the involved regions during flaring and/or schedule clinical examinations late in the day if possible. In addition, during diagnostic assessment, physicians may possibly recommend exercise or immersion of an affected region in hot water for a certain period (e.g., approximately 10 to 30 minutes), to provoke a flare so a diagnosis may be made.
As mentioned above (see "Symptoms"), in individuals with erythromelalgia, associated symptoms are typically relieved with cooling. More specifically, in almost all cases, affected individuals may experience pain relief by immersing the affected regions in ice water. However, according to experts, it is essential to note that the repeated immersion sometimes performed by those with severe erythromelalgia may actually serve to trigger symptom episodes (i.e., reactive flaring) and may lead to skin injury and potentially serious complications. Such complications may include infection; nonhealing skin sores (ulcers); softening and breaking down of skin due to abnormally prolonged exposure to moisture (maceration); and/or localized tissue loss (necrosis).
Many with the disorder may also experience symptom relief by exposing affected areas to cold air, such as through the use of air conditioners or fans. In addition, even those with mild disease may find themselves avoiding warm or hot temperatures in an effort to help minimize symptoms.
Many affected individuals find that symptoms worsen with a dependent (or "hanging down") position. Accordingly, episodes may potentially be avoided or reduced by elevating involved regions.
Unfortunately, in some cases, the use of such measures as described above--such as avoidance of warm temperatures, ongoing elevation required by some with severe erythromelalgia, etc.--may significantly affect daily functioning.
For many patients, medications are available that can help to reduce symptoms. Such medications include calcium antagonists, magnesium selective serotonin reuptake inhibitors, tricyclic antidepressants, gabapentin or carbamazepine, antihistamines, clonazepam, misoprostol, cyproheptadine, and others. No single medication works for all EM patients, and some trial and error may be necessary. Some individuals with EM require lower doses of these drugs, and when started at higher doses, side effects can occur. Sometimes a combination of medications is more effective than one drug alone. Experts indicate that through such measures and careful ongoing monitoring, many affected individuals may obtain significant benefit.
Genetic counseling may be of benefit for people with erythromelalgia and their families. Other treatment for the condition is symptomatic and supportive.
(For further treatment information, please see the "Investigational Therapies" section below.)
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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In some cases, such as for some individuals who have an insufficient response to appropriate oral medication regimens and/or who have severe erythromelalgia, various other measures may be recommended.
As an example, infusion of the low blood pressure (hypotensive) agent sodium nitroprusside (sodium nitroferricyanide) has been used with some success in some children and adolescents for the treatment of severe erythromelalgia.
In addition, some reports suggest that prostaglandin infusion may result in improvement in some individuals with erythromelalgia. Prostaglandin agents may inhibit certain vasoconstrictor effects as well as the accumulation and clumping (aggregation) of platelets.
Various invasive measures have also been conducted in some severe cases, such as epidural analgesia or bilateral sympathectomies. Epidural analgesia involves the infusion of certain local anesthetics into the space surrounding the spinal cord within the lower back to provide pain relief. Sympathectomies are procedures in which part of certain sympathetic nerve pathways are surgically interrupted. Sympathetic nerves are part of the autonomic nervous system, which, as described above, regulates certain involuntary functions, including the diameter of the opening of blood vessels. Sympathectomies are performed to help improve blood supply by promoting vasodilation and/or to relieve chronic pain. However, both of these methods have also been reported to flare erythromelalgia.
Reports indicate that no one medication, therapeutic method, or procedure has been consistently effective for individuals treated for erythromelalgia, potentially supporting the possibility that there may be different subtypes of the disorder (e.g., vasoconstrictive-reactive hyperemia type, vasodilation type, thrombocytosis type). (For more, see "Causes" above.) However, although treatment response is variable, experts indicate that many achieve significant alleviation of symptoms with appropriate medication regimens; in addition, although uncommon, remissions have been reported in some patients. Further research is needed to determine the long-term safety and effectiveness of such therapies for the treatment of erythromelalgia; to define optimal treatment or treatments for the disorder; and to learn more about the underlying cause or causes.
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FROM THE INTERNET
McCusick VA. ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No: 133020; Last Update:12/5/11. Available at http://omim.org/entry/133020 Accessed on: January 13, 2012.
Report last updated: 2012/01/19 00:00:00 GMT+0