What is erythromelalgia?
Erythromelalgia is a “zebra” diagnosis occurring in 1 : 100,000 people that also happens to the first chronic neuropathic pain disorder associated with a discovered ion channel mutation, specifically in the Na v 1.7 channel. A subset of erythromelalgia has this mutation.
Erythromelalgia is an uncommon pain syndrome that is characterized by the presence of a clinical triad consisting of periodic excruciating extremity pain, redness, and increased temperature. Erythromelalgia is also known as Mitchell disease, after Silas Weir Mitchell, the civil war surgeon who is best known for his description of causalgia. The symptoms associated with erythromelalgia are triggered by the exposure of the affected areas to increased temperature, pressure, exertion, insomnia, stress, or mild to moderate activity. Occurring as both a primary and secondary pain syndrome, erythromelalgia most commonly affects the extremities, except the face and ears. Primary erythromelalgia is an autosomal dominant condition that is caused by an ion channel channelopathy mutation in the gene SCN9A encoding the voltage-gated sodium channel α-subunit of Na V 1.7. These specific voltage-gated sodium channel subunits are found in the C fibers of peripheral nerves as well as throughout the sympathetic nervous system.
Erythromelalgia can be familial (hereditary, more likely associated with the Na v 1.7 mutation) or spontaneous. It is primarily a vascular peripheral pain disorder in which peripheral blood vessels (typically in the lower extremities or hands) periodically spasm, causing skin redness and severe burning pain via small sensory fibers. Attacks can be precipitated by heat exertion (even mild), pressure, dependent position, or stress. Differential diagnosis includes polycythemia and SFPN.
Erythromelalgia is a neurovascular peripheral pain disorder in which blood vessels are episodically blocked and then become hyperemic and inflamed. The attacks are episodic and characterized by red, warm, swollen, and painful (burning) extremities. Feet are affected more than hands. Attacks are triggered by exertion, heat, pressure, caffeine, and alcohol. Symptoms are bilateral but not necessarily symmetric. Rarely symptoms may progress to gangrene. Other diseases such as Fabry disease, peripheral neuropathy, complex regional pain syndrome, and vasculitis can mimic erythromelalgia and need to be excluded. Erythromelalgia is categorized as primary or secondary.
What are the symptoms of Erythromelalgia
Erythromelalgia is characterized by the presence of a clinical triad consisting of periodic excruciating extremity pain, redness, and increased temperature. It occurs in the lower extremities more commonly than in the upper extremities, face, and ears. In most patients, the symptoms of erythromelalgia present symmetrically, with the patient describing intense burning pain. The pain may also be deep and aching in nature and often has a radiating or lancinating component. Elevation of the affected body part may result in a reduction of the intense rubor. The duration of attacks of erythromelalgia vary from hours to days and occur with varying frequency. The symptoms associated with erythromelalgia are triggered by the exposure of the affected areas to increased temperature, pressure, exertion, insomnia, stress, or mild to moderate activity. Spicy foods, alcohol, and caffeine are known to trigger attacks as is the wearing of socks or shoes. Application of cold will often provide symptomatic relief in patients suffering from erythromelalgia. Often, ulcers and chronic scarring will be observed in affected areas due to cold injury
How is Erythromelalgia diagnosed?
The diagnosis of erythromelalgia is made on clinical grounds as there is no specific test that will accurately diagnose this painful condition. Given the rarity of erythromelalgia, it must be a diagnosis of exclusion. Tests that may help solidify the clinical diagnosis include biopsy of the affected skin, which may reveal decreased capillary density.
Quantitative sensory nerve testing, sudomotor testing, laser evoked potentials, and epidermal sensory nerve fiber density testing may all be abnormal due to abnormalities in peripheral nerve C fibers and small sympathetic fibers. Routine testing for autoimmune diseases should be undertaken in all patients suspected of suffering from erythromelalgia. Genetic testing may help elucidate the sodium channelopathy associated with primary erythromelalgia.
As mentioned previously erythromelalgia is a diagnosis of exclusion. Infection and reflex sympathetic dystrophy and causalgia may mimic erythromelalgia, although these complex regional pain syndromes are almost always unilateral, whereas erythromelalgia is almost always bilateral.
Furthermore, heat rarely triggers the pain associated with chronic regional pain syndromes and cold, rather than relieving the pain as in erythromelalgia, worsens the pain of chronic regional pain syndromes. Factitious disease should also be considered, given the rarity and unusual presentation of this uncommon pain syndrome.
How is Erythromelalgia treated?
Initial treatment of the pain and symptoms of erythromelalgia should be focused on symptomatic relief by elevation of the affected area and cooling of the ambient temperature. Autonomic dysfunction and neuropathy associated with erythromelalgia makes the application of cold problematic.
By the time the patient seeks medical attention, cold induced injury to the affected area has already occurred as the patient is desperate to obtain pain relief. If the patient insists on immersing the affected areas in cold water, the application of a plastic bag as a barrier to the affected body part may decrease the incidence of cold induced tissue injury.
Anecdotal reports suggest that aspirin, mexiletine, misoprostol, intravenous lidocaine, magnesium sulfate, gabapentin, and venlafaxine may provide some amelioration of the pain and symptoms associated with erythromelalgia.
A careful search for underlying diseases, medications, substances, and other triggers of the patient’s pain and symptoms should be immediately undertaken and, when these triggers are identified, promptly removed and/or treated.
Misdiagnosis of erythromelalgia is a problem as is the failure to identify underlying treatable diseases that may be triggering the disease. Mercury poisoning is notoriously hard to diagnosis on purely clinical grounds and is often missed. Cold induced injury is the rule rather than the exception in patients suffering from both primary and secondary erythromelalgia as patients are desperate to obtain pain relief. Factitious disease must always be considered and can be extremely difficult to diagnose.
Erythromelalgia is a rare uncommon pain syndrome that is difficult to diagnose and difficult to treat. The identification of a primary form of the disease that is the result of a sodium channelopathy may lead to more targeted treatment options. Another mutation of the same gene responsible for erythromelalgia is thought to be responsible for a heritable inability to feel pain.
• Primary erythromelalgia: may be genetic or idiopathic in origin. Early-onset erythromelalgia is usually familial with an autosomal dominant inheritance. It is associated with a gain-of-function mutation of the voltage-gated sodium channel α subunit gene (SCN9A) located on chromosome 2. This mutation causes hyperexcitability of dorsal root ganglion leading to symptoms similar to chronic regional pain syndrome. The severity of the mutation determines if the clinical symptoms start at puberty or later in adulthood. Elevation and cold exposure including emersion of feet in ice water give relief. There is no consistently effective therapy. It does not respond to aspirin therapy. Mexiletine may be helpful. Prostacyclin and gabapentin have also been used. Most of the patients presenting with adult-onset erythromelalgia do not have an identifiable genetic mutation or an associated disease and are considered to have primary idiopathic erythromelalgia.
• Secondary erythromelalgia: is similar to primary erythromelalgia clinically, has its onset during adulthood, and is associated with various diseases or medications. Treatment of the underlying disease or withdrawal of the offending medication is helpful. There are two types of secondary erythromelalgia: aspirin-sensitive and aspirin-insensitive.
Secondary erythromelalgia is associated with a variety of neuropathies and vasculopathies including small fiber peripheral neuropathy, polycythemia vera, essential thrombocytosis as well as autoimmune disorders, paraneoplastic syndrome, and multiple sclerosis. Secondary erythromelalgia has also been associated with mercury intoxication, mushroom poisoning, and hypercholesterolemia, and is a side effect of the calcium channel blocking medications verapamil and nifedipine.
• Aspirin-sensitive erythromelalgia is associated with polycythemia vera, essential thrombocytosis, and other chronic myeloproliferative disorders. In 85% of patients, the cutaneous symptoms precede the myelodysplastic syndrome by months to years (median 2.5 years). Erythromelalgia is diagnosed on the basis of platelet counts exceeding 400,000/mm 3 , relief of symptoms lasting for days with low-dose aspirin, and histopathologic evidence of arterioles with fibromuscular proliferation. The response to aspirin suggests that platelet-derived prostaglandins cause the symptoms.
• Aspirin-insensitive erythromelalgia is typically attributable to a medication (calcium channel blockers, bromocriptine) or another disease (small fiber neuropathy, autoimmune disease, mushroom poisoning).
Erythromelalgia is a very specific syndrome of severe burning pain in both feet that is reproducibly precipitated by skin warming, alleviated by cooling, and associated with striking erythema and swelling. All of these features should be present for the diagnosis to be made with confidence, as many patients with painful distal symmetric polyneuropathy will note some changes in the severity of their pain with skin warming or cooling but do not demonstrate the dramatic erythema, warmth, and temperature sensitivity seen in this condition.
Erythromelalgia has been described in the presence of hematologic malignancies and chronic inflammatory states, and therefore a careful investigation for both is important. In these circumstances, exquisite responsiveness to treatment with aspirin or nonsteroidal antiinflammatory medications has been reported. When it does not respond to these simple measures, erythromelalgia is usually treated with medications used for distal symmetric painful sensory polyneuropathy, but can be refractory to treatment.
Erythromelalgia also occurs in a familial form, which has been shown to be due to a mutation in the SCN9A gene encoding for a sodium channel in nociceptors. The causative mutation results in a lowered firing threshold in affected neurons, essentially resulting in a neuropathic pain state with thermal allodynia and hyperalgesia, whereby skin warming into the normally innocuous range is perceived as painful. Familial erythromelalgia is allelic to paroxysmal extreme pain disorder, which presents with episodic facial or rectal pain.